Kidney Diseases (Part 1) PDF

THE KIDNEY (PART 1) Alexander C. Florentino, RMT, MD, DPSP I. Clinical Manifestations of B. Rapidly Progressive (Crescentic) Glomerulonephritis Renal Diseases VII....

THE KIDNEY (PART 1) Alexander C. Florentino, RMT, MD, DPSP I. Clinical Manifestations of B. Rapidly Progressive (Crescentic) Glomerulonephritis Renal Diseases VII. A. Nephrotic Syndrome Membranous Nephropathy II. Glomerular Diseases B. Minimal-Change Disease C. Focal Segmental Glomerulosclerosis (FSGS) III. Pathologic Responses of the Glomerulus to Injury D. Membranoproliferative Glomerulonephritis (MPGN) IV. Pathogenesis of Glomerular Injury E. Dense Deposit Disease A. Diseases Caused by In Situ Formation of Immune Complexes VIII. Isolated Glomerular Abnormalities B. Disease Caused by Antibodies Directed Against Normal A. IgA Nephropathy (Berger Disease) Components of the Glomerular Basement Membrane B. Hereditary Nephritis C. Glomerulonephritis Resulting from Deposition of Circulating Immune Complexes IX. Chronic Glomerulonephritis D. Mediation of Glomerular Injury Following Immune Complex Formation X. Glomerular Lesions Associated with Systemic E. Cell-Mediated Immunity in Glomerulonephritis Diseases A. Lupus Nephritis F. Activation of Alternative Complement Pathway B. Henoch-Schönlein Purpura G. Mediators of Glomerular Injury C. Glomerulonephritis Associated with Bacterial H. Epithelial Cell Injury Endocarditis and Other Systemic Infections V. Mechanisms of Progression in Glomerular Diseases D. Diabetic Nephropathy E. Fibrillary Glomerulonephritis VI. Nephritic Syndrome F. Other Systemic Disorders A. Acute Proliferative (Poststreptococcal, Postinfectious) Glomerulonephritis  CLINICAL MANIFESTATIONS OF RENAL DISEASES Azotemia BUN and Creatinine level elevation due to decreased GFR Feature of both acute and chronic injury Prerenal – hypoperfusion of kidneys Postrenal – urine flow is obstructed distal to the kidney Uremia Azotemia + clinical S/Sx + biochemical abnormalities Char: failure of renal excretory function + metabolic and endocrine alterations due to renal damage Secondary involvement: GIT: uremic gastroenteritis Peripheral nerves: peripheral neuropathy Heart: uremic fibrinous pericarditis Nephritic syndrome Caused by inflammatory glomerular disease Acute onset of grossly visible hematuria OR microscopic hematuria with dysmorphic red cells and red cell casts on urinalysis Diminished GFR (Azotemia) Mild to moderate proteinuria Hypertension The classic presentation of acute PSGN RPGN is char. as a nephritic syndrome with rapid decline in GFR (within hours to days). Nephritic syndrome Caused by: Postinfectious glomerulonephritis (GN) Crescentic GN SLE Nephrotic syndrome Due to glomerular disease Heavy proteinuria (more than 3.5 gm/day) Hypoalbuminemia Severe edema Hyperlipidemia Lipiduria (lipid in the urine) Nephrotic syndrome Most important of the primary glomerular lesions: Focal segmental glomerulosclerosis (FSGS) – adult Minimal change disease – children Primary kidney dse Membranous nephropathy Membranoproliferative glomerulonephritis Complication of DM Asymptomatic hematuria and/or proteinuria Manifestation of subtle or mild glomerular abnormalities Typical clinical presentation of: IgA nephropathy Alport syndrome Mild forms or early presentations of other glomerular diseases Acute kidney injury (AKI) Result from glomerular, interstitial, vascular or acute tubular injury. Characterized by: Rapid decline in GFR (within hours to days) Concurrent dysregulation of fluid and electrolyte balance Retention of urea and creatinine If severe → oliguria or anuria Chronic Kidney Disease Defined as presence of a diminished GFR that is persistently less than 60 mL/minute/1.73 m2 for at least 3 months, from any cause, and/or persistent albuminuria end result of all chronic renal parenchymal diseases. End-stage renal disease (ESRD) GFR < 5% of normal Terminal stage of uremia Renal tubular defects Dominated by polyuria, nocturia, and electrolyte disorders* Caused by diseases that either: Directly affect tubular structures* Cause defects in specific tubular functions. Defects in tubular function may be : Inherited (e.g., familial nephrogenic diabetes, cystinuria, renal tubular acidosis) Acquired (e.g., lead nephropathy) Urinary tract obstruction and renal tumors Urinary tract infection is characterized by bacteriuria and pyuria (bacteria and leukocytes in the urine) May be a/symptomatic May affect the kidney (pyelonephritis) or the bladder (cystitis). Nephrolithiasis (renal stones) spasms of severe pain (renal colic) and hematuria often with recurrent stone formation.  Clinical Manifestations of Renal Diseases Nephrotic Syndrome Membranous Nephropathy Glomerular Diseases Minimal-Change Disease Focal Segmental Glomerulosclerosis (FSGS) Pathologic Responses of the Glomerulus to Injury Membranoproliferative Glomerulonephritis (MPGN) Pathogenesis of Glomerular Injury Dense Deposit Disease Diseases Caused by In Situ Formation of Immune Complexes Isolated Glomerular Abnormalities Disease Caused by Antibodies Directed Against Normal IgA Nephropathy (Berger Disease) Components of the Glomerular Basement Membrane Hereditary Nephritis Glomerulonephritis Resulting from Deposition of Circulating Immune Complexes Chronic Glomerulonephritis Mediation of Glomerular Injury Following Immune Complex Formation Glomerular Lesions Associated with Systemic Diseases Lupus Nephritis Cell-Mediated Immunity in Glomerulonephritis Henoch-Schönlein Purpura Activation of Alternative Complement Pathway Glomerulonephritis Associated with Bacterial Endocarditis Mediators of Glomerular Injury and Other Systemic Infections Epithelial Cell Injury Diabetic Nephropathy Fibrillary Glomerulonephritis Mechanisms of Progression in Glomerular Diseases Other Systemic Disorders 926 Nephritic Syndrome Acute Proliferative (Poststreptococcal, Postinfectious) Glomerulonephritis Rapidly Progressive (Crescentic) Glomerulonephritis GLOMERULAR DISEASES Primary glomerulopathies Classified by histology Subdivided into: 1. Diffuse – all glomeruli 2. Global – entirety of individual glomeruli 3. Focal – fraction of glomeruli 4. Segmental – part of each glomerulus 5. Capillary loop or mesangial – predominantly capillary or mesangial regions Primary versus secondary  Clinical Manifestations of Renal Diseases Rapidly Progressive (Crescentic) Glomerulonephritis Glomerular Diseases Nephrotic Syndrome Membranous Nephropathy Pathologic Responses of the Minimal-Change Disease Glomerulus to Injury Focal Segmental Glomerulosclerosis (FSGS) Membranoproliferative Glomerulonephritis (MPGN) Pathogenesis of Glomerular Injury Dense Deposit Disease Diseases Caused by In Situ Formation of Immune Complexes Isolated Glomerular Abnormalities Disease Caused by Antibodies Directed Against Normal IgA Nephropathy (Berger Disease) Components of the Glomerular Basement Membrane Hereditary Nephritis Glomerulonephritis Resulting from Deposition of Circulating Immune Complexes Chronic Glomerulonephritis Mediation of Glomerular Injury Following Immune Complex Formation Glomerular Lesions Associated with Systemic Diseases Cell-Mediated Immunity in Glomerulonephritis Lupus Nephritis Activation of Alternative Complement Pathway Henoch-Schönlein Purpura Mediators of Glomerular Injury Glomerulonephritis Associated with Bacterial Endocarditis and Other Systemic Infections Epithelial Cell Injury Diabetic Nephropathy Mechanisms of Progression in Glomerular Diseases Fibrillary Glomerulonephritis Other Systemic Disorders 926 Nephritic Syndrome Acute Proliferative (Poststreptococcal, Postinfectious) Glomerulonephritis PATHOLOGIC RESPONSES OF THE GLOMERULUS TO INJURY 4 basic tissue reactions: 1. Hypercellularity 2. BM thickening 3. Hyalinosis 4. Sclerosis Hypercellularity Char.: increase in the number of cells in the glomerular tufts 1. Proliferation of mesangial or endothelial cells 2. Infiltration of leukocytes Endocapillary proliferation = #1 + #2 3. Formation of crescents Proliferating glomerular ECs and infiltrating WBCs Following an immune/inflammatory injury involving the capillary walls Basement Membrane thickening LM: Thickening of the capillary walls EM: 3 forms; 1. Deposition of immune complexes on the endothelial or epithelial side of the BM or within the GBM itself. 2. Increased synthesis of the protein components of the BM (diabetic GS) 3. Formation of additional layers of BM matrices (membrano- proliferative GN) Hyalinosis LM: accumulation of homogeneous and eosinophilic material Hyaline - extracellular, amorphous material composed of plasma proteins that have insudated from the circulation into glomerular structures; may obliterate capillary lumen of glomerular tuft consequence of endothelial or capillary wall injury Sclerosis Char: deposition of extracellular collagenous matrix Confined to mesangial areas (diabetic glomerulosclerosis), involve the capillary loops, or both. May lead to capillary lumen obliteration  Clinical Manifestations of Renal Diseases Mechanisms of Progression in Glomerular Diseases Glomerular Diseases Nephritic Syndrome Acute Proliferative (Poststreptococcal, Postinfectious) Structure of the Glomerulus Glomerulonephritis Rapidly Progressive (Crescentic) Glomerulonephritis Pathologic Responses of the Glomerulus to Injury Nephrotic Syndrome Pathogenesis of Glomerular Injury Membranous Nephropathy 1. Diseases Caused by In Situ Formation of Minimal-Change Disease Immune Complexes Focal Segmental Glomerulosclerosis (FSGS) Membranoproliferative Glomerulonephritis (MPGN) 2. Disease Caused by Antibodies Directed Against Normal Components of the Dense Deposit Disease Glomerular Basement Membrane Isolated Glomerular Abnormalities 3. Glomerulonephritis Resulting from IgA Nephropathy (Berger Disease) Deposition of Circulating Immune Hereditary Nephritis Complexes Chronic Glomerulonephritis 4. Mediation of Glomerular Injury Following Immune Complex Formation Glomerular Lesions Associated with Systemic Diseases Lupus Nephritis 5. Cell-Mediated Immunity in Henoch-Schönlein Purpura Glomerulonephritis Glomerulonephritis Associated with Bacterial Endocarditis and Other 6. Activation of Alternative Complement Systemic Infections Pathway Diabetic Nephropathy 7. Mediators of Glomerular Injury Fibrillary Glomerulonephritis Other Systemic Disorders 926 8. Epithelial Cell Injury  PATHOGENESIS OF GLOMERULAR INJURY Immune mechanisms underlie most forms of primary glomerulopathy and many of the secondary glomerular disorders Two forms of Ab-associated injury 1. Antibodies reacting in-situ within the glomerulus either binding to insoluble fixed (intrinsic) glomerular Ags OR extrinsic molecules planted within the glomerulus major cause of GN resulting from formation of Ag-Ab complexes 2. Deposition of circulating Ag-Ab complexes in the glomerulus 1) Diseases Caused by In Situ Formation of Immune Complexes Immune complexes formed locally by Abs that react with intrinsic tissue Ags or with extrinsic Ags “planted” in glomerulus from circulation 1) Diseases Caused by In Situ Formation of Immune Complexes Antibody binding to PLA2R (in glomerular epithelial cell membrane) → complement activation → shedding of the immune aggregates → characteristic deposits of immune complexes along subepithelial aspect of BM 1) Diseases Caused by In Situ Formation of Immune Complexes Antibodies against planted antigens Cationic molecules: bind to anionic components of the glomerulus DNA, nucleosomes, and other nuclear proteins: affinity for GBM components bacterial products large aggregated proteins (e.g., IgG), which deposit in the mesangium immune complexes themselves  The pattern of immune deposition by immunofluorescence (IF) microscopy is granular rather than linear, reflective of the very localized antigen- antibody interaction. 2) Anti-GBM Ab-mediated GN Abs bind to intrinsic antigens on GBM →diffuse linear pattern of staining for the antibodies by IF These intrinsic, fixed antigens cannot be mobilized to form large, discrete complexes. 2) Anti-GBM Ab-mediated GN Anti-GBM antibodies cross-react with other BM, esp. lung alveoli, resulting in simultaneous lung and kidney lesions (Goodpasture syndrome) Known Ag target of anti-GBM antibodies - α3 chain of the type IV collagen of the GBM 2) Anti-GBM Ab-mediated GN Causes severe necrotizing and crescentic glomerular damage and the clinical syndrome of rapidly progressive glomerulonephritis 3) Glomerulonephritis Resulting from Deposition of Circulating Immune Complexes Injury caused by trapping of circulating Ag-Ab complexes w/in glomeruli → complement activation, WBC recruitment Abs have no immunologic specificity for glomerular constituents Complexes localize within the glomeruli Ag may be endogenous (SLE, IgA nephropathy) or exogenous (post-infection) 3) Glomerulonephritis Resulting from Deposition of Circulating Immune Complexes EM: electron-dense immune deposits in one or more of three locations: 1. Between endothelial cells and GBM – subendothelial deposits 2. Between outer surface of GBM and podocytes – subepithelial deposits 3. Mesangium 4) Mechanisms of Glomerular Injury Following Immune Complex Formation Ag-Ab complexes formed/deposited in the glomeruli → local inflammatory reaction → injury Glomerular lesions exhibit leukocytic infiltration and proliferation of mesangial and endothelial cells. EM: electron-dense deposits, presumably containing immune complexes 4) Mechanisms of Glomerular Injury Following Immune Complex Formation In summary: Most cases of immune complex mediated GN are a consequence of deposition of discrete immune complexes, which give rise to granular immunofluorescence staining along the basement membranes or in the mesangium 5) Cell-Mediated Immunity in Glomerulonephritis Sensitized T cells cause glomerular injury Evidence is still lacking 6) Activation of Alternative Complement Pathway GN Dense-deposit disease, recently referred to as membranoproliferative glomerulonephritis (MPGN type II) C3 glomerulopathies Systemic disease complement-mediated thrombotic microangiopathy [TMA] or atypical hemolytic uremic syndrome  7) MEDIATORS OF GLOMERULAR INJURY Cells Neutrophils and monocytes Neutrophils release: Proteases→ GBM degradation Oxygen-derived free radicals → cell damage Arachidonic acid metabolites → reductions in GFR Macrophages and T lymphocytes infiltrate the glomerulus in antibody- and cell-mediated reactions Cells Platelets Aggregate in the glomerulus during immune-mediated injury Release of eicosanoids, growth factors and other mediators → vascular injury and proliferation of glomerular cells. Resident glomerular cells – mesangial cells Produce inflammatory mediators reactive oxygen species (ROS), cytokines, chemokines, growth factors, eicosanoids, nitric oxide, and endothelin Soluble mediators Complement activation Generation of chemotactic products that induce complement neutrophil–dependent injury and formation of C5b-C9, the membrane attack complex MAC – cell lysis & stimulates mesangial cells to produce oxidants, proteases, and other mediators MAC can cause proteinuria Eicosanoids, nitric oxide, angiotensin, and endothelin → hemodynamic changes Cytokines - IL-1 and TNF: induce leukocyte adhesion  Soluble mediators Chemokines Monocyte chemoattractant protein 1 → monocyte and lymphocyte influx Growth factors → mesangial cell proliferation TGF-β, connective tissue growth factor, and fibroblast growth factor seem to be critical in the ECM deposition and hyalinization → glomerulosclerosis in chronic injury. Coagulation system Mediator of glomerular damage Fibrin is frequently present in the glomeruli and Bowman space in GN 8) EPITHELIAL CELL INJURY  Epithelial cell injury Podocyte injury – Morphologic change: effacement of foot processes, vacuolization, and retraction and detachment of cells from the GBM Functional change: proteinuria  Clinical Manifestations of Renal Diseases Acute Proliferative (Poststreptococcal, Postinfectious) Glomerulonephritis Glomerular Diseases Rapidly Progressive (Crescentic) Glomerulonephritis Structure of the Glomerulus Nephrotic Syndrome Pathologic Responses of the Glomerulus to Injury Membranous Nephropathy Minimal-Change Disease Pathogenesis of Glomerular Injury Focal Segmental Glomerulosclerosis (FSGS) Diseases Caused by In Situ Formation of Immune Membranoproliferative Glomerulonephritis (MPGN) Complexes Disease Caused by Antibodies Directed Against Normal Dense Deposit Disease Components of the Glomerular Basement Membrane Glomerulonephritis Resulting from Deposition of Isolated Glomerular Abnormalities Circulating Immune Complexes IgA Nephropathy (Berger Disease) Mediation of Glomerular Injury Following Immune Hereditary Nephritis Complex Formation Cell-Mediated Immunity in Glomerulonephritis Chronic Glomerulonephritis Activation of Alternative Complement Pathway Glomerular Lesions Associated with Systemic Diseases Mediators of Glomerular Injury Lupus Nephritis Epithelial Cell Injury Henoch-Schönlein Purpura Glomerulonephritis Associated with Bacterial Endocarditis Mechanisms of Progression and Other Systemic Infections Diabetic Nephropathy in Glomerular Diseases Fibrillary Glomerulonephritis Other Systemic Disorders 926 Nephritic Syndrome  MECHANISMS OF PROGRESSION IN GLOMERULAR DISEASES case Mechanisms of Progression in Glomerular Diseases Two major histologic characteristics: 1. Focal segmental glomerulosclerosis (FSGS) 2. Tubulointerstitial fibrosis. Focal Segmental Glomerulosclerosis (FSGS) Progressive fibrosis involving portions of some glomeruli → proteinuria and increasing functional impairment. → Adaptive change of unaffected glomeruli compensatory hypertrophy with hemodynamic changes Tubulointerstitial Fibrosis Manifested by tubular damage and interstitial inflammation Component of many acute and chronic glomerulonephritides Much better correlation of decline in renal function with the extent of tubulointerstitial damage than with the severity of glomerular injury  Clinical Manifestations of Renal Diseases 2. Rapidly Progressive (Crescentic) Glomerular Diseases Glomerulonephritis Pathologic Responses of the Glomerulus to Injury Nephrotic Syndrome Membranous Nephropathy Pathogenesis of Glomerular Injury Minimal-Change Disease Diseases Caused by In Situ Formation of Immune Complexes Focal Segmental Glomerulosclerosis (FSGS) Disease Caused by Antibodies Directed Against Normal Membranoproliferative Glomerulonephritis (MPGN) Components of the Glomerular Basement Membrane Dense Deposit Disease Glomerulonephritis Resulting from Deposition of Circulating Immune Complexes Isolated Glomerular Abnormalities Mediation of Glomerular Injury Following Immune IgA Nephropathy (Berger Disease) Complex Formation Hereditary Nephritis Cell-Mediated Immunity in Glomerulonephritis Activation of Alternative Complement Pathway Chronic Glomerulonephritis Mediators of Glomerular Injury Glomerular Lesions Associated with Systemic Diseases Epithelial Cell Injury Lupus Nephritis Henoch-Schönlein Purpura Mechanisms of Progression in Glomerular Diseases Glomerulonephritis Associated with Bacterial Endocarditis and Other Systemic Infections Nephritic Syndrome Diabetic Nephropathy 1. Acute Proliferative Fibrillary Glomerulonephritis (Poststreptococcal, Postinfectious) Other Systemic Disorders 926 Glomerulonephritis NEPHRITIC SYNDROME Nephritic syndrome Char.: inflammation in the glomeruli. S/Sx: hematuria, red cell casts in the urine, azotemia, oliguria, and mild to moderate hypertension Proteinuria and edema are common (not severe) Characteristic of acute proliferative and exudative glomerulonephritis 1) Acute Proliferative (Poststreptococcal, Postinfectious) Glomerulonephritis Char.: diffuse proliferation of glomerular cells associated with influx (exudation) of leukocytes Caused by immune complexes May be exogenous or endogenous Exogenous antigen-induced disease pattern is postinfectious glomerulonephritis Endogenous antigen-induced disease is the nephritis of SLE Most common underlying infections are streptococcal Poststreptococcal Glomerulonephritis Prototypical glomerular disease of immune complex etiology Appears 1 to 4 weeks after a streptococcal infection of the pharynx or skin (impetigo) Children: 6 to 10 years of age Etiology and pathogenesis Cause: immune complexes w/ streptococcal Ag-Ab (formed in situ) Group A β-hemolytic streptococci 90% are types 12, 4, and 1 (M protein of bacterial cell wall) Streptococcal pyrogenic exotoxin B (SpeB) as the principal antigenic determinant Activate complement Secreted by nephritogenic strains of streptococci Char:. Localized to the “humplike” deposits Morphology Light microscopy: Enlarged, hypercellular glomeruli Hypercellularity due to: 1. Infiltration by WBC – global, diffuse, involving all lobules of all glomeruli 2. Endothelial and mesangial cells proliferation 3. crescent formation (if severe) Capillary lumen obliteration, interstitial edema and inflammation, red cell casts in tubules Morphology Immunofluorescence microscopy: Granular deposits of IgG, and C3, and sometimes IgM in mesangium and along GBM Electron microscopy: discrete, amorphous, electron-dense deposits on the epithelial side of the membrane, often having the appearance of “humps” Clinical Features Young child Malaise, fever, nausea, oliguria, and hematuria (smoky or cola- colored urine) 1 to 2 weeks after recovery from a sore throat. Dysmorphic RBCs or RBC casts in the urine, mild proteinuria (usually less than 1 gm/day), periorbital edema, and mild to moderate hypertension. 95% recover with proper hydration Prolonged and persistent heavy proteinuria and abnormal GFR = unfavorable prognosis. Clinical course Adults – atypical presentation Sudden appearance of hypertension or edema Frequently with elevation of BUN GN is subclinical; discovered only on screening for microscopic hematuria Less benign; 60% recover Persistent proteinuria, hematuria, and hypertension = unresolved Clinical course Laboratory findings: Elevations of antistreptococcal antibody (ASO) titers Decline in the serum concentration of C3 and other components of the complement cascade. Nonstreptococcal Acute Glomerulonephritis (Postinfectious Glomerulonephritis) Bacterial (e.g., staphylococcal endocarditis, pneumococcal pneumonia, and meningococcemia) Viral (e.g., hepatitis B, hepatitis C, mumps, HIV infection, varicella, and infectious mononucleosis) Parasitic (malaria, toxoplasmosis) Granular immunofluorescent deposits and subepithelial humps characteristic of immune complex nephritis are present. 2) Rapidly Progressive (Crescentic) Glomerulonephritis Syndrome associated with severe glomerular injury, but does not denote a specific etiologic form of GN Char: rapid and progressive loss of renal function associated with severe oliguria and signs of nephritic syndrome Death from renal failure occurs within weeks to months if untreated Most common histologic picture: presence of crescents in most of the glomeruli Classification 3 groups on the basis of immunologic findings Common denominator in all types is severe glomerular injury Classification and Pathogenesis Pathogenesis 1. Anti-GBM antibody-mediated disease (type I) Char: linear deposits of IgG and C3 in the GBM Anti-GBM antibodies cross-react with pulmonary alveolar BM → pulmonary hemorrhage associated with renal failure (Goodpasture syndrome). Tx: Plasmapheresis – remove the pathogenic circulating antibodies Pathogenesis 2. Diseases caused by immune complex deposition (type II) Complication of any of the immune complex nephritides postinfectious GN, lupus nephritis, IgA nephropathy, and Henoch- Schönlein purpura. IF: granular pattern of staining characteristic of immune complex deposition Plasmapheresis not effective Treat underlying disease Pathogenesis 3. Pauci-immune RPGN (type III) Lack of detectable anti-GBM Abs or immune complexes (IF & EM) Have circulating anti-neutrophil cytoplasmic antibodies (ANCAs) that produce cytoplasmic (c) or perinuclear (p) staining pattern May be a component of a systemic vasculitis or idiopathic ANCAs - highly sensitive diagnostic marker Summary 20%: anti-GBM antibody-mediated GN without lung involvement 25%: immune complex-mediated crescentic glomerulonephritis 55%: remainder are of the pauci-immune type Morphology Kidneys are enlarged and pale with petechial hemorrhages on the cortical surfaces Segmental glomerular necrosis adjacent to uninvolved glomerular segments is the feature most typical of pauci-immune RPGN Morphology LM: dominated by distinctive crescents Proliferation of parietal cells and by migration of monocytes and macrophages into the urinary space Fibrin strands are frequently prominent between the cellular layers in the crescents Morphology Immunofluorescence microscopy: Immune complex-mediated cases show granular immune deposits Goodpasture syndrome cases show linear GBM fluorescence for Ig and complement Pauci-immune cases have little or no deposition of immune reactants Morphology Electron microscopy Regardless of type Ruptures in the GBM Severe injury that allows leukocytes, plasma proteins, and inflammatory mediators to reach the urinary space → crescent formation Clinical course All forms: hematuria with RBC casts in the urine, moderate proteinuria occasionally reaching the nephrotic range, and variable hypertension and edema. Progressive (weeks) → severe oliguria Goodpasture syndrome: dominated by recurrent hemoptysis or even life-threatening pulmonary hemorrhage Dx: Serum analyses for anti-GBM antibodies, antinuclear antibodies, and ANCAs Clinical course Tx:early intensive plasmapheresis (plasma exchange) + steroids and cytotoxic agents in Goodpasture syndrome Chronic dialysis or transplantation, if late stage.  Clinical Manifestations of Renal Diseases Nephrotic Syndrome Glomerular Diseases 1. Membranous Nephropathy Structure of the Glomerulus 2. Minimal-Change Disease Pathologic Responses of the Glomerulus to Injury 3. Focal Segmental Glomerulosclerosis (FSGS) Pathogenesis of Glomerular Injury Diseases Caused by In Situ Formation of Immune Complexes 4. Membranoproliferative Disease Caused by Antibodies Directed Against Normal Glomerulonephritis (MPGN) Components of the Glomerular Basement Membrane 5. Dense Deposit Disease Glomerulonephritis Resulting from Deposition of Circulating Immune Complexes Isolated Glomerular Abnormalities Mediation of Glomerular Injury Following Immune Complex IgA Nephropathy (Berger Disease) Formation Hereditary Nephritis Cell-Mediated Immunity in Glomerulonephritis Activation of Alternative Complement Pathway Chronic Glomerulonephritis Mediators of Glomerular Injury Glomerular Lesions Associated with Systemic Diseases Epithelial Cell Injury Lupus Nephritis Henoch-Schönlein Purpura Mechanisms of Progression in Glomerular Diseases Glomerulonephritis Associated with Bacterial Endocarditis Nephritic Syndrome and Other Systemic Infections Acute Proliferative (Poststreptococcal, Postinfectious) Diabetic Nephropathy Glomerulonephritis Fibrillary Glomerulonephritis Rapidly Progressive (Crescentic) Glomerulonephritis Other Systemic Disorders 926 NEPHROTIC SYNDROME Pathophysiology Caused by a derangement in glomerular capillary walls resulting in increased permeability to plasma proteins Manifestations: Massive proteinuria, with the daily loss of 3.5 gm or more of protein (less in children) Hypoalbuminemia, with plasma albumin levels