Gn csbrp
•Download as PPT, PDF•
25 likes•4,333 views
This document discusses glomerular diseases and their patterns based on four morphological components: glomeruli, tubules, interstitium, and blood vessels. It provides details on specific glomerular diseases including their presentations, causes, mechanisms of injury, histopathological features, and clinical courses. Key diseases discussed include acute proliferative glomerulonephritis, rapidly progressive glomerulonephritis, membranous nephropathy, minimal-change disease, and focal segmental glomerulosclerosis.
Recommended
More Related Content
What's hot
What's hot (20)
Viewers also liked
Viewers also liked (20)
Similar to Gn csbrp
Similar to Gn csbrp (20)
More from Prasad CSBR
More from Prasad CSBR (20)
Recently uploaded
Recently uploaded (20)
Gn csbrp
- 1. Glomerular DiseasesGlomerular Diseases Dr.CSBR.Prasad, M.D., CSBRP-June-2014
- 2. Disease patterns based on FOUR morphologic components 1. Glomeruli 2. Tubules 3. Interstitium 4. Blood vessels CSBRP-June-2014
- 3. Disease patterns based on FOUR morphologic components 1. Glomeruli Presents with hematuria / proteinuria Puffiness of face / generalized edema Oliguria / Azotemia Usually immune mediated CSBRP-June-2014
- 4. Disease patterns based on FOUR morphologic components 1. Glomeruli 2. Tubules Presents with inability to concentrate urine Polyuria / nocturia / electrolyte disturbances Acute renal failure Azotemia Usually due to toxins / infections / inheritedCSBRP-June-2014
- 5. Disease patterns based on FOUR morphologic components 1. Glomeruli 2. Tubules 3. Interstitium Presents with inability to concentrate urine Acute renal failure Pyuria Usually due to Drugs / infections CSBRP-June-2014
- 6. Disease patterns based on FOUR morphologic components 1. Glomeruli 2. Tubules 3. Interstitium 4. Blood vessels Presents with hypertension Acute renal failure Ischemic injury – papillary necrosis / infarcts Usually due to congenital / DrugsCSBRP-June-2014
- 7. Disease patterns based on FOUR morphologic components These four components are interdependent and disease affecting one may affect the other components secondarily in the course of time Example: 1.Disease affecting the blood vessels affect invariably other components 2.Severe glomerular damage impairs blood flow to the tubules CSBRP-June-2014
- 11. CSBRP-June-2014
- 12. Proteins of the glomerular slit diaphragm CSBRP-June-2014
- 13. Glomerular SyndromesGlomerular Syndromes 1. Nephritic syndrome (Hematuria, Azotemia, mild proteinuria and hypertension) 2. Nephrotic syndrome (>3.5gm/day protein excretion in urine, Hypoalbuminemia, hyperlidemia, lipiduria) 3. Rapidly progressive glomerulonephritis (proteinuria / hematuria and acute renal failure) 4. Chronic renal failure (Azotemia > uremia) 5. Isolated urinary abnormalities (Hematuria / proteinuria) CSBRP-June-2014
- 14. CSBRP-June-2014
- 15. CSBRP-June-2014
- 16. Mechanisms of glomerular injury • Ab mediated injury: – Ab reacting with in situ Ag • Intrinsic (fixed, insoluble – Type-IV collagen, Mesangeal Ags) • Extrinsic (molecule planted with in glomerulus) – Exogenous – infective agents, drugs – Endogenous – DNA, nuclear proteins Ig, Ag+Ab, IgA – Circulating Ag+Ab complexes • Cytotoxic antibodies CSBRP-June-2014
- 17. Circulating Ag+Ab complexes Ab have no immunological specificity for the glomerular constituents, and the complexes are localized within the glomeruli because of their physicochemical properties and the hemodynamic factors peculiar to the glomerulus Ag+Ab complexes are trapped in the glomeruli CSBRP-June-2014
- 18. Circulating Ag+Ab complexes 1. Endogenous Ags: – DNA, nuclear proteins, Ig, IgA 1. Microbial agents: – Syphilis – Treponema pallidum – Malaria – HCV – HBV 1. Some tumor antigens CSBRP-June-2014
- 19. Circulating Ag+Ab complexes Ag+Ab complexes are trapped in the glomeruli Activation of complement Recruitment of inflammatory cells Damage CSBRP-June-2014
- 20. Localization of immune complexes in the glomerulus 1-Subepithelial humps 2-Epimembranous deposits 3-Subendothelial deposits 4-Mesangial deposits CSBRP-June-2014
- 21. Localization of immune complexes in the glomerulus Factors affecting the glomerular localization: – Molecular charge – Size of these reactants Subepithelial localization: Highly cationic immunogenic molecules tend to cross the GBM and reside in subepithelial region Subendothelial localization: Highly anionic macromolecules Mesangial deposition: Neutrally charged molecules Immune complexes containing these molecules gets deposited in the mesangium NOTE: Very large molecules are not nephritogenic and are cleared by the macrophage system CSBRP-June-2014
- 22. Antibodies to glomerular cell Ags • Abs to mesangial cell antigens – Mesnagiolysis – Mesangial cell proliferation • Ab to endothelial cell Ags – Endothelial injury and – Thrombosis • Abs to visceral epithelial cell Ags – Protineuria CSBRP-June-2014
- 23. Cell mediated immunity in glomerulonephritis Evidence: •Presence of macrophages •Presence of sensitized T-lymphocytes and their products in the glomerulus CSBRP-June-2014
- 24. Epithelial cell injury Caused by Ab to Visceral epithelil cell Ags – Drugs – Toxins – Experimentally by Puromycin Changes in epithelial cells: – Vacuolations – Effacement of foot processes – Retraction & – Detachment of cells from GBM CSBRP-June-2014
- 26. Mediators of glomerular injury • Cells – PMNs – Monocytes – Macrophages – Platelets – Resident glomerular cells • Mesangial cells • Soluble mediators – All mediators of inflammation CSBRP-June-2014
- 27. Mediators of immune glomerular injury including cells and soluble mediators CSBRP-June-2014
- 28. Individual glomerular diseases Primary glomerulopathiesPrimary glomerulopathies 1. Acute proliferative GN 2. RPGN 3. Minimal change disease 4. Membranous GN 5. Membranoproliferative GN 6. FSGS 7. IgA nephropathy 8. Chronic GN CSBRP-June-2014
- 29. Nephritic features • Hematuria • Red cell casts • Mild proteinuria • Hypertension • Periorbital edema • Oliguria • Azotemia CSBRP-June-2014
- 30. Acute proliferative glomerulonephritis (Post Streptococcal GN) • Proliferation of glomerular cells • Neutrophilic infiltration • Typically immune complex mediated • Inciting Ag may be: – Exogenous (eg - infective agents) – Endogenous (eg - SLE) CSBRP-June-2014
- 31. Acute proliferative glomerulonephritis (Post Streptococcal GN) • Children 6-10yrs of age / rarely adults • Common infective agent is Streptococcus – Nephritogenic strains of Streptococcus • M protein in cell wall • Griffith types 12, 4, 1 – Other Antigens: • Nephritis associated Streptococcal plasmin receptor (NAP1r) • Eotoxin B (SepB) • Zymogen precursor (zSepB) – Mechanism: Planted Ag / Ag+Ab / Altered GBM CSBRP-June-2014
- 32. Acute Proliferative Glomerulonephritis (Post Streptococcal GN) Morphology: Diffuse & Global •Enlarged hypercellular glomeruli – Infiltration by Leucocytes & macrophages – Proliferation of Endothelial & mesangial cells •Obliteration of lumen of capillaries •Interstitial edema •Tubular red cell casts •Immunofluorescence: – Sparse and focal IgG, Ig M in GBM and C3 in mesangium •Electron microscopy: – Subepithelial electron dense HUMPS – Subepithelial and mesangial deposits CSBRP-June-2014
- 33. ACUTEACUTE GLOMERULONEPHRITISGLOMERULONEPHRITIS Some termsSome terms:: •Diffuse / FocalDiffuse / Focal •Global / SegmentalGlobal / Segmental
- 34. Acute proliferative glomerulonephritis CSBRP-June-2014 Normal glomerulus – PAS stainNormal glomerulus – PAS stain
- 35. Clinical features • Abrupt onset • 1-2 weeks after recovery form sore throat • Fever / malaise / oliguria / smoky urine • Azotemia • Hypertension • Oliguria • > ASLO titer • < C3 levels • Children: – >90% recover with conservative Tx – 1% may develop RPGN • Adults: – Epidemics – good prognosis – Sporadic - 60% recovery CSBRP-June-2014
- 36. Non-Streptococcal Acute GN • Staphylococcus • Pneumococcus • HBV • HCV • Mumps • HIV • Varicella • IMN • Malaria • Toxoplasmosis CSBRP-June-2014
- 37. Rapidly Progressive GN [Crescentic GN] Salient features: •Indicative of severe glomerular injury •Progresses rapidly, if not treated death occurs in weeks to 3 months •Most common histological feature is the presence of crescents in glomeruli •Glomerular injury is immunologically mediated CSBRP-June-2014
- 38. RPGN – Classification based on immunological findings CSBRP-June-2014
- 39. Rapidly Progressive GN [Crescentic GN] 1-Anti-GBM Ab induced disease: •Linear deposits of IgG and C3 in GBM •Goodpasture syndrome: Anti-GBM Ab may cross react with pulmonary alveolar BM resulting in pulmonary hemorrhages – Ag is non-collagenous portion of the α3 chain of Type-IV collagen – Exposure to various solvents (in paints & dyes) has been implicated – HLA-DRB1 •Plasmapheresis helps CSBRP-June-2014
- 40. Rapidly Progressive GN [Crescentic GN] 2-Immune complex induced: •Granular pattern of deposits •In addition to crescents there is cellular proliferation in the glomerular tufts •Plasmapheresis not helpful •Underlying disease must be treated – HS purpura – SLE CSBRP-June-2014
- 41. Rapidly Progressive GN [Crescentic GN] 3-Pauci-Immune type: •No anti-GBM Abs / Immune complexes •Have circulating anti-neutrophil cytoplasmic Ab (ANCA) •Recent concept: Probably these cases are examples of polyangiitis which is limited to glomeruli CSBRP-June-2014
- 42. Rapidly Progressive GN [Crescentic GN] Morphology: •Enlarged kidneys, pale, petechial hemorrhages on the cortical surface •Crescent formation: – Proliferation of parietal cells + monocytes/Macrophages + Fibrin + PMNs – Crescents obliterate Bowman space •Immunofluorescence: – Granular immune deposits – Goodpasture syndrome shows linear GBM Ig+C deposits •In pauci-immune type there is vasculitis CSBRP-June-2014
- 43. Rapidly Progressive GN [Flea bitten kidney] Causes for Flea bitten kidneyCauses for Flea bitten kidney: RPGN Benign nephrosclerosis Bacterial endocarditis CSBRP-June-2014
- 44. Crescentic glomerulonephritis (PAS stain) CSBRP-June-2014
- 46. Crescentic glomerulonephritis CSBRP-June-2014 Investigations: •Anti-GBM Abs •ANCA •ANA may be of help Treatment: •Plasmapheresis •Cytotoxic Tx •Steroids Renal involvement may progress over a matter of weeks resulting in Oliguria
- 47. Membranous nephropathy CSBRP-June-2014 • Common cause of NS in adults • A form of chronic immune complex–mediated disease Characterized by: – Diffuse thickening of glomerular capillary wall due to Ig deposits in the subepithelial side of GBM Causes: – Drugs: Penicillamine, Captopril, gold, NASID – Cancers: Lung, Colon, Melanoma – SLE – Infections: Malaria, HBV, HCV, Syphilis – Other autoimmune diseases
- 48. Membranous nephropathy CSBRP-June-2014 Morphology: – Diffuse thickening of glomerular capillary wall due to Ig deposits in the subepithelial side of GBM – Antigens can be demonstrated in the deposits – Paucity of PMNs and Monocytes and platelets – C3 deposition – Effacement of foot processes – There may be progressive sclerosis of glomeruli
- 50. Membranous nephropathy Clinical features: • Insidious onset • Mostly as nephrotic syndrome • 15% present with non-nephrotic proteinuria • 15% - 35% Hematuria and hypertension • First rule out the secondary causes as it can reverse the injury
- 51. Membranous nephropathy Clinical Course: • Indolent disease • Nonselective proteinuria and does not respond well to corticosteroid therapy • Progression is associated with increasing sclerosis of glomeruli, rising serum creatinine and development of hypertension • About 10% die or progress to renal failure within 10 years, and no more than 40% eventually develop renal insufficiency
- 52. Minimal-change disease CSBRP-June-2014 • Most frequent cause of NS in children • Peak incidence 2-6yrs of age • Diffuse effacement of foot processes • Characteristic feature: Dramatic response to steroids • In a few cases there is preceeding respiratory infection
- 53. Minimal-change disease CSBRP-June-2014 Pointers to immunological basis: •Associated with respiratory infections / immunization •Dramatic response to steroids •Associated with other atopic disorders •Associated some HLA haplotypes •More common in Hodgkin’s lymphoma
- 54. Minimal-change disease CSBRP-June-2014 Basis of the disease: Visceral epithelial cell injury •Loss of glomerular polyanion > defective charge barrier > proteinuria •Mutations in podocyte proteins –Nephrin, podocin •Mutation in nephrin gene causes a hereditary form of congential nephrotic syndrome – Finnish type
- 55. Minimal-change disease CSBRP-June-2014 Morphology: – Glomeruli are normal by light microscopy – EM: • Loss of foot processes • Cytoplasm shows vacuolations, swelling of villi – No Ig, C deposition in glomeruli – PCT show lipid and protein deposition •Prognosis: is very good. 90% of children respond to steroids
- 57. Minimal-change disease Clinical Features: • Despite massive proteinuria, renal function remains good • No hypertension / No hematuria • Respond rapidly to corticosteroid therapy • Some patients may become steroid-dependent or resistant • Long-term prognosis is excellent • Adults are slower to respond - long-term prognosis is also excellent
- 58. Minimal-change disease In adults: • can be associated with Hodgkin lymphoma • may follow NSAID therapy
- 59. Focal segmental glomerulosclerosis (FSGS) This lesion is characterized by: Sclerosis of some, but not all, glomeruli (thus, it is focal) and In the affected glomeruli, only a portion of the capillary tuft is involved (thus, it is segmental)
- 60. ACUTEACUTE GLOMERULONEPHRITISGLOMERULONEPHRITIS Some termsSome terms:: •Diffuse / FocalDiffuse / Focal •Global / SegmentalGlobal / Segmental
- 61. FSGS-Classification and Types FSGS occurs in the following settings: • Idiopathic focal segmental glomerulosclerosis • In association with other known conditions: – HIV infection (HIV-associated nephropathy) – Heroin addiction (heroin nephropathy) – Sickle-cell disease, and – Massive obesity • As a secondary event: – Scarring of previously active necrotizing lesions (e.g., IgA nephropathy) – Renal ablation – in advanced stages of other renal disorders, such as: • Reflux nephropathy • Hypertensive nephropathy • Unilateral renal agenesis • Mutations in genes that encode proteins localized to the slit diaphragm – e.g., Podocin, α-Actinin 4, and TRPC6 (transient receptor potential calcium channel-6)
- 62. FSGS - Pathogenesis • Epithelial damage that is the hallmark of FSGS • Damage mediated by different mechanisms: – Circulating cytokines and – Genetic defects affecting components of the slit diaphragm • The hyalinosis and sclerosis are due to: – Entrapped plasma proteins & – Increased ECM deposition
- 63. ESGS - Morphology • Initial lesions involve the juxtamedullary glomeruli • In the sclerotic segments there is collapse of capillary loops • Increase in matrix, and segmental deposition of plasma proteins along the capillary wall (hyalinosis) • Lipid droplets and foam cells are often present • Glomeruli that do not show segmental lesions usually appear normal on light microscopy but may show increased mesangial matrix
- 64. ESGS - Morphology • Diffuse effacement of foot processes - both sclerotic and nonsclerotic areas EM: • Focal detachment of the epithelial cells • Denudation of the underlying GBM IF: • IgM and C3 (in the sclerotic areas and/or in the mesangium)
- 65. ESGS - Morphology • A morphologic variant of FSGS, called collapsing glomerulopathy – characterized by retraction and/or collapse of the entire glomerular tuft – proliferation and hypertrophy of glomerular visceral epithelial cells – there is associated prominent tubular injury with formation of microcysts • It has poor prognosis
- 68. FSGS – Clinical Course • Response to steroids – variable • Children have better prognosis • Progression to renal failure – variable – 20% rapid • Recurrence in allograft 25%-50% CSBRP-June-2014
- 69. Membranoproliferative glomerulonephritis (MPGN) • MPGN = mesangiocapillary GN • MPGN accounts for 10-20% NS in children and young adults • MPGN can be Primary or Secondary Histology – Basic alterations: • Alterations in BM • proliferation of glomerular cells • Leucocyte infiltration CSBRP-June-2014
- 70. Membranoproliferative glomerulonephritis (MPGN) • MPGN can be Primary or Secondary Primary MPGN (Based on EM, IF and LM) • Type-I – Mesangiocapillary glomerulonephritis – Immune complexes to planted Ags (HBV,HCV) – Activation of both Complement pathways • Type-II – Dense deposit disease – Activation of alternate complement pathway (low C3, Normal C1, C4) CSBRP-June-2014
- 71. The alternative complement pathway in MPGN CSBRP-June-2014
- 72. Membranoproliferative glomerulonephritis (MPGN) Morphology: (Types I&II) •Glomeruli are large, hypercellular, lobular accentuation •Hypercellularity is due to: – Neutrophilic infiltration – Mesangial cell proliferation •GBM is thickened degmentaly •GBM in silver stain – “Tram track” CSBRP-June-2014
- 73. Membranoproliferative glomerulonephritis (MPGN) Type-I & II differ in EM appearances: •Type-I: – Subendothelail electron dense deposits – Occasionally – mesangial, subepithelial deposits – C3 - granular deposits – C1, C4 and IgG deposits •Type-II: – Lamina densa converted into irregular ribbon like electron dense structure – C3 – granular deposits – IgG, C1 and C4 are absent – Hence, has a higher frequency of hypocomplementemia and C3 nephritic factor than type I MPGN CSBRP-June-2014
- 79. Membranoproliferative glomerulonephritis Secondary MPGN: Invariably type-I Causes: •Chronic immune complex disorders – SLE, HBV, HCV, HIV, Endocarditis, Schistosomiasis •A1AT deficiency •Malignancies: CLL, Lymphomas •Hereditary deficiency of regulatory proteins CSBRP-June-2014
- 80. IgA nephropathy (Berger Disease) CSBRP-June-2014 • Prominent IgA deposits in the mesangium • This is the frequent cause of recurrent gross or microscopic hematuria • Sometimes mild proteinuria
- 81. IgA nephropathy (Berger Disease) CSBRP-June-2014 Pathogenesis: •IgA levels are increased in these patients •IgA1 is nephritogenic •Activates alternate complement pathway •Genetic influence: – Runs in some families – Certain HLA genotype •Seen in Celiac disease •Initiating events are not known
- 82. IgA nephropathy (Berger Disease) CSBRP-June-2014 Morphology: •Mesangial widening •Endocapillary proliferations •Presence of PMN in glomeruli is variable •Mesangial deposition of IgA, C3, Properdin •Early complement component are absent
- 84. IgA nephropathy (Berger Disease) CSBRP-June-2014 Clinical features: •Any age (more common in older children / young adults) •Present with hematuria (after respiratory infection) •Hematuria lasts for several days and then subsides only to recur every few months •Renal functions are maintained for decades •Recur in transplanted kidney •Slowly progressive
- 85. Hereditary nephritis Hereditary nephritis 1.Alport’s syndrome 2.Thin GBM lesion – Most common cause of benign familial hematuria CSBRP-June-2014
- 86. Alport’s syndrome Traid of: 1.Hematuria with progression to renal failure 2.Nerve deafness 3.Eye disorders – Lens dislocation – Posterior cataract – Corneal dystrophies CSBRP-June-2014
- 87. Alport’s syndrome • Due to abnormal alfa chain of Type-IV collagen • X-linked inheritance (in some AD / AR) – X linked: COL4A3 – AD: COL4A4, COL4A5 Morphology: – Diffuse GBM thinning – Interstitial foam cells – FSGS – Vascular sclerosis / tubular atrophy / interstitial fibrosis CSBRP-June-2014
- 88. CSBRP-June-2014
- 89. CSBRP-June-2014
- 90. Thin GBM lesion (Benign Familial Hematuria) • Hematuria is usually an incidental finding • Diffuse thinning of GBM (150-200nm) • Mild to moderate proteinuria • Renal functions are preserved • Prognosis is excellent Genes: • Mutations in alfa-3 or alfa-4 chains of type-IV collagen CSBRP-June-2014
- 91. Chronic Glomerulonephritis • End stage of many glomerulonephritides – MPGN, IgA nephropathy, MGN, RPGN, FSGS • Post Streptococcal GN is rare to end in CGN CSBRP-June-2014
- 92. Primary glomerular diseases leading to chronic glomerulonephritis CSBRP-June-2014
- 93. Chronic Glomerulonephritis Morphology: •Symmetrically contracted kidneys •Granular cortical surface •c/s thinned out cortex •Increase in peripelvic fat •Obliterated glomeruli – hyalinization •Arterial arteriolar sclerosis •Marked atrophy of tubules •Interstitial fibrosis •Mononuclear infiltrate in the Interstitium CSBRP-June-2014
- 95. Granular contracted kidneys Causes: •Chronic glomerulonephritis •Benign nephrosclerosis
- 96. Chronic Glomerulonephritis Morphology: Dialysis changes: •Arterial initmal thickening •Focal calcification •Deposition of calcium oxalate crystals in tubules and interstitium •Acquired cystic disease •Increased number of renal adenomas & carcinomas CSBRP-June-2014
- 97. Chronic Glomerulonephritis Morphology: Uremic complications: •Pericarditis •Secondary hyperparathyroidism •Left ventricular hypertrophy •Diffuse alveolar damage CSBRP-June-2014
- 99. CSBRP-June-2014
- 100. CSBRP-June-2014
- 101. Causes of Nephrotic Syndrome CSBRP-June-2014
- 104. CSBRP-June-2014
- 105. CSBRP-June-2014
- 106. CSBRP-June-2014
- 107. CSBRP-June-2014
- 109. Lupus Nephritis •40-75% SLE cases •Class I – minimal lesion •Class II - Mesangial lupus GN •Class III -Focal segmental GN •Class IV -Diffuse proliferative GN •Class V - Membranous GN •Calss VI – sclerosing lupus nephritis
- 114. Morphology Diabetic Nephropathy: Kidneys are the prime targets of DM Renal failure is the second leading cause of death in DM 3 lesions are encountered: 1-Glomerular lesions 2-Renal vascular lesion 3-Pyelonephritis (necrotizing papillitis)
- 115. Morphology - Diabetic Nephropathy 1- capillary basement membrane thickening 2 -Diffuse mesangial sclerosis 3-Nodular glomerulosclerosis Other changes: -- Renal AS -- Arteriosclerosis -- Pyelonephritis -- Necrotizing papillitis
- 116. Diffuse mesangial sclerosis (DMS): --Diffuse increase in mesangial matrix --Thickening of BM When DMS becomes marked the pateint suffers from Nephrotic syndrome Morphology - Diabetic Nephropathy
- 118. Nodular glomerulosclerosis: Other name: Kimmelsteil-Wisoln’s lesion -- This is very pathognomonic of DM -- It’s the major cause of morbidity & mortality -- Seen in 15-30% of long standing DM Micro: Ball like deposits of a laminated matrix situated in the periphery of the glomerulus Nodules are PAS + also contains trapped mesangial cells This sclerosis induces sufficient ischemia to cause overall fine scarring of the kidneys (finely granular cortical surface) Morphology - Diabetic Nephropathy
- 121. Diabetic Nephropathy • Microalbuminuria (>30 - <300 mg/day)
- 125. How to assess the cellularity of glomeruli ? CSBRP-June-2014
- 126. How to assess the cellularity of glomeruli ? CSBRP-June-2014
- 127. CSBRP-June-2014
- 128. CSBRP-June-2014
- 129. CSBRP-June-2014
- 130. CSBRP-June-2014
- 131. CSBRP-June-2014
- 132. CSBRP-June-2014
- 133. CSBRP-June-2014
Editor's Notes
- FIGURE 20-1 A, Low-power electron micrograph of renal glomerulus. CL, capillary lumen; EP, visceral epithelial cells with foot processes; END, endothelium; MES, mesangium. B, Schematic representation of a glomerular lobe. (A, Courtesy of Dr. Vicki Kelley, Brigham and Women&apos;s Hospital, Boston, MA.)
- Arrows= 20nm Filtration slits with thin diaphragm
- FIGURE 20-2 Glomerular filter consisting, from bottom to top, of fenestrated endothelium, basement membrane, and foot processes of epithelial cells. Note the filtration slits (arrows) and diaphragm situated between the foot processes. Note also that the basement membrane consists of a central lamina densa, sandwiched between two looser layers, the lamina rara interna and lamina rara externa. (Courtesy of Dr. Helmut Rennke, Brigham and Women&apos;s Hospital, Boston, MA.)
- FIGURE 20-3 A simplified schematic diagram of some of the best-studied proteins of the glomerular slit diaphragm. CD2AP, CD2-associated protein
- There is little confusion in the terminology. Best and easy to remember is Fixed and Planted Ags. Fixed = already present in the glomerulus. Planted = not normally present in the glomerulus but are planted there.
- FIGURE 20-5 Localization of immune complexes in the glomerulus: (1) subepithelial humps, as in acute glomerulonephritis; (2) epimembranous deposits, as in membranous nephropathy and Heymann glomerulonephritis; (3) subendothelial deposits, as in lupus nephritis and membranoproliferative glomerulonephritis; (4) mesangial deposits, as in IgA nephropathy; (5) basement membrane. EN, endothelium; EP, epithelium; LD, lamina densa; LRE, lamina rara externa; LRI, lamina rara interna; MC, mesangial cell; MM, mesangial matrix. (Modified from Couser WG: Mediation of immune glomerular injury. J Am Soc Nephrol 1:13, 1990.)
- FIGURE 20-6 Epithelial cell injury. The postulated sequence is a consequence of antibodies specific to epithelial cell antigens, toxins, cytokines, or other factors causing injury; this results in foot process effacement and sometimes detachment of epithelial cells and protein leakage through defective GBM and filtration slits.
- FIGURE 20-7 Mediators of immune glomerular injury including cells and soluble mediators
- Post Streptococcal GN (Old term)
- Post Streptococcal GN (Old term)
- Post Streptococcal GN (Old term)
- Recollect the terms we used in the previous lectures: Diffuse / Focal Global / Segmental
- FIGURE 20-9 Acute proliferative glomerulonephritis. A, Normal glomerulus. B, Glomerular hypercellularity is due to intracapillary leukocytes and proliferation of intrinsic glomerular cells. C, Typical electron-dense subepithelial “hump” and a neutrophil in the lumen. D, Immunofluorescent stain demonstrates discrete, coarsly granular deposits of complement protein C3, corresponding to “humps” illustrated in part C. (A–C, courtesy of Dr. H. Rennke, Brigham and Women&apos;s Hospital, Boston, MA. D, courtesy of D. J. Kowaleska, University of Washington, Seattle, WA.)
- FIGURE 20-10 Crescentic glomerulonephritis (PAS stain). Note the collapsed glomerular tufts and the crescent-shaped mass of proliferating parietal epithelial cells and leukocytes internal to Bowman capsule. (Courtesy of Dr. M.A. Venkatachalam, University of Texas Health Sciences Center, San Antonio, TX.)
- FIGURE 20-11 Crescentic glomerulonephritis. Electron micrograph showing characteristic wrinkling of GBM with focal disruptions (arrows).
- FIGURE 20-11 Crescentic glomerulonephritis. Electron micrograph showing characteristic wrinkling of GBM with focal disruptions (arrows).
- FIGURE 20-12 Membranous nephropathy. A, Silver methenamine stain. Note the marked diffuse thickening of the capillary walls without an increase in the number of cells. There are prominent “spikes” of silver-staining matrix (arrow) projecting from the basement membrane lamina densa toward the urinary space, which separate and surround deposited immune complexes that lack affinity for the silver stain. B, Electron micrograph showing electron-dense deposits (arrow) along the epithelial side of the basement membrane (B). Note the effacement of foot processes overlying deposits. CL, capillary lumen; End, endothelium; Ep, epithelium. C, Characteristic granular immunofluorescent deposits of IgG along GBM. D, Diagrammatic representation of membranous nephropathy. (A, Courtesy of Dr. Charles Lassman, UCLA School of Medicine, Los Angeles, CA.)
- FIGURE 20-12 Membranous nephropathy. A, Silver methenamine stain. Note the marked diffuse thickening of the capillary walls without an increase in the number of cells. There are prominent “spikes” of silver-staining matrix (arrow) projecting from the basement membrane lamina densa toward the urinary space, which separate and surround deposited immune complexes that lack affinity for the silver stain. B, Electron micrograph showing electron-dense deposits (arrow) along the epithelial side of the basement membrane (B). Note the effacement of foot processes overlying deposits. CL, capillary lumen; End, endothelium; Ep, epithelium. C, Characteristic granular immunofluorescent deposits of IgG along GBM. D, Diagrammatic representation of membranous nephropathy. (A, Courtesy of Dr. Charles Lassman, UCLA School of Medicine, Los Angeles, CA.)
- FIGURE 20-12 Membranous nephropathy. A, Silver methenamine stain. Note the marked diffuse thickening of the capillary walls without an increase in the number of cells. There are prominent “spikes” of silver-staining matrix (arrow) projecting from the basement membrane lamina densa toward the urinary space, which separate and surround deposited immune complexes that lack affinity for the silver stain. B, Electron micrograph showing electron-dense deposits (arrow) along the epithelial side of the basement membrane (B). Note the effacement of foot processes overlying deposits. CL, capillary lumen; End, endothelium; Ep, epithelium. C, Characteristic granular immunofluorescent deposits of IgG along GBM. D, Diagrammatic representation of membranous nephropathy. (A, Courtesy of Dr. Charles Lassman, UCLA School of Medicine, Los Angeles, CA.)
- FIGURE 20-13 Minimal-change disease. A, Glomerulus stained with PAS. Note normal basement membranes and absence of proliferation. B, Ultrastructural characteristics of minimal-change disease include effacement of foot processes (arrows) and absence of deposits. CL, capillary lumen; M, mesangium; P, podocyte cell body.
- Recollect the terms we used in the previous lectures: Diffuse / Focal Global / Segmental
- The hyalinosis and sclerosis stem from entrapment of plasma proteins in extremely hyperpermeable foci and increased ECM deposition
- The hyalinosis and sclerosis stem from entrapment of plasma proteins in extremely hyperpermeable foci and increased ECM deposition
- The hyalinosis and sclerosis stem from entrapment of plasma proteins in extremely hyperpermeable foci and increased ECM deposition
- The hyalinosis and sclerosis stem from entrapment of plasma proteins in extremely hyperpermeable foci and increased ECM deposition
- FIGURE 20-14 Focal segmental glomerulosclerosis, PAS stain. A, Low-power view showing segmental sclerosis in one of three glomeruli (at 3 o&apos;clock). B, High-power view showing hyaline insudation and lipid (small vacuoles) in sclerotic area
- FIGURE 20-15 Collapsing glomerulopathy. Visible are retraction of the glomerular tuft, narrowing of capillary lumens, proliferation and swelling of visceral epithelial cells, and prominent accumulation of intracellular protein absorption droplets in the visceral epithelial cells. The appearance is identical in cases wherein the etiology is idiopathic to cases associated with HIV infection. Silver methenamine stain. (Courtesy of Dr. Jolanta Kowalewska, University of Washington, Seattle, WA.)
- FIGURE 20-8 Focal segmental glomerulosclerosis associated with loss of renal mass. The adaptive changes in glomeruli (hypertrophy and glomerular capillary hypertension), as well as systemic hypertension, cause epithelial and endothelial injury and resultant proteinuria. The mesangial response, involving mesangial cell proliferation and ECM production together with intraglomerular coagulation, causes the glomerulosclerosis. This results in further loss of functioning nephrons and a vicious circle of progressive glomerulosclerosis.
- In summary, a pathologic diagnosis of MPGN requires not merely light microscopic recognition of an appropriate pattern of glomerular injury, but, more importantly, specific ultrastructural changes that are the diagnostic features of these diseases. Many types of glomerular disease can produce light microscopic patterns of glomerular injury that mimic MPGN, but the diagnostic term MPGN should be reserved for the specific types of disease just described, and should be further qualified as MPGN type I, MPGN type II or MPGN type III. Otherwise, a diagnosis of MPGN would be of no value for predicting prognosis, identifying possible causes and directing therapy.
- Type-I Planted antigens: HCV, HBV When the deposits in the subepithelial zone are as numerous as in membranous glomerulopathy, the glomerulonephritis may be designated type III membranoproliferative glomerulonephritis or mixed membranous and proliferative glomerulonephritis (although the term type III MPGN also has been used for another patterns of glomerular injury characterized by irregular electron-lucent thickening of glomerular basement membranes).
- FIGURE 20-16 The alternative complement pathway in MPGN. Note that C3NeF, an antibody present in the serum of individuals with membranoproliferative glomerulonephritis, acts at the same step as properdin, serving to stabilize the alternative pathway C3 convertase, thus enhancing C3 activation and consumption, causing hypocomplementemia.
- Type-I Planted antigens: HCV, HBV
- FIGURE 20-18 A, Membranoproliferative glomerulonephritis, type I. Note discrete electron-dense deposits (arrows) incorporated into the glomerular capillary wall between duplicated (split) basement membranes (double arrows), and in mesangial regions (M); CL, capillary lumen. B, Dense-deposit disease (type II membranoproliferative glomerulonephritis). There are markedly dense homogeneous deposits within the basement membrane proper. CL, capillary lumen. In both, mesangial interposition gives the appearance of split basement membranes when viewed in the light microscope. C, 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. (A, Courtesy of Dr. Jolanta Kowalewska, University of Washington, Seattle, WA.)
- FIGURE 20-18 A, Membranoproliferative glomerulonephritis, type I. Note discrete electron-dense deposits (arrows) incorporated into the glomerular capillary wall between duplicated (split) basement membranes (double arrows), and in mesangial regions (M); CL, capillary lumen. B, Dense-deposit disease (type II membranoproliferative glomerulonephritis). There are markedly dense homogeneous deposits within the basement membrane proper. CL, capillary lumen. In both, mesangial interposition gives the appearance of split basement membranes when viewed in the light microscope. C, 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. (A, Courtesy of Dr. Jolanta Kowalewska, University of Washington, Seattle, WA.)
- FIGURE 20-17 Membranoproliferative glomerulonephritis, showing mesangial cell proliferation, increased mesangial matrix (staining black with silver stain), basement membrane thickening with segmental splitting, accentuation of lobular architecture, swelling of cells lining peripheral capillaries, and influx of leukocytes (endocapillary proliferation).
- FIGURE 20-18 A, Membranoproliferative glomerulonephritis, type I. Note discrete electron-dense deposits (arrows) incorporated into the glomerular capillary wall between duplicated (split) basement membranes (double arrows), and in mesangial regions (M); CL, capillary lumen. B, Dense-deposit disease (type II membranoproliferative glomerulonephritis). There are markedly dense homogeneous deposits within the basement membrane proper. CL, capillary lumen. In both, mesangial interposition gives the appearance of split basement membranes when viewed in the light microscope. C, 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. (A, Courtesy of Dr. Jolanta Kowalewska, University of Washington, Seattle, WA.)
- FIGURE 20-18 A, Membranoproliferative glomerulonephritis, type I. Note discrete electron-dense deposits (arrows) incorporated into the glomerular capillary wall between duplicated (split) basement membranes (double arrows), and in mesangial regions (M); CL, capillary lumen. B, Dense-deposit disease (type II membranoproliferative glomerulonephritis). There are markedly dense homogeneous deposits within the basement membrane proper. CL, capillary lumen. In both, mesangial interposition gives the appearance of split basement membranes when viewed in the light microscope. C, 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. (A, Courtesy of Dr. Jolanta Kowalewska, University of Washington, Seattle, WA.)
- FIGURE 20-19 IgA nephropathy. A, Light microscopy showing mesangial proliferation and matrix increase. B, Characteristic deposition of IgA, principally in mesangial regions, detected by immunofluorescence.
- FIGURE 20-19 IgA nephropathy. A, Light microscopy showing mesangial proliferation and matrix increase. B, Characteristic deposition of IgA, principally in mesangial regions, detected by immunofluorescence.
- FIGURE 20-19 IgA nephropathy. A, Light microscopy showing mesangial proliferation and matrix increase. B, Characteristic deposition of IgA, principally in mesangial regions, detected by immunofluorescence.
- FIGURE 20-19 IgA nephropathy. A, Light microscopy showing mesangial proliferation and matrix increase. B, Characteristic deposition of IgA, principally in mesangial regions, detected by immunofluorescence.
- FIGURE 20-19 IgA nephropathy. A, Light microscopy showing mesangial proliferation and matrix increase. B, Characteristic deposition of IgA, principally in mesangial regions, detected by immunofluorescence.
- Normal GBM thickening is 300-4000nm.
- FIGURE 20-21 Primary glomerular diseases leading to chronic glomerulonephritis (GN). The thickness of the arrows reflects the approximate proportion of patients in each group who progress to chronic GN: poststreptococcal (1% to 2%); rapidly progressive (crescentic) (90%), membranous (30% to 50%), focal segmental glomerulosclerosis (50% to 80%), membranoproliferative GN (50%), IgA nephropathy (IgAN, 30% to 50%).
- FIGURE 20-22 Chronic glomerulonephritis. A Masson trichrome preparation shows complete replacement of virtually all glomeruli by blue-staining collagen. (Courtesy of Dr. M.A. Venkatachalam, Department of Pathology, University of Texas Health Sciences Center, San Antonio, TX.)
- Glomerular BM is diffusely thickenend throughout the entire length. (EM can detect this lesion very early before any changes can be appreciated in renal function).
- Source: AFIP fascicle
- Source: AFIP fascicle
- Source: AFIP fascicle.
- Source: AFIP fascicle.
- Source: AFIP fascicle.
- Source: AFIP fascicle.
- Source: AFIP fascicle.
- In the diagram in slide 2 are my conceptions of the major distinctions between the three major categories of FSGS. There is a perihilar predominance of sclerosis in one variant of FSGS, a glomerular tip location for a distinctive injury in the tip lesion variant of FSGS, and a particular type of collapsing pattern of destruction of capillaries and matrix expansion in the collapsing glomerulopathy variant of FSGS.
- The diagram in Picture3 depicts perihilar segmental sclerosis, which is continuous with the afferent arteriole where the blood is coming into the glomerulus. A leading theory for the pathogenesis of this variant is single nephron hypertension, hyperperfusion, hyperfiltration. This is possibly analogous to a small local area of arteriosclerosis (arteriolosclerosis) where plasma constituents are exuding into the glomerular tuft much as plasma proteins exude into the walls of arterioles causing the hyaline arteriolosclerosis of hypertension. The PAS-stained section in Picture 4 shows the perihilar location of sclerosis with hyalinosis and lipids vacuolation and an adhesion to Bowman&apos;s capsule. These are very distinctive and characteristic features of focal segmental glomerulosclerosis, but they are not specific. These features should be present in the absence of any other cause of focal glomerular scarring in order to diagnose FSGS.