Trans Glomerularpatho Final
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OS 214 Renal
Dr. Teresita Tuazon Exam # 1
Pathology of Glomerular Diseases
OUTLINE I. II. III. IV.
V. VI. VII. VIII. IX.
X. XI.
Review of the Glomerulus Histologic Alterations Pathogenesis of Glomerular Injury The Glomerular Diseases a. Nephrotic Syndrome b. Minimal Change Disease Focal Segmental Glomerulosclerosis (FSGS) Membranous Glomerulonephropathy Nephritic Syndrome Acute Glomerulonephritis Glomerulonephropathies Associated with Isolated “Essential” Hematuria a. IgA Nephropathy ( Berger’s Disease ) b. Thin Basement Membrane Disease c. Alport’s Disease d. Non-specific changes Membranoproliferative Glomerulonephritis Acute Renal Failure
Figure 3. low power EM of renal glomerulus; CL – capillary lumen; MES – mesangium; END – endothelium; US – urinary space
Review of the Glomerulus
Figure 4.picture of glomerulus
Figure 1. The normal glomerulus
Figure 5. glomerular BM and blood space interface. Podocytes are seen oriented toward the epithelial cell. Glomerular BM negatively charged thus anionic molecules are repelled. Normal Glomerulus • Consists of an anastomosing network of capillaries lined by fenestrated endothelium invested by two layers of epithelium
• • •
Figure 2. glomerulus (normal)
• •
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The anatomical glomerulus is enclosed by two layers of epithelium, Bowman's capsule. Cells of the outer or parietal layer of Bowman's capsule form a simple squamous epithelium. Cells of the inner layer, podocytes in the visceral layer, are extremely complex in shape. Between the podocytes and the endothelial cells of the capillaries we find a comparatively thick basal membrane. Mesangial cells in the glomerulus form the connective tissue that gives structural support to
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OS 214 Renal
Dr. Teresita Tuazon Exam # 1
Pathology of Glomerular Diseases
podocytes and vessels.
Figure 8. Collapsed capillaries, a feature of sclerosis
From Block B Trans:
Pathogenesis of Glomerular Injury
Histologic Alterations 1. HYPERCELLULARITY a. Cellular proliferation of mesangial or endothelial cells b. Leukocytic infiltration consisting of neutrophils, monocytes and lymphocytes. c. Formation of crescents. Accumulations of cells composed of proliferating parietal epithelial cells and infiltrating leukocytes
1. ANTIBODY MEDIATED • • •
In situ Immune Complex formation Deposition of circulating immune complexes Antineutrophil cytoplasmic immune complexes
From Block B Trans: Complement Activation
• •
•
Ag-Ab complexes may be intrinsic or extrinsic Complexes can either be circulating in the bloodstream or are in situ (extrinsic Ag deposited at the GBM and Ab complexes with it directly) After some time, these complexes may cause tissue lesions due to complement activation which elaborates other molecules and eventually cause glomerular injury.
Figure 6. Collapsed glomerular tuft. Note the crescent-shaped mass (demarcated)
2. BASEMENT MEMBRANE THICKENING - Thickening of the capillary walls in light microscopy
Figure 9. Circulating complexes
Figure 7. Thickened capillary wall pointed in arrow.
3. HYALINIZATION AND SCLEROSIS - Accumulation of homogenous and eosinophilic material - Contributes to the obliteration of the capillary lumina of the glomerular tuft
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OS 214 Renal
Dr. Teresita Tuazon Exam # 1
Pathology of Glomerular Diseases
• • •
Due to loss of adhesive interactions with the GBM. Detachment contributes to protein leakage No antigens involved
Figure 12. Epithelial cell injury leading to detachment.
Figure 10. Complement activation
2. GLOMERULAR LOCALIZATION OF IMMUNE COMPLEXES •
Molecular charge and size
•
Highly CATIONIC – cross GBM – (1) subepithelial
• • •
Highly ANIONIC – repelled - (2) subendothelial More NEUTRAL charge – (4) mesangial Large complexes are cleared reticuloendothelial system
1
by
the
2 4 3
4. CELL-MEDIATED IMMUNITY • Sensitized T cells can cause glomerular injury • Presence of macrophages and T lymphocytes in glomeruli, particularly in allografts • May account for no deposits in GN or noncorrelation of deposits with severity of damage From Block B Trans: a. Neutrophils and monocytes release protease (GBM degradation), free radicals (cell damage), and arachidonic acid metabolites (decrease in GFR) b. Macrophages, T-lymphocytes and natural killer cells when activated release a vast number of biologically active molecules. c. Platelets release eiconasoids and growth factors that contribute to the manisfestation of glomerulonephritis. d. Resident glomerular cells like mesangial cells can be stimulated to produce cytokines, chemokines and growth factors 5. CELL-MEDIATED MECHANISMS •
• Figure 11. Localization of immune complexes in the glomerulus
Minimal change disease, crescenteric GN type III, allograft rejection, acute drug-induced interstitial nephritis, various vasculitides o Endogenous antigens o Exogenous antigens Anti-TBM disease in Brown-Norway rats, acute tubulointerstitial nephritis in mice, acute glomerulitis in bursectomized chicken
3. EPITHELIAL DETACHMENT • •
Results when an antibody cytokine toxin destroys the BM leaving no more surface for the cells to attach Effacement of foot processes, vacuolization, retraction and detachment of cells from the GBM.
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OS 214 Renal
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Pathology of Glomerular Diseases
•
•
•
o children >40 mg/h Clinical features o Proteinuria o Edema o Hyperlipidemia o Hypoalbuminemia Hypercoagulable o urinary loss of anti-thrombin III and plasminogen o hemoconcentration Risk of Infections
Types •
Figure 13. Mediators of immune glomerular injury including cells and soluble mediators
Glomerular Diseases • • • • •
Asymptomatic proteinuria Nephrotic syndrome Asymptomatic hematuria Nephritic syndrome Rapidly progressive nephritic syndrome
Nephrotic Syndrome •
Proteinuria greater than 3.5 gms/ 24 hours (less in children) • Hypoalbuminemia- plasma albumin less than 3 g/dL
•
• Edema Hyperlipidemia and lipiduria
•
The initial event is a derangement in glomerular capillary walls resulting increased permeability to plasma proteins
•
Diseases frequently responsible for nephrotic syndrome include (each will be discussed separately in this trans): o Minimal change disease o Focal segmental glomerulosclerosis o Membranous glomerulopathy (idiopathic)
Primary o Membranous Glomerulopathy o Focal Segmental Glomerulosclerosis o Minimal Change Disease o Membranoproliferative GN • Secondary o Diabetic glomerulosclerosis o Paraproteinemia/Amyloidosis o Lupus Nephritis Evaluation • History and Physical Exam • Urine Analysis • Lab Studies • Renal Biopsy Table 1. Urine Sediment Types. Nephritic Urine Nephrotic Urine Red cells Heavy (hematuria) proteinuria Variable proteinuria Free fat droplets Granular casts Fatty casts
Chronic GN Proteinuria Variable hematuria Broad waxy casts
Minimal Change Disease Clinical Features • Most common features – proteinuria and periorbital edema, with or without other manifestations of nephrotic syndrome
•
Most frequent cause of nephrotic syndrome in children Light Microscopy • Minimal histologic changes • Normal cellularity • Proximal convoluted tubules with resorption droplets • Vessels and interstitium are unremarkable
Figure 14. Primary nephrotic syndrome From 2011 Trans: More stringent definition • Nephrotic range proteinuria o adults >3.0-3.5 grams/d
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Figure 15. Minimal Change Disease
•
In electron microscopy: in the visceral epithelial cells
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Pathology of Glomerular Diseases
o o
o o
uniform and diffuse effacement of foot processes replaced by a rim of cytoplasm often showing vacuolization, swelling and hyperplasia of villi “fusion” of foot processes/ effacement > proteinuria 85% responsive to steroids with reversal of ultrastructural changes; overall prognosis good
Pathogenesis • Loss of polyanions and the glomerular chargebarrier > loss of negative charge of BM • Primary visceral epithelial cell injury • Immune dysfunction leads to production of cytokine-like circulating substance that affects visceral epithelial cells
Focal Segmental Glomerulosclerosis (FSGS) Clinical Features • Severe proteinuria or nephrotic syndrome- most common manifestation • Hematuria common, usually microscopic • Hypertension common • Male preponderance • May be primary or secondary Light Microscopy • Some glomeruli (especially juxtamedullary ones) with segmental sclerosis (mesangial matrix material, collapse, basement membrane- like material , +/- hyalinosis
Figure 16. Normal podocytes (individually sticking out) with slit pores. Endothelial layer has fenestrations > basement membrane
Figure 18. Focal collapse of glomerulus (encircled).
Figure 17. Fused podocytes in minimal change disease (white arrows) •
In immunofluorescence microscopy: o Negative immunofluorescence staining within glomeruli – no immune complexes
Figure 20. Hyalinosis in glomerulus
Figure 18. Immunofluorescence microscopy of Minimal Change Disease
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OS 214 Renal
Dr. Teresita Tuazon Exam # 1
Pathology of Glomerular Diseases
Figure 23. EM – denuded BM, will progress to ESRD -> dialysis, transplant. Accumulation in collapsed loops of matrix like material
Figure 21. Tubular atrophy – normal glomerulus but with thickened tubular walls, it could indicate presence of FSGS even if glomerulus is normal as seen here. Immunofluorescence Microscopy • Usually normal except for sclerotic segment which may have IgM, with or without C3
Pathogenesis • initiating pathogenetic mechanisms are varied • common element is injury manifested by sclerosis in the setting of nephrotic range proteinuria., • Degeneration and focal disruption of visceral epithelial cells • Hyalinosis and sclerosis represent entrapment of plasma proteins in extremely hyperpermeable foci with increased ECM deposition • Mutations in genes encoding for the proteins nephrin and/or podocin causes increased permeability to proteins – PROTEINURIA! Primary/idiopathic FSGS Secondary/variants FSGS • I.V. drugs
• • • • • • •
Collapsing gn: HIV, parvovirus B-19, pamidronate, CS2, Loa Loa Obesity-associated - reversible with weight reduction Familial FSGS - podocin, alpha-actinin-4 mutations Congenital - Finnish type (nephrin mutation) Cholesterol emboli Lithium Mitochondrial myopathies/cytopathies
Figure 22. IF – usually normal except for sclerotic segment which may have IgM, with or without C3. Electron Microscopy and Course of Disease • uniform and diffuse effacement of foot processes on sclerotic and non-sclerotic areas plus • focal detachment of epithelial cells with denudation of the underlying GBM • Accumulation in collapsed loops of matrix- like material • Course – 15% responsive to steroids, over 1/3 progress to end stage renal disease
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Figure 24. FSGS survival rate
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OS 214 Renal
Dr. Teresita Tuazon
Pathology of Glomerular Diseases
Exam # 1
Figure 25. Reductions in renal mass leading to focal glomerulosclerosis which in turn leads to reductions in renal mass creating a cycle Does hyperfiltration injure the glomerulus? Observations: 1.
2. 3. 4.
Subtotal nephrectomy (83%) in rats is followed by: a. Increase blood flow and filtration per glomerulus b. Proteinuria c. Focal glomerular sclerosis d. Progressive renal failure High protein diets a. Increase GFR and accelerate glomerular sclerosis Low protein diets Similar lesions occur in some patients with unilateral renal agenesis and in association with other diseases that reduce renal function mass
Figure 26. LM: Hypercellularity of glomerular tuft
Membranous Glomerulonephropathy Clinical Features • Proteinuria with or without the full nephrotic syndrome - most common finding • Peak incidence in the fourth to fifth decades • Male preponderance
•
Most common cause of nephrotic syndrome in adults (remember minimal change disease – most common cause of NS in children!)
Clinical Course • Spontaneous remission of proteinuria occur in approximately ¼ of patients, approximately half will have stable renal function with or without continued proteinuria • Minority of patients will have slow decline in renal function, a few will have rapid decline in renal function • 1/3 progress, 1/3 remit, 1/3 protenuria only
Figure 27. LM: silver staining BM spikes trying to cover the deposits
In light microscopy: • Normal to extreme diffuse thickening of the capillary wall • +/- tuft hypercellularity
•
foam cells in interstitium
In electron microscopy: • Numerous subepithelial deposits (+/-) spikes of GBM in between In immunofluorescence microscopy: • Finely granular diffuse capillary wall staining (-) IgG, (+/-) C3 and other immunoreactants
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Figure 28. IF: Finely granular diffuse capillary wall
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Pathology of Glomerular Diseases
Exam # 1
Figure 29. EM: Large subendothelial deposit (not just a hump)
Figure 30. LM: Uniformly and diffusely enlarged hypercellular glomeruli and reduced Bowman spaces
Pathogenesis • Believed to be chronic antigen-antibody mediated • Genetic susceptibility • Circulating immune complexes in 15-25% • Direct action of C5b-9, the membrane –attack complex of complement • in-situ immune complex formation in the subepithelial zone • Native or foreign antigens planted in the glomerular basement membranes are present beforehand and antibodies to these antigens combine with them in situ to form immune complexes. • presence of immune complexes alters the permeability of the capillary loops leading to proteinuria.
Immunofluorescence Microscopy • Coarse granular staining in first few weeks for IgG and C3 • Later, predominant C3 and IgG scant to absent
Nephritic Syndrome • • • • • • • •
Hematuria Proteinuria Decreased glomerular filtration rate Elevated BUN and serum creatinine Oliguria Salt and water retention Edema Hypertension
Glomerular Changes • Leucocytic infiltration • Hyperplasia of glomerular cells • Necrosis (severe lesions) • Injury to capillaries
Figure 31. IF: Variable-sized coarse granular deposits of immunoglobulins and complement in glomerular loops.
Electron Microscopy • “Immune-type” deposits on subepithelial surface described as “humps” • Occasional patchy GBM thickening
Acute Glomerulonephritis Clinical Features • Also called poststreptococcal or postinfectious glomerulonephritis • Latent period between infection and onset of GN ( 1-2 wks for pharyngitis and 3-6 wks for skin infections ) • Smoky urine and edema common initial manif, hypertension common, transient oliguria Light microscopy • Global and usually uniform hypercellularity • Capillary lumina may be occluded • Neutrophils frequent in the acute phase ( exudative glomerulonephritis)
Figure 32. EM: Variable-sized granular dense deposits of IgG and C3 (“humps”) irregularly arrayed in the subepithelial space of the glomeruli. Pathogenesis
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OS 214 Renal
Dr. Teresita Tuazon Exam # 1
Pathology of Glomerular Diseases
• • •
Streptococcal antigens from the infection elicit the production of anti-streptococcal antibodies. Immune complexes form in situ in glomeruli due to previously planted streptococcal antigens. The immune complex formation with complement activation incites acute glomerular inflammation
Figure 34. Glomerular tuft with global mesangial hypercellularity/proliferation. (Note that “normal” is less than or equal to 2 or 3 cells per mesangial area)
Figure 35. Red cell casts (arrows)
Figure 33. Hypercellular glmeruli due to proliferation of endothelial cells and mesangial cells, swelling of endothelial cells, and inflammatory infiltrate (neutrophils and monocytes). Initially, tubules are not affected (but as disease progresses, they may present hydropic change).
Immunofluorescence Microscopy • Mesangial granular IgA (in the absence of SLE, HSP, active liver disease) • Usually C1q is absent
Glomerulonephropathies Associated with Isolated “Essential” Hematuria • • • •
IgA Nephropathy ( Berger’s Disease ) Thin Basement Membrane Disease Alport’s Disease Non-specific changes
IgA Nephropathy Clinical Features • Most common during the 2nd and 3rd decades • Male preponderance • Asymptomatic microhematuria to rapidly progressive renal failure • 5 to 15% have nephrotic syndrome Light Microscopy Histologic Subclasses • Type I – Minimal histologic lesion • Type II- Focal segmental glomerulosclerosis-like • Type III – Focal proliferative glomerulonephritis • Type IV – Diffuse proliferative GN • Type V – Advanced chronic GN
Figure 36. IF: Granular deposits of IgA and C3 in the glomerular mesangium. The fundamental characteristic in IgA Nephropathy is the intense, diffuse mesangial immunostaining for IgA that is limited to mesangial areas, (without deposits in capillary walls). Diagnosis rests on the finding of dominant IgA mesangial deposits. C3 is also present in mesangial areas, but usually equal to or less than IgA staining. Electron Microscopy & Clinical Course • Mesangial electron dense deposits • Variable clinical course and prognosis
Figure 37. Pathogenesis
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Dr. Teresita Tuazon
Pathology of Glomerular Diseases
– –
presence of IgA immune complexes in the glomerular tufts Presumably mucosal derived IgA combines with antigens to form circulating immune complexes that deposit in the glomerular mesangium.,
Exam # 1
Unfortunately it usually destroys the transplant.
Membranoproliferative Glomerulonephritis Clinical Features • Nephrotic syndrome common • May have manifestations of the acute nephritic syndrome such as hematuria, • ( gross or microscopic), hypertension MPGN Type I Light Microscopy • Proliferative, polymorphonuclears • Lobulation/ tram-tracking
Figure 38. EM: Electron-dense mesangial deposits and foot process effacement.
Thin Basement Membrane Disease • thin GBM nephropathy is a genetically heterogeneous disorder, with some but not all familial cases linked to mutations within the genetic locus encoding the α3 and α4 chains of type IV collagen (COL4A3/COL4A4 locus).
Figure 39. The main morphological feature in Thin Basement Membrane Disease (TBMD) is diffuse thinning of the GBM, particularly the lamina densa. Accurate measurement of the GBM thickness is therefore essential in the diagnosis of TBMD.
Figure 40. There is massive mesangial cell proliferation, mesangial matrix expansion and diffuse thickening and focal splitting of the glomerular basement membrane. There is also accentuation of lobular architecture, swelling of cells lining peripheral capillaries, and influx of leukocytes.Basement membrane thickening is due to mesangial cell and mesangial matrix interposition along the subendothelial side of the lamina densa with consequent neoformation of basement membrane – basically a doubling or complex replication of the BM that gives the morphological aspect of ‘double contour’ (tramtracking). In other words, tram-tracking is caused by an increase in mesangial cells and matrix in the capillary loops, called ‘mesangial interposition’, which leads to new subendothelial basement membrane deposition. The mesangial matrix increase can be more severe in peripheral areas of the tuft, giving the glomerular tuft a ‘lobular’ appearance.
Alport syndrome •
•
•
•
In Alport syndrome, type IV collagen, one of the proteins that makes up the GBM, is absent or abnormal. Although the GBM looks normal in childhood, it deteriorates with time because it lacks the special type IV collagen that should be there Alport syndrome is much more common in boys and men because the gene that usually causes it (called COL4A5) is on the X chromosome. Women have two X chromosomes (XX), so they usually have a normal copy as well as an abnormal copy of the gene in less than 1 in 20 Alport transplants) kidney transplants meet with a unique problem. Because the transplanted kidney has normal type IV collagen, the immune system may see it as 'foreign' and attack it. This causes Alport antiGBM disease, which is very similar to the kidney disease seen in Goodpasture's disease.
March 3, 2009 | Tuesday
Figure 41. Increased mesangial matrix (stained black with silver stain) Immunofluorescence Microscopy • Broad capillary wall deposits – • C3 +/- other things
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Pathology of Glomerular Diseases
Figure 42. Immunofluorescence microscopy reveals granular staining for the complement protein C3 Electron Microscopy • Interposition of mesangial cells and matrix between GBM and capillary endothelium accounts for “tram-track” appearance • Subendothelial and mesangial deposit
Figure 43. EM: Subendothelial deposit incorporated into mesangial matrix (M).
Exam # 1
Figure 44. Schematic representation of patterns in the two types of membranoproliferative GN. In type I there are subendothelial deposits; type II is characterized by intramembranous dense deposits (dense-deposit disease). In both, mesangial interposition gives the appearance of split basement membranes when viewed in the light microscope. MPGN Type II/Dense Deposit Disease (DDD) Notes from http://path.upmc.edu/cases/case148/dx.html Membranoproliferative glomerulonephritis type II (MPGN-II), also known as dense deposit disease (DDD), is a clinicopathologic entity associated with renal abnormalities which often culminate in renal failure. DDD commonly affects children and young adults with a roughly equal male to female preponderance. These patients present with varying degrees of hematuria and/or proteinuria. In addition, serum analysis often but not invariably reveals hypocomplementemia, particularly of the complement protein C3, which has led some researchers to speculate that abnormalities of the complement cascade contribute to the pathogenesis of DDD. Distinguishing DDD from membranoproliferative glomerulonephritis type I (MPGN-I) may be quite difficult clinically since both are characterized by a nephrotic and/or nephritic clinical picture. However, microscopic examination reveals differences that allow their separation. In MPGN-I, most glomeruli demonstrate global hypercellularity in a lobular pattern. This differs from DDD in which a variety of light microscopic patterns may be seen - including membranoproliferative glomerulonephritis (lobular glomerulonephritis), glomerular sclerosis, pure mesangial hypercellularity, membranous glomerulonephritis-like pattern, cresenteric glomerulonephritis, minimal changes, or focal and segmental necrotizing glomerulonephritis.
Light microscopy • Any glomerular pattern (membranous, membranoproliferative, normal, crescentic GN, etc.)
Pathogenesis of MPGN I • Immune complex mediated disorder.
• •
•
IC are deposited in the mesangium and subendothelial spaces. Mesangial cells proliferate in response to the immune complex deposition and extend beyond the confines of the mesangium to mesangialize the capillary loops. A second internal basement membrane is formed by the mesangial cell and the undermined endothelial cells
Figure 45.MPGN Type II – Light Microscope. Immunoflourescence Microscopy • Broad capillary wall deposits – C3 +/-, other things, extraglomerular deposits
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OS 214 Renal
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Pathology of Glomerular Diseases
Figure 46. IF: Presence of the complement protein C3 which produces a characteristic ribbon-like staining pattern of the peripheral capillary loop; however, there is a lack of staining of the dense deposits. Electron Microscopy • Large electron dense deposits in GBM, +/Robbins book notes TBM,BC,etc
Types I and II have altogether different ultrastructural and immunofluorescent features. Type I MPGN (two thirds of cases) is characterized by the presence of subendothelial electron-dense deposits. Mesangial and occasional subepithelial deposits may also be present. By immunofluorescence, C3 is deposited in a granular pattern, and IgG and early complement components (C1q and C4) are often also present, suggesting an immune complex pathogenesis.
In Type II MPGN lesions, the lamina densa of the GBM is transformed into an irregular, ribbon-like, extremely electrondense structure because of the deposition of dense material of unknown composition in the GBM proper, giving rise to the term dense-deposit disease. In type II, C3 is present in irregular granular-linear foci in the basement membranes on either side, but not within the dense deposits. C3 is also present in the mesangium in characteristic circular aggregates (mesangial rings). IgG is usually absent, as are the earlyacting complement components and C4).by the presence Figure 47. Histologically, DDD(C1q is defined
of irregular electron dense deposits in the lamina densa of Pathophysiology the glomerular basement membrane, which are observed Although there are exceptions, most cases of type I MPGN by EM. deposits arecomplexes strongly PAS positive and and are present These evidence of immune in the glomerulus dark blue when stained with toluidine blue. complement activation of both classic and alternative pathways. The antigens involved in idiopathic MPGN are unknown. Conversely, most patients with dense-deposit disease (type II) have abnormalities that suggest activation of the alternative complement pathway. These patients have a consistently decreased serumand C3, but normal C1 and C4, the MPGN Types I & II Course Diagnosis immune complex-activated early components of complement. • Course: Progressive (many to renal failure) They also have diminished serum levels of factor B and • Diagnosis: Low complement persistent, pathway. nephritic properdin, components of the alternative complement syndrome More thanand/ 70%orofnephrotic patients with dense-deposit disease have a • Autoimmune disorder circulating antibody termed C3 nephritic factor (C3NeF), which is a •conformational autoantibody thatisbinds to the alternative C3 nephritic factor which an IgG C3 convertase. Binding directed of the against antibody C3 stabilizes the immunoglobulin convertase convertase, it from enzymatic andprotecting on binding stabilizes it. degradation and thus favoring C3 degradation and hypocomplementemia. • persistent The stabilized C3 convertase continuously drives There is also decreased C3 synthesis by the liver, further the alternative complement pathway, consuming contributing to the profound hypocomplementemia. Precisely complement. how C3NeF is related to glomerular injury and the • of As consequence, have marked nature the a dense deposits arepatients unknown. C3NeF activity also occurs in hypocomplementemia. some patients with a genetically determined disease, partial lipodystrophy, some of whom develop type II MPGN. Clinical Presentation The principal mode of presentation is the nephrotic syndrome occurring in older children or young adults, but usually with nephritic component manifested by hematuria or, more insidiously, as mild proteinuria. Few remissions occur spontaneously in either type, and the disease follows a slowly progressive but unremitting course. Some patients develop numerous crescents and a clinical picture of RPGN. About 50% develop chronic renal failure within 10 years. Treatments with steroids, immunosuppressive agents, and antiplatelet drugs have not been proved to be materially effective. There is aMarch high incidence of |recurrence 3, 2009 Tuesdayin transplant recipients, particularly in type II disease; dense deposits may recur in 90% of such patients, although renal failure in the allograft is much less common.
Secondary MPGN arises in the following settings:
Chronic immune complex disorders, such as SLE; hepatitis B infection; hepatitis C infection, usually with cryoglobulinemia; endocarditis; infected ventriculoatrial shunts; chronic visceral abscesses; HIV infection; and schistosomiasis.
Partial lipodystrophy associated with C3NeF (type 2)
Alpha1 -Antitrypsin deficiency Malignant diseases (chronic lymphocytic leukemia, lymphoma, melanoma) Hereditary complement deficiency states
Notes from http://path.upmc.edu/cases/case148/dx.html Distinguishing DDD from membranoproliferative glomerulonephritis type I (MPGN-I) may be quite difficult clinically since both are characterized by a nephrotic and/or nephritic clinical picture. However, microscopic examination reveals differences that allow their separation. In MPGN-I, most glomeruli demonstrate global hypercellularity in a lobular pattern. This differs from DDD in which a variety of light microscopic patterns may be seen, as mentioned above. The capillary walls in the glomeruli are markedly thickened and show intense staining with PAS in MPGN-I. Methenamine silver also stains the glomerular basement membrane of the thickened capillary loops to reveal splitting or tram tracking similar to what is observed in DDD; however, the material deposited between the glomerular basement membrane borders is nonargyrophilic and different from the deposits in DDD. Tram tracking in MPGN-I is caused by an increase in mesangial cells and mesangial matrix in the capillary loops, called 'mesangial interposition', which leads to new subendothelial basement membrane deposition. Electron microscopic findings in MPGN-I show mesangial interposition, subendothelial immune deposits and a new layer of subendothelial basement membrane. Immunofluorescence microscopy reveals granular staining for the complement protein C3 differs from the ribbony pattern seen inPage DDD. In12 addition, of 16 MPGN-I biopsies, unlike those of DDD, may show staining for Canoy, Carasco, Cielo, complement proteins Clq, C4 and one or more immunoglobulins, particularly IgG and frequently IgM. MPGN-I has a recognized Co association with chronic hepatitis C infection and
OS 214 Renal
Dr. Teresita Tuazon Exam # 1
Pathology of Glomerular Diseases
Clinical Features • Clinical onset of disease usually abrupt • Severe oliguria or anuria common at initial examination • Course is aggressive if without treatment Robbins book notes Rapidly progressive glomerulonephritis (RPGN) is a syndrome associated with severe glomerular injury and does not denote a specific etiologic form of glomerulonephritis. It is characterized clinically by rapid and progressive loss of renal function associated with severe oliguria and (if untreated) death from renal failure within weeks to months. Regardless of the cause, the histologic picture is characterized by the presence of crescents in most of the glomeruli (crescentic glomerulonephritis). These are produced in part by proliferation of the parietal epithelial cells and Bowman capsule and in part by infiltration of monocytes and macrophages. RPGN may be caused by a number of different diseases, some restricted to the kidney and others systemic. Although no single mechanism can explain all cases, there is little doubt that in most cases the glomerular injury is immunologically mediated. Thus, a practical classification divides RPGN into three groups on the basis of immunologic findings. In each group, the disease may be associated with a known disorder or it may be idiopathic.
Figure 48. The alternative complement pathway. Note that C3NeF, present in the serum of patients with membranoproliferative glomerulonephritis, acts at the same step as properdin, serving to stabilize the alternative pathway C3 convertase, thus enhancing C3 breakdown and causing hypocomplementemia. MPGN Type III • with prominent subepithelial electron dense deposits (Burkholder) • with complex disruptions of the basement membrane (Strife & Anders), focal and segmental gloerular hyalin deposits, and infiltration by foamy macrophages Robbins book notes Rare variants (type III) segregated because they exhibit both subendothelial and subepithelial deposits are associated with GBM disruption and reduplication.
Acute Renal Failure • • •
Creatinine increases rapidly over a few days Oliguria/anuria frequent Etiologies: Pre-renal Renal Post-renal
Notes from http://path.upmc.edu/cases/case148/dx.html Crescentic glomerulonephritis or rapidly progressive glomerulonephritis (RPGN) is a term given to a diverse group of diseases which all have cresents present within the glomerular tuft. These include primary or renal limited (so-called idiopathic) crescentic glomerulonephritis, anti-glomerular basment membrane (anti-GBM) antibody diseases, and systemic disorders. Considered within the entire clinical spectrum of renal disease, RPGN produces the most rapidly progressive and destructive of glomerular diseases which in the most severe forms proceeds inexorably to renal failure if not treated aggressively and early. Fortunately, RPGN accounts for only 2 to 7% of renal biopsies, with a disproportionately large percentage of these patients progressing to end stage renal disease. RPGN is categorized based on the biopsy immunofluorescence pattern into three groups: RPGN Type I (20%), RPGN Type II (40%), and RPGN Type III (40%) (Table 3). RPGN types I and II have greater than 2+ (on a 4+ scale) immunofluorescence staining intensity with linear and granular staining patterns, respectively. RPGN Type III or pauci-immune type has weak or no demonstrable immunoglobulin / complement deposition, corresponding to an immunofluorescence staining intensity of < 2+.
Table 1. Three Types of Immunofluorescence Pattern
RPGN
Based
on
Robbins book notes Acute renal failure is dominated by oliguria or anuria (no urine flow), with recent onset of azotemia*. It can result from glomerular (e.g., crescentic glomerulonephritis), interstitial, and vascular injury or acute tubular necrosis. *Azotemia is a biochemical abnormality that refers to an elevation of the blood urea nitrogen (BUN) and creatinine levels and is related largely to a decreased glomerular filtration rate (GFR). Azotemia is produced by many renal disorders, but it also arises from extrarenal disorders. Prerenal azotemia is encountered when there is hypoperfusion of the kidneys (e.g., in hemorrhage, shock, volume depletion, and congestive heart failure) that impairs renal function in the absence of parenchymal damage.
Crescentic Glomerulonephritis/Rapidly Progressive Glomerulonephritis (RPGN)
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Pathology of Glomerular Diseases
Exam # 1
Light Microscopy • Over 50% of glomeruli with crescents. • Look at the most preserved glomeruli for tuft hypercellularity
Figure 49. Collapsed glomerular tufts and crescentshaped mass of proliferating cells and leukocytes internal to the Bowman capsule.
Robbins book notes Type I RPGN is best remembered as anti-GBM disease and hence is characterized by linear deposits of IgG and, in many cases, C3 in the GBM, as previously described. In some of these patients, the anti-GBM antibodies cross-react with pulmonary alveolar basement membranes to produce the clinical picture of pulmonary hemorrhages associated with renal failure (Goodpasture syndrome). The Goodpasture antigen, as noted, resides in the noncollagenous portion of the alpha3 chain of collagen type IV. What triggers the formation of these Figure antibodies 50. is unclear in most patients. Exposure to viruses or hydrocarbon solvents (found in paints and dyes) has been implicated in some patients, as have various drugs and Immunoflourescence cancers. Cigarette smoking appears to play a permissive role, • most RPGN Typewho 1 - Linear since patients developimmunoflourescence pulmonary hemorrhage are o is 20% smokers. There a high prevalence of certain HLA subtypes o (e.g., Goodpasture and haplotypes HLA-DRB1),syndrome a finding consistent with the genetic predisposition to autoimmunity.basement membrane o Anti-glomerular Type II RPGN is an immune complex-mediated disease. It can disease be a complication of any of the immune complex nephritides, • RPGN Type 2 - Granular immunoflourescence including postinfectious glomerulonephritis, SLE, IgA nephropathy, oand 40% Henoch-Schonlein purpura. In some cases, immune complexes can be demonstrated, but the underlying o Many primary and secondary immune cause is undetermined. In all of these cases, complex diseases immunofluorescence studies reveal the characteristic ("lumpy • RPGN Type 3 Negative (pauci-immune) bumpy") granular pattern of staining. These patients cannot usually immunoflourescence be helped by plasmapheresis, and they require o underlying 40% treatment for the disease. Type III RPGN, called pauci-immune type,anti-neutrophil is defined by o also Predominately the lack of anti-GBM antibodies orantibody immune complexes by cytoplasmic associated immunofluorescence and electron microscopy. Most of these systemic vasculitis and renal limited patients have antineutrophil cytoplasmic antibody (ANCA) in the GN vasculitides. Hence, in some serum, which playscrescentic a role in some Weak or no demonstrable cases, type IIIoRPGN is a component of a systemic vasculitis such as Wegener immunoglobulin/complement granulomatosis or microscopic polyarteritis. deposition, In many cases, however, pauci-immune crescentic corresponding to an glomerulonephritis immunofluorescence is isolated and hence idiopathic. than staining More intensity 90% of such idiopathic cases have C-ANCA or P-ANCA in the of <2+ sera. To summarize, all three types of RPGN may be associated with a well-defined renal or extrarenal disease, but in many cases (approximately 50%) the disorder is idiopathic. Of the idiopathic cases, about one fourth have anti-GBM disease (RPGN type I) without lung involvement; another one fourth have type II March | Tuesday RPGN; and3, the2009 remainder are pauci-immune or type III RPGN. The common denominator in all types of RPGN is severe glomerular injury.
Figure 51. This immunofluorescence pattern shows positivity with antibody to IgG and has a smooth, diffuse, linear pattern that is characteristic for deposition of glomerular basement membrane antibody with Goodpasture syndrome.
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Figure 52.
Figure 52. Granular Immunofluorescence (“lumpy bumpy” granular pattern of staining) Pathogenesis of Anti-GBM disease (RPGN Type 1) • autoimmune disorder • Anti-glomerular basement membrane antibodies are produced and complex with glomerular basement membranes and in some instances with the pulmonary alveolar basement membranes leading to their destruction
Figure 53. Granular, cytoplasmic staining of C-ANCA and perinuclear staining typical of P-ANCA, respectively. Electron Microscopy • Either glomerular deposits anywhere (immune complexes ) or no deposits (either anti-GBM or no deposit disease )
Anti-neutrophil Cytoplasmic Antibodies (ANCA) • A family of autoantibodies that have specificity for proteases located in primary granules of neutrophils and monocytes • Useful in the diagnosis and monitoring of patients with several forms of systemic vasculitis and renal-limited (pauci-immune) crescentic glomerulonephritis Types of ANCA 1. C-ANCA - cytoplasmic pattern
2.
• •
Major specificity: proteinase 3
• •
Major specificity: myeloperoxidase
Major clinical association: Wegener’s granulomatosis P-ANCA - perinuclear pattern Major clinical associations: microscopic polyangiitis and renal-limited crescentic glomerulonephritis
Robbins book notes Serum from many patients with vasculitis in small vessels reacts with cytoplasmic antigens in neutrophils, indicating the presence of antineutrophil cytoplasmic autoantibodies (ANCA). ANCA comprise a heterogeneous group of autoantibodies against enzymes mainly found within the azurophil or primary granules in neutrophils but also found in the lysosomes of monocytes and in endothelial cells. ANCA can be detected in serum by immunofluorescent microscopy of ethanol-fixed neutrophils and by immunochemical assays. Two main patterns of immunofluorescent staining distinguish different ANCA types. One ANCA type shows cytoplasmic localization of the staining (c-ANCA), and the most common target antigen is proteinase 3 (PR-3), a neutrophil granule constituent. The second type shows perinuclear staining (p-ANCA) and is usually specific for myeloperoxidase (MPO). Either ANCA specificity may occur in a patient with ANCA-associated small vessel vasculitis, but cANCA (PR-3 specificity) are typically found in Wegener granulomatosis and p-ANCA (MPO specificity) are found in most cases of microscopic polyangiitis and Churg-Strauss syndrome. Approximately 10% of patients with these disorders, however, do not demonstrate ANCA by typical assays. ANCA serve as useful quantitative diagnostic markers for these disorders, and their discovery has led to segregation of a group of these disorders as the ANCA-associated vasculitides. The close association between ANCA titers and disease activity, particularly c-ANCA in Wegener granulomatosis, suggests that they may be important in the pathogenesis of this disease, but the precise mechanisms by which ANCA induce injury are March 3, 2009 | Tuesday unknown.
Figure 54. Cellular crescent formation*
Figure 55. Fibrous crescent*
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Figure 56. RPGN Type III or pauci-immune type
Figure 57.
Figure 57.
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Pathology of Glomerular Diseases
OUTLINE I. II. III. IV.
V. VI. VII. VIII. IX.
X. XI.
Review of the Glomerulus Histologic Alterations Pathogenesis of Glomerular Injury The Glomerular Diseases a. Nephrotic Syndrome b. Minimal Change Disease Focal Segmental Glomerulosclerosis (FSGS) Membranous Glomerulonephropathy Nephritic Syndrome Acute Glomerulonephritis Glomerulonephropathies Associated with Isolated “Essential” Hematuria a. IgA Nephropathy ( Berger’s Disease ) b. Thin Basement Membrane Disease c. Alport’s Disease d. Non-specific changes Membranoproliferative Glomerulonephritis Acute Renal Failure
Figure 3. low power EM of renal glomerulus; CL – capillary lumen; MES – mesangium; END – endothelium; US – urinary space
Review of the Glomerulus
Figure 4.picture of glomerulus
Figure 1. The normal glomerulus
Figure 5. glomerular BM and blood space interface. Podocytes are seen oriented toward the epithelial cell. Glomerular BM negatively charged thus anionic molecules are repelled. Normal Glomerulus • Consists of an anastomosing network of capillaries lined by fenestrated endothelium invested by two layers of epithelium
• • •
Figure 2. glomerulus (normal)
• •
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The anatomical glomerulus is enclosed by two layers of epithelium, Bowman's capsule. Cells of the outer or parietal layer of Bowman's capsule form a simple squamous epithelium. Cells of the inner layer, podocytes in the visceral layer, are extremely complex in shape. Between the podocytes and the endothelial cells of the capillaries we find a comparatively thick basal membrane. Mesangial cells in the glomerulus form the connective tissue that gives structural support to
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podocytes and vessels.
Figure 8. Collapsed capillaries, a feature of sclerosis
From Block B Trans:
Pathogenesis of Glomerular Injury
Histologic Alterations 1. HYPERCELLULARITY a. Cellular proliferation of mesangial or endothelial cells b. Leukocytic infiltration consisting of neutrophils, monocytes and lymphocytes. c. Formation of crescents. Accumulations of cells composed of proliferating parietal epithelial cells and infiltrating leukocytes
1. ANTIBODY MEDIATED • • •
In situ Immune Complex formation Deposition of circulating immune complexes Antineutrophil cytoplasmic immune complexes
From Block B Trans: Complement Activation
• •
•
Ag-Ab complexes may be intrinsic or extrinsic Complexes can either be circulating in the bloodstream or are in situ (extrinsic Ag deposited at the GBM and Ab complexes with it directly) After some time, these complexes may cause tissue lesions due to complement activation which elaborates other molecules and eventually cause glomerular injury.
Figure 6. Collapsed glomerular tuft. Note the crescent-shaped mass (demarcated)
2. BASEMENT MEMBRANE THICKENING - Thickening of the capillary walls in light microscopy
Figure 9. Circulating complexes
Figure 7. Thickened capillary wall pointed in arrow.
3. HYALINIZATION AND SCLEROSIS - Accumulation of homogenous and eosinophilic material - Contributes to the obliteration of the capillary lumina of the glomerular tuft
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• • •
Due to loss of adhesive interactions with the GBM. Detachment contributes to protein leakage No antigens involved
Figure 12. Epithelial cell injury leading to detachment.
Figure 10. Complement activation
2. GLOMERULAR LOCALIZATION OF IMMUNE COMPLEXES •
Molecular charge and size
•
Highly CATIONIC – cross GBM – (1) subepithelial
• • •
Highly ANIONIC – repelled - (2) subendothelial More NEUTRAL charge – (4) mesangial Large complexes are cleared reticuloendothelial system
1
by
the
2 4 3
4. CELL-MEDIATED IMMUNITY • Sensitized T cells can cause glomerular injury • Presence of macrophages and T lymphocytes in glomeruli, particularly in allografts • May account for no deposits in GN or noncorrelation of deposits with severity of damage From Block B Trans: a. Neutrophils and monocytes release protease (GBM degradation), free radicals (cell damage), and arachidonic acid metabolites (decrease in GFR) b. Macrophages, T-lymphocytes and natural killer cells when activated release a vast number of biologically active molecules. c. Platelets release eiconasoids and growth factors that contribute to the manisfestation of glomerulonephritis. d. Resident glomerular cells like mesangial cells can be stimulated to produce cytokines, chemokines and growth factors 5. CELL-MEDIATED MECHANISMS •
• Figure 11. Localization of immune complexes in the glomerulus
Minimal change disease, crescenteric GN type III, allograft rejection, acute drug-induced interstitial nephritis, various vasculitides o Endogenous antigens o Exogenous antigens Anti-TBM disease in Brown-Norway rats, acute tubulointerstitial nephritis in mice, acute glomerulitis in bursectomized chicken
3. EPITHELIAL DETACHMENT • •
Results when an antibody cytokine toxin destroys the BM leaving no more surface for the cells to attach Effacement of foot processes, vacuolization, retraction and detachment of cells from the GBM.
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•
•
•
o children >40 mg/h Clinical features o Proteinuria o Edema o Hyperlipidemia o Hypoalbuminemia Hypercoagulable o urinary loss of anti-thrombin III and plasminogen o hemoconcentration Risk of Infections
Types •
Figure 13. Mediators of immune glomerular injury including cells and soluble mediators
Glomerular Diseases • • • • •
Asymptomatic proteinuria Nephrotic syndrome Asymptomatic hematuria Nephritic syndrome Rapidly progressive nephritic syndrome
Nephrotic Syndrome •
Proteinuria greater than 3.5 gms/ 24 hours (less in children) • Hypoalbuminemia- plasma albumin less than 3 g/dL
•
• Edema Hyperlipidemia and lipiduria
•
The initial event is a derangement in glomerular capillary walls resulting increased permeability to plasma proteins
•
Diseases frequently responsible for nephrotic syndrome include (each will be discussed separately in this trans): o Minimal change disease o Focal segmental glomerulosclerosis o Membranous glomerulopathy (idiopathic)
Primary o Membranous Glomerulopathy o Focal Segmental Glomerulosclerosis o Minimal Change Disease o Membranoproliferative GN • Secondary o Diabetic glomerulosclerosis o Paraproteinemia/Amyloidosis o Lupus Nephritis Evaluation • History and Physical Exam • Urine Analysis • Lab Studies • Renal Biopsy Table 1. Urine Sediment Types. Nephritic Urine Nephrotic Urine Red cells Heavy (hematuria) proteinuria Variable proteinuria Free fat droplets Granular casts Fatty casts
Chronic GN Proteinuria Variable hematuria Broad waxy casts
Minimal Change Disease Clinical Features • Most common features – proteinuria and periorbital edema, with or without other manifestations of nephrotic syndrome
•
Most frequent cause of nephrotic syndrome in children Light Microscopy • Minimal histologic changes • Normal cellularity • Proximal convoluted tubules with resorption droplets • Vessels and interstitium are unremarkable
Figure 14. Primary nephrotic syndrome From 2011 Trans: More stringent definition • Nephrotic range proteinuria o adults >3.0-3.5 grams/d
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Figure 15. Minimal Change Disease
•
In electron microscopy: in the visceral epithelial cells
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o o
o o
uniform and diffuse effacement of foot processes replaced by a rim of cytoplasm often showing vacuolization, swelling and hyperplasia of villi “fusion” of foot processes/ effacement > proteinuria 85% responsive to steroids with reversal of ultrastructural changes; overall prognosis good
Pathogenesis • Loss of polyanions and the glomerular chargebarrier > loss of negative charge of BM • Primary visceral epithelial cell injury • Immune dysfunction leads to production of cytokine-like circulating substance that affects visceral epithelial cells
Focal Segmental Glomerulosclerosis (FSGS) Clinical Features • Severe proteinuria or nephrotic syndrome- most common manifestation • Hematuria common, usually microscopic • Hypertension common • Male preponderance • May be primary or secondary Light Microscopy • Some glomeruli (especially juxtamedullary ones) with segmental sclerosis (mesangial matrix material, collapse, basement membrane- like material , +/- hyalinosis
Figure 16. Normal podocytes (individually sticking out) with slit pores. Endothelial layer has fenestrations > basement membrane
Figure 18. Focal collapse of glomerulus (encircled).
Figure 17. Fused podocytes in minimal change disease (white arrows) •
In immunofluorescence microscopy: o Negative immunofluorescence staining within glomeruli – no immune complexes
Figure 20. Hyalinosis in glomerulus
Figure 18. Immunofluorescence microscopy of Minimal Change Disease
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Figure 23. EM – denuded BM, will progress to ESRD -> dialysis, transplant. Accumulation in collapsed loops of matrix like material
Figure 21. Tubular atrophy – normal glomerulus but with thickened tubular walls, it could indicate presence of FSGS even if glomerulus is normal as seen here. Immunofluorescence Microscopy • Usually normal except for sclerotic segment which may have IgM, with or without C3
Pathogenesis • initiating pathogenetic mechanisms are varied • common element is injury manifested by sclerosis in the setting of nephrotic range proteinuria., • Degeneration and focal disruption of visceral epithelial cells • Hyalinosis and sclerosis represent entrapment of plasma proteins in extremely hyperpermeable foci with increased ECM deposition • Mutations in genes encoding for the proteins nephrin and/or podocin causes increased permeability to proteins – PROTEINURIA! Primary/idiopathic FSGS Secondary/variants FSGS • I.V. drugs
• • • • • • •
Collapsing gn: HIV, parvovirus B-19, pamidronate, CS2, Loa Loa Obesity-associated - reversible with weight reduction Familial FSGS - podocin, alpha-actinin-4 mutations Congenital - Finnish type (nephrin mutation) Cholesterol emboli Lithium Mitochondrial myopathies/cytopathies
Figure 22. IF – usually normal except for sclerotic segment which may have IgM, with or without C3. Electron Microscopy and Course of Disease • uniform and diffuse effacement of foot processes on sclerotic and non-sclerotic areas plus • focal detachment of epithelial cells with denudation of the underlying GBM • Accumulation in collapsed loops of matrix- like material • Course – 15% responsive to steroids, over 1/3 progress to end stage renal disease
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Figure 24. FSGS survival rate
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Figure 25. Reductions in renal mass leading to focal glomerulosclerosis which in turn leads to reductions in renal mass creating a cycle Does hyperfiltration injure the glomerulus? Observations: 1.
2. 3. 4.
Subtotal nephrectomy (83%) in rats is followed by: a. Increase blood flow and filtration per glomerulus b. Proteinuria c. Focal glomerular sclerosis d. Progressive renal failure High protein diets a. Increase GFR and accelerate glomerular sclerosis Low protein diets Similar lesions occur in some patients with unilateral renal agenesis and in association with other diseases that reduce renal function mass
Figure 26. LM: Hypercellularity of glomerular tuft
Membranous Glomerulonephropathy Clinical Features • Proteinuria with or without the full nephrotic syndrome - most common finding • Peak incidence in the fourth to fifth decades • Male preponderance
•
Most common cause of nephrotic syndrome in adults (remember minimal change disease – most common cause of NS in children!)
Clinical Course • Spontaneous remission of proteinuria occur in approximately ¼ of patients, approximately half will have stable renal function with or without continued proteinuria • Minority of patients will have slow decline in renal function, a few will have rapid decline in renal function • 1/3 progress, 1/3 remit, 1/3 protenuria only
Figure 27. LM: silver staining BM spikes trying to cover the deposits
In light microscopy: • Normal to extreme diffuse thickening of the capillary wall • +/- tuft hypercellularity
•
foam cells in interstitium
In electron microscopy: • Numerous subepithelial deposits (+/-) spikes of GBM in between In immunofluorescence microscopy: • Finely granular diffuse capillary wall staining (-) IgG, (+/-) C3 and other immunoreactants
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Figure 28. IF: Finely granular diffuse capillary wall
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Figure 29. EM: Large subendothelial deposit (not just a hump)
Figure 30. LM: Uniformly and diffusely enlarged hypercellular glomeruli and reduced Bowman spaces
Pathogenesis • Believed to be chronic antigen-antibody mediated • Genetic susceptibility • Circulating immune complexes in 15-25% • Direct action of C5b-9, the membrane –attack complex of complement • in-situ immune complex formation in the subepithelial zone • Native or foreign antigens planted in the glomerular basement membranes are present beforehand and antibodies to these antigens combine with them in situ to form immune complexes. • presence of immune complexes alters the permeability of the capillary loops leading to proteinuria.
Immunofluorescence Microscopy • Coarse granular staining in first few weeks for IgG and C3 • Later, predominant C3 and IgG scant to absent
Nephritic Syndrome • • • • • • • •
Hematuria Proteinuria Decreased glomerular filtration rate Elevated BUN and serum creatinine Oliguria Salt and water retention Edema Hypertension
Glomerular Changes • Leucocytic infiltration • Hyperplasia of glomerular cells • Necrosis (severe lesions) • Injury to capillaries
Figure 31. IF: Variable-sized coarse granular deposits of immunoglobulins and complement in glomerular loops.
Electron Microscopy • “Immune-type” deposits on subepithelial surface described as “humps” • Occasional patchy GBM thickening
Acute Glomerulonephritis Clinical Features • Also called poststreptococcal or postinfectious glomerulonephritis • Latent period between infection and onset of GN ( 1-2 wks for pharyngitis and 3-6 wks for skin infections ) • Smoky urine and edema common initial manif, hypertension common, transient oliguria Light microscopy • Global and usually uniform hypercellularity • Capillary lumina may be occluded • Neutrophils frequent in the acute phase ( exudative glomerulonephritis)
Figure 32. EM: Variable-sized granular dense deposits of IgG and C3 (“humps”) irregularly arrayed in the subepithelial space of the glomeruli. Pathogenesis
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• • •
Streptococcal antigens from the infection elicit the production of anti-streptococcal antibodies. Immune complexes form in situ in glomeruli due to previously planted streptococcal antigens. The immune complex formation with complement activation incites acute glomerular inflammation
Figure 34. Glomerular tuft with global mesangial hypercellularity/proliferation. (Note that “normal” is less than or equal to 2 or 3 cells per mesangial area)
Figure 35. Red cell casts (arrows)
Figure 33. Hypercellular glmeruli due to proliferation of endothelial cells and mesangial cells, swelling of endothelial cells, and inflammatory infiltrate (neutrophils and monocytes). Initially, tubules are not affected (but as disease progresses, they may present hydropic change).
Immunofluorescence Microscopy • Mesangial granular IgA (in the absence of SLE, HSP, active liver disease) • Usually C1q is absent
Glomerulonephropathies Associated with Isolated “Essential” Hematuria • • • •
IgA Nephropathy ( Berger’s Disease ) Thin Basement Membrane Disease Alport’s Disease Non-specific changes
IgA Nephropathy Clinical Features • Most common during the 2nd and 3rd decades • Male preponderance • Asymptomatic microhematuria to rapidly progressive renal failure • 5 to 15% have nephrotic syndrome Light Microscopy Histologic Subclasses • Type I – Minimal histologic lesion • Type II- Focal segmental glomerulosclerosis-like • Type III – Focal proliferative glomerulonephritis • Type IV – Diffuse proliferative GN • Type V – Advanced chronic GN
Figure 36. IF: Granular deposits of IgA and C3 in the glomerular mesangium. The fundamental characteristic in IgA Nephropathy is the intense, diffuse mesangial immunostaining for IgA that is limited to mesangial areas, (without deposits in capillary walls). Diagnosis rests on the finding of dominant IgA mesangial deposits. C3 is also present in mesangial areas, but usually equal to or less than IgA staining. Electron Microscopy & Clinical Course • Mesangial electron dense deposits • Variable clinical course and prognosis
Figure 37. Pathogenesis
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– –
presence of IgA immune complexes in the glomerular tufts Presumably mucosal derived IgA combines with antigens to form circulating immune complexes that deposit in the glomerular mesangium.,
Exam # 1
Unfortunately it usually destroys the transplant.
Membranoproliferative Glomerulonephritis Clinical Features • Nephrotic syndrome common • May have manifestations of the acute nephritic syndrome such as hematuria, • ( gross or microscopic), hypertension MPGN Type I Light Microscopy • Proliferative, polymorphonuclears • Lobulation/ tram-tracking
Figure 38. EM: Electron-dense mesangial deposits and foot process effacement.
Thin Basement Membrane Disease • thin GBM nephropathy is a genetically heterogeneous disorder, with some but not all familial cases linked to mutations within the genetic locus encoding the α3 and α4 chains of type IV collagen (COL4A3/COL4A4 locus).
Figure 39. The main morphological feature in Thin Basement Membrane Disease (TBMD) is diffuse thinning of the GBM, particularly the lamina densa. Accurate measurement of the GBM thickness is therefore essential in the diagnosis of TBMD.
Figure 40. There is massive mesangial cell proliferation, mesangial matrix expansion and diffuse thickening and focal splitting of the glomerular basement membrane. There is also accentuation of lobular architecture, swelling of cells lining peripheral capillaries, and influx of leukocytes.Basement membrane thickening is due to mesangial cell and mesangial matrix interposition along the subendothelial side of the lamina densa with consequent neoformation of basement membrane – basically a doubling or complex replication of the BM that gives the morphological aspect of ‘double contour’ (tramtracking). In other words, tram-tracking is caused by an increase in mesangial cells and matrix in the capillary loops, called ‘mesangial interposition’, which leads to new subendothelial basement membrane deposition. The mesangial matrix increase can be more severe in peripheral areas of the tuft, giving the glomerular tuft a ‘lobular’ appearance.
Alport syndrome •
•
•
•
In Alport syndrome, type IV collagen, one of the proteins that makes up the GBM, is absent or abnormal. Although the GBM looks normal in childhood, it deteriorates with time because it lacks the special type IV collagen that should be there Alport syndrome is much more common in boys and men because the gene that usually causes it (called COL4A5) is on the X chromosome. Women have two X chromosomes (XX), so they usually have a normal copy as well as an abnormal copy of the gene in less than 1 in 20 Alport transplants) kidney transplants meet with a unique problem. Because the transplanted kidney has normal type IV collagen, the immune system may see it as 'foreign' and attack it. This causes Alport antiGBM disease, which is very similar to the kidney disease seen in Goodpasture's disease.
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Figure 41. Increased mesangial matrix (stained black with silver stain) Immunofluorescence Microscopy • Broad capillary wall deposits – • C3 +/- other things
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Figure 42. Immunofluorescence microscopy reveals granular staining for the complement protein C3 Electron Microscopy • Interposition of mesangial cells and matrix between GBM and capillary endothelium accounts for “tram-track” appearance • Subendothelial and mesangial deposit
Figure 43. EM: Subendothelial deposit incorporated into mesangial matrix (M).
Exam # 1
Figure 44. Schematic representation of patterns in the two types of membranoproliferative GN. In type I there are subendothelial deposits; type II is characterized by intramembranous dense deposits (dense-deposit disease). In both, mesangial interposition gives the appearance of split basement membranes when viewed in the light microscope. MPGN Type II/Dense Deposit Disease (DDD) Notes from http://path.upmc.edu/cases/case148/dx.html Membranoproliferative glomerulonephritis type II (MPGN-II), also known as dense deposit disease (DDD), is a clinicopathologic entity associated with renal abnormalities which often culminate in renal failure. DDD commonly affects children and young adults with a roughly equal male to female preponderance. These patients present with varying degrees of hematuria and/or proteinuria. In addition, serum analysis often but not invariably reveals hypocomplementemia, particularly of the complement protein C3, which has led some researchers to speculate that abnormalities of the complement cascade contribute to the pathogenesis of DDD. Distinguishing DDD from membranoproliferative glomerulonephritis type I (MPGN-I) may be quite difficult clinically since both are characterized by a nephrotic and/or nephritic clinical picture. However, microscopic examination reveals differences that allow their separation. In MPGN-I, most glomeruli demonstrate global hypercellularity in a lobular pattern. This differs from DDD in which a variety of light microscopic patterns may be seen - including membranoproliferative glomerulonephritis (lobular glomerulonephritis), glomerular sclerosis, pure mesangial hypercellularity, membranous glomerulonephritis-like pattern, cresenteric glomerulonephritis, minimal changes, or focal and segmental necrotizing glomerulonephritis.
Light microscopy • Any glomerular pattern (membranous, membranoproliferative, normal, crescentic GN, etc.)
Pathogenesis of MPGN I • Immune complex mediated disorder.
• •
•
IC are deposited in the mesangium and subendothelial spaces. Mesangial cells proliferate in response to the immune complex deposition and extend beyond the confines of the mesangium to mesangialize the capillary loops. A second internal basement membrane is formed by the mesangial cell and the undermined endothelial cells
Figure 45.MPGN Type II – Light Microscope. Immunoflourescence Microscopy • Broad capillary wall deposits – C3 +/-, other things, extraglomerular deposits
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Figure 46. IF: Presence of the complement protein C3 which produces a characteristic ribbon-like staining pattern of the peripheral capillary loop; however, there is a lack of staining of the dense deposits. Electron Microscopy • Large electron dense deposits in GBM, +/Robbins book notes TBM,BC,etc
Types I and II have altogether different ultrastructural and immunofluorescent features. Type I MPGN (two thirds of cases) is characterized by the presence of subendothelial electron-dense deposits. Mesangial and occasional subepithelial deposits may also be present. By immunofluorescence, C3 is deposited in a granular pattern, and IgG and early complement components (C1q and C4) are often also present, suggesting an immune complex pathogenesis.
In Type II MPGN lesions, the lamina densa of the GBM is transformed into an irregular, ribbon-like, extremely electrondense structure because of the deposition of dense material of unknown composition in the GBM proper, giving rise to the term dense-deposit disease. In type II, C3 is present in irregular granular-linear foci in the basement membranes on either side, but not within the dense deposits. C3 is also present in the mesangium in characteristic circular aggregates (mesangial rings). IgG is usually absent, as are the earlyacting complement components and C4).by the presence Figure 47. Histologically, DDD(C1q is defined
of irregular electron dense deposits in the lamina densa of Pathophysiology the glomerular basement membrane, which are observed Although there are exceptions, most cases of type I MPGN by EM. deposits arecomplexes strongly PAS positive and and are present These evidence of immune in the glomerulus dark blue when stained with toluidine blue. complement activation of both classic and alternative pathways. The antigens involved in idiopathic MPGN are unknown. Conversely, most patients with dense-deposit disease (type II) have abnormalities that suggest activation of the alternative complement pathway. These patients have a consistently decreased serumand C3, but normal C1 and C4, the MPGN Types I & II Course Diagnosis immune complex-activated early components of complement. • Course: Progressive (many to renal failure) They also have diminished serum levels of factor B and • Diagnosis: Low complement persistent, pathway. nephritic properdin, components of the alternative complement syndrome More thanand/ 70%orofnephrotic patients with dense-deposit disease have a • Autoimmune disorder circulating antibody termed C3 nephritic factor (C3NeF), which is a •conformational autoantibody thatisbinds to the alternative C3 nephritic factor which an IgG C3 convertase. Binding directed of the against antibody C3 stabilizes the immunoglobulin convertase convertase, it from enzymatic andprotecting on binding stabilizes it. degradation and thus favoring C3 degradation and hypocomplementemia. • persistent The stabilized C3 convertase continuously drives There is also decreased C3 synthesis by the liver, further the alternative complement pathway, consuming contributing to the profound hypocomplementemia. Precisely complement. how C3NeF is related to glomerular injury and the • of As consequence, have marked nature the a dense deposits arepatients unknown. C3NeF activity also occurs in hypocomplementemia. some patients with a genetically determined disease, partial lipodystrophy, some of whom develop type II MPGN. Clinical Presentation The principal mode of presentation is the nephrotic syndrome occurring in older children or young adults, but usually with nephritic component manifested by hematuria or, more insidiously, as mild proteinuria. Few remissions occur spontaneously in either type, and the disease follows a slowly progressive but unremitting course. Some patients develop numerous crescents and a clinical picture of RPGN. About 50% develop chronic renal failure within 10 years. Treatments with steroids, immunosuppressive agents, and antiplatelet drugs have not been proved to be materially effective. There is aMarch high incidence of |recurrence 3, 2009 Tuesdayin transplant recipients, particularly in type II disease; dense deposits may recur in 90% of such patients, although renal failure in the allograft is much less common.
Secondary MPGN arises in the following settings:
Chronic immune complex disorders, such as SLE; hepatitis B infection; hepatitis C infection, usually with cryoglobulinemia; endocarditis; infected ventriculoatrial shunts; chronic visceral abscesses; HIV infection; and schistosomiasis.
Partial lipodystrophy associated with C3NeF (type 2)
Alpha1 -Antitrypsin deficiency Malignant diseases (chronic lymphocytic leukemia, lymphoma, melanoma) Hereditary complement deficiency states
Notes from http://path.upmc.edu/cases/case148/dx.html Distinguishing DDD from membranoproliferative glomerulonephritis type I (MPGN-I) may be quite difficult clinically since both are characterized by a nephrotic and/or nephritic clinical picture. However, microscopic examination reveals differences that allow their separation. In MPGN-I, most glomeruli demonstrate global hypercellularity in a lobular pattern. This differs from DDD in which a variety of light microscopic patterns may be seen, as mentioned above. The capillary walls in the glomeruli are markedly thickened and show intense staining with PAS in MPGN-I. Methenamine silver also stains the glomerular basement membrane of the thickened capillary loops to reveal splitting or tram tracking similar to what is observed in DDD; however, the material deposited between the glomerular basement membrane borders is nonargyrophilic and different from the deposits in DDD. Tram tracking in MPGN-I is caused by an increase in mesangial cells and mesangial matrix in the capillary loops, called 'mesangial interposition', which leads to new subendothelial basement membrane deposition. Electron microscopic findings in MPGN-I show mesangial interposition, subendothelial immune deposits and a new layer of subendothelial basement membrane. Immunofluorescence microscopy reveals granular staining for the complement protein C3 differs from the ribbony pattern seen inPage DDD. In12 addition, of 16 MPGN-I biopsies, unlike those of DDD, may show staining for Canoy, Carasco, Cielo, complement proteins Clq, C4 and one or more immunoglobulins, particularly IgG and frequently IgM. MPGN-I has a recognized Co association with chronic hepatitis C infection and
OS 214 Renal
Dr. Teresita Tuazon Exam # 1
Pathology of Glomerular Diseases
Clinical Features • Clinical onset of disease usually abrupt • Severe oliguria or anuria common at initial examination • Course is aggressive if without treatment Robbins book notes Rapidly progressive glomerulonephritis (RPGN) is a syndrome associated with severe glomerular injury and does not denote a specific etiologic form of glomerulonephritis. It is characterized clinically by rapid and progressive loss of renal function associated with severe oliguria and (if untreated) death from renal failure within weeks to months. Regardless of the cause, the histologic picture is characterized by the presence of crescents in most of the glomeruli (crescentic glomerulonephritis). These are produced in part by proliferation of the parietal epithelial cells and Bowman capsule and in part by infiltration of monocytes and macrophages. RPGN may be caused by a number of different diseases, some restricted to the kidney and others systemic. Although no single mechanism can explain all cases, there is little doubt that in most cases the glomerular injury is immunologically mediated. Thus, a practical classification divides RPGN into three groups on the basis of immunologic findings. In each group, the disease may be associated with a known disorder or it may be idiopathic.
Figure 48. The alternative complement pathway. Note that C3NeF, present in the serum of patients with membranoproliferative glomerulonephritis, acts at the same step as properdin, serving to stabilize the alternative pathway C3 convertase, thus enhancing C3 breakdown and causing hypocomplementemia. MPGN Type III • with prominent subepithelial electron dense deposits (Burkholder) • with complex disruptions of the basement membrane (Strife & Anders), focal and segmental gloerular hyalin deposits, and infiltration by foamy macrophages Robbins book notes Rare variants (type III) segregated because they exhibit both subendothelial and subepithelial deposits are associated with GBM disruption and reduplication.
Acute Renal Failure • • •
Creatinine increases rapidly over a few days Oliguria/anuria frequent Etiologies: Pre-renal Renal Post-renal
Notes from http://path.upmc.edu/cases/case148/dx.html Crescentic glomerulonephritis or rapidly progressive glomerulonephritis (RPGN) is a term given to a diverse group of diseases which all have cresents present within the glomerular tuft. These include primary or renal limited (so-called idiopathic) crescentic glomerulonephritis, anti-glomerular basment membrane (anti-GBM) antibody diseases, and systemic disorders. Considered within the entire clinical spectrum of renal disease, RPGN produces the most rapidly progressive and destructive of glomerular diseases which in the most severe forms proceeds inexorably to renal failure if not treated aggressively and early. Fortunately, RPGN accounts for only 2 to 7% of renal biopsies, with a disproportionately large percentage of these patients progressing to end stage renal disease. RPGN is categorized based on the biopsy immunofluorescence pattern into three groups: RPGN Type I (20%), RPGN Type II (40%), and RPGN Type III (40%) (Table 3). RPGN types I and II have greater than 2+ (on a 4+ scale) immunofluorescence staining intensity with linear and granular staining patterns, respectively. RPGN Type III or pauci-immune type has weak or no demonstrable immunoglobulin / complement deposition, corresponding to an immunofluorescence staining intensity of < 2+.
Table 1. Three Types of Immunofluorescence Pattern
RPGN
Based
on
Robbins book notes Acute renal failure is dominated by oliguria or anuria (no urine flow), with recent onset of azotemia*. It can result from glomerular (e.g., crescentic glomerulonephritis), interstitial, and vascular injury or acute tubular necrosis. *Azotemia is a biochemical abnormality that refers to an elevation of the blood urea nitrogen (BUN) and creatinine levels and is related largely to a decreased glomerular filtration rate (GFR). Azotemia is produced by many renal disorders, but it also arises from extrarenal disorders. Prerenal azotemia is encountered when there is hypoperfusion of the kidneys (e.g., in hemorrhage, shock, volume depletion, and congestive heart failure) that impairs renal function in the absence of parenchymal damage.
Crescentic Glomerulonephritis/Rapidly Progressive Glomerulonephritis (RPGN)
March 3, 2009 | Tuesday
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Canoy, Carasco, Cielo, Co
OS 214 Renal
Dr. Teresita Tuazon
Pathology of Glomerular Diseases
Exam # 1
Light Microscopy • Over 50% of glomeruli with crescents. • Look at the most preserved glomeruli for tuft hypercellularity
Figure 49. Collapsed glomerular tufts and crescentshaped mass of proliferating cells and leukocytes internal to the Bowman capsule.
Robbins book notes Type I RPGN is best remembered as anti-GBM disease and hence is characterized by linear deposits of IgG and, in many cases, C3 in the GBM, as previously described. In some of these patients, the anti-GBM antibodies cross-react with pulmonary alveolar basement membranes to produce the clinical picture of pulmonary hemorrhages associated with renal failure (Goodpasture syndrome). The Goodpasture antigen, as noted, resides in the noncollagenous portion of the alpha3 chain of collagen type IV. What triggers the formation of these Figure antibodies 50. is unclear in most patients. Exposure to viruses or hydrocarbon solvents (found in paints and dyes) has been implicated in some patients, as have various drugs and Immunoflourescence cancers. Cigarette smoking appears to play a permissive role, • most RPGN Typewho 1 - Linear since patients developimmunoflourescence pulmonary hemorrhage are o is 20% smokers. There a high prevalence of certain HLA subtypes o (e.g., Goodpasture and haplotypes HLA-DRB1),syndrome a finding consistent with the genetic predisposition to autoimmunity.basement membrane o Anti-glomerular Type II RPGN is an immune complex-mediated disease. It can disease be a complication of any of the immune complex nephritides, • RPGN Type 2 - Granular immunoflourescence including postinfectious glomerulonephritis, SLE, IgA nephropathy, oand 40% Henoch-Schonlein purpura. In some cases, immune complexes can be demonstrated, but the underlying o Many primary and secondary immune cause is undetermined. In all of these cases, complex diseases immunofluorescence studies reveal the characteristic ("lumpy • RPGN Type 3 Negative (pauci-immune) bumpy") granular pattern of staining. These patients cannot usually immunoflourescence be helped by plasmapheresis, and they require o underlying 40% treatment for the disease. Type III RPGN, called pauci-immune type,anti-neutrophil is defined by o also Predominately the lack of anti-GBM antibodies orantibody immune complexes by cytoplasmic associated immunofluorescence and electron microscopy. Most of these systemic vasculitis and renal limited patients have antineutrophil cytoplasmic antibody (ANCA) in the GN vasculitides. Hence, in some serum, which playscrescentic a role in some Weak or no demonstrable cases, type IIIoRPGN is a component of a systemic vasculitis such as Wegener immunoglobulin/complement granulomatosis or microscopic polyarteritis. deposition, In many cases, however, pauci-immune crescentic corresponding to an glomerulonephritis immunofluorescence is isolated and hence idiopathic. than staining More intensity 90% of such idiopathic cases have C-ANCA or P-ANCA in the of <2+ sera. To summarize, all three types of RPGN may be associated with a well-defined renal or extrarenal disease, but in many cases (approximately 50%) the disorder is idiopathic. Of the idiopathic cases, about one fourth have anti-GBM disease (RPGN type I) without lung involvement; another one fourth have type II March | Tuesday RPGN; and3, the2009 remainder are pauci-immune or type III RPGN. The common denominator in all types of RPGN is severe glomerular injury.
Figure 51. This immunofluorescence pattern shows positivity with antibody to IgG and has a smooth, diffuse, linear pattern that is characteristic for deposition of glomerular basement membrane antibody with Goodpasture syndrome.
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OS 214 Renal
Dr. Teresita Tuazon
Pathology of Glomerular Diseases
Exam # 1
Figure 52.
Figure 52. Granular Immunofluorescence (“lumpy bumpy” granular pattern of staining) Pathogenesis of Anti-GBM disease (RPGN Type 1) • autoimmune disorder • Anti-glomerular basement membrane antibodies are produced and complex with glomerular basement membranes and in some instances with the pulmonary alveolar basement membranes leading to their destruction
Figure 53. Granular, cytoplasmic staining of C-ANCA and perinuclear staining typical of P-ANCA, respectively. Electron Microscopy • Either glomerular deposits anywhere (immune complexes ) or no deposits (either anti-GBM or no deposit disease )
Anti-neutrophil Cytoplasmic Antibodies (ANCA) • A family of autoantibodies that have specificity for proteases located in primary granules of neutrophils and monocytes • Useful in the diagnosis and monitoring of patients with several forms of systemic vasculitis and renal-limited (pauci-immune) crescentic glomerulonephritis Types of ANCA 1. C-ANCA - cytoplasmic pattern
2.
• •
Major specificity: proteinase 3
• •
Major specificity: myeloperoxidase
Major clinical association: Wegener’s granulomatosis P-ANCA - perinuclear pattern Major clinical associations: microscopic polyangiitis and renal-limited crescentic glomerulonephritis
Robbins book notes Serum from many patients with vasculitis in small vessels reacts with cytoplasmic antigens in neutrophils, indicating the presence of antineutrophil cytoplasmic autoantibodies (ANCA). ANCA comprise a heterogeneous group of autoantibodies against enzymes mainly found within the azurophil or primary granules in neutrophils but also found in the lysosomes of monocytes and in endothelial cells. ANCA can be detected in serum by immunofluorescent microscopy of ethanol-fixed neutrophils and by immunochemical assays. Two main patterns of immunofluorescent staining distinguish different ANCA types. One ANCA type shows cytoplasmic localization of the staining (c-ANCA), and the most common target antigen is proteinase 3 (PR-3), a neutrophil granule constituent. The second type shows perinuclear staining (p-ANCA) and is usually specific for myeloperoxidase (MPO). Either ANCA specificity may occur in a patient with ANCA-associated small vessel vasculitis, but cANCA (PR-3 specificity) are typically found in Wegener granulomatosis and p-ANCA (MPO specificity) are found in most cases of microscopic polyangiitis and Churg-Strauss syndrome. Approximately 10% of patients with these disorders, however, do not demonstrate ANCA by typical assays. ANCA serve as useful quantitative diagnostic markers for these disorders, and their discovery has led to segregation of a group of these disorders as the ANCA-associated vasculitides. The close association between ANCA titers and disease activity, particularly c-ANCA in Wegener granulomatosis, suggests that they may be important in the pathogenesis of this disease, but the precise mechanisms by which ANCA induce injury are March 3, 2009 | Tuesday unknown.
Figure 54. Cellular crescent formation*
Figure 55. Fibrous crescent*
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OS 214 Renal Pathology of Glomerular Diseases
Dr. Teresita Tuazon Exam # 1
Figure 56. RPGN Type III or pauci-immune type
Figure 57.
Figure 57.
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