Glomerular Diseases Part 1 PDF

Glomerular diseases Dr. Ala Aljehani Outlines: • Structure of the glomerulus • Pathologic Responses of the Glomerulus to Injury Part 1 • Pathogenesis of Glomerular Injury • Nephrotic syndrome • Nephritic syndrome • Rapidly Progressive Glomerulonephritis • Chronic Glomerulonephritis Part 2 Gl...

Glomerular diseases Dr. Ala Aljehani Outlines: • Structure of the glomerulus • Pathologic Responses of the Glomerulus to Injury Part 1 • Pathogenesis of Glomerular Injury • Nephrotic syndrome • Nephritic syndrome • Rapidly Progressive Glomerulonephritis • Chronic Glomerulonephritis Part 2 Glomerular diseases part 1 Structure of the glomerulus Cont. Pathologic Responses of the Glomerulus to Injury Various types of glomerulopathies are characterized by one or more of four basic tissue reactions: • • • • Hypercellularity. Basement Membrane Thickening. Hyalinosis Sclerosis. Hypercellularity Results from one or more of the following: • Proliferation of mesangial or endothelial cells. • Infiltration of leukocytes (The combination of infiltration of leukocytes and swelling and proliferation of mesangial and/or endothelial cells is often referred to as endocapillary proliferation. • Formation of crescents. These are accumulations of cells composed of proliferating glomerular epithelial cells (predominately parietal but including some visceral cells) and infiltrating leukocytes. Basement membrane thickening • By electron microscopy such thickening takes one of three forms: 1. Deposition of amorphous electron-dense material, most often immune complexes, on the endothelial or epithelial side of the basement membrane or within the GBM itself. • Fibrin, amyloid, cryoglobulins, and abnormal fibrillary proteins may also deposit in the GBM. Cont. • By electron microscopy such thickening takes one of three forms: 2. Increased synthesis of the protein components of the basement membrane, as occurs in diabetic glomerulosclerosis. 3. Formation of additional layers of basement membrane matrices, (often occupy subendothelial locations) as occurs in membranoproliferative glomerulonephritis Hylanosis • The accumulation of material that is homogeneous and eosinophilic by LM (extracellular and amorphous) • It is made up of plasma proteins that have insudated from the circulation into glomerular structures • It is a consequence of endothelial or capillary wall injury • When extensive → obliteration of the capillary lumens of the glomerular tuft Sclerosis • characterized by deposition of extracellular collagenous matrix. • It may be confined to mesangial areas (diabetic glomerulosclerosis) involve the capillary loops, or both. • May also result in obliteration of some or all of the capillary lumens in affected glomeruli. Pathogenesis of glomerular injury Pathogenesis of Glomerular Injury • Although much remains unknown about etiologic agents and triggering events, it is clear that immune mechanisms underlie most forms of primary glomerulopathy and many of the secondary glomerular disorders Cont. Pathogenesis of Glomerular Injury Two forms of antibody-associated injury have been established: 1. injury by antibodies reacting in situ within the glomerulus, either binding to insoluble fixed (intrinsic) glomerular antigens or extrinsic molecules planted within the glomerulus. 2. injury resulting from deposition of circulating antigen-antibody complexes in the glomerulus. Pathogenesis of Glomerular Injury Figure 20-4 Antibody-mediated glomerular injury can result either from the deposition of circulating immune complexes (A) more commonly, from in situ formation of complexes exemplified by anti-GBM disease (B) or Heymann nephritis (C) or, Mechanisms of Glomerular Injury Following Immune Complex Formation Electron microscopy reveals electron-dense deposits, presumably containing immune complexes, that may lie in: • the mesangium • between the endothelial cells and the GBM (subendothelial deposits) • between the outer surface of the GBM and the podocytes (subepithelial deposits) subepithelial humps subendothelial deposits mesangial deposits Cont. • Factors affect glomerular localization of antigen, antibody or immune complexes: • molecular charge and size • changes in glomerular hemodynamics, mesangial function, and integrity of the charge-selective barrier in the glomerulus. • In turn, the distinct patterns of localization of immune complexes is a key determinant of the injury response and the histologic features that subsequently develop. Activation of Alternative Complement Pathway Alternative complement pathway activation occurs in the clinicopathologic entity called dense-deposit disease, until recently referred to as membranoproliferative glomerulonephritis Mediators of Glomerular Injury Epithelial Cell Injury • Podocyte injury is common to many forms of both primary and secondary glomerular diseases, of both immune and non-immune etiologies. • The term podocytopathy has been applied to diseases with disparate etiologies whose principal manifestation is injury to podocytes Mechanisms of Progression in Glomerular Diseases The outcome of such injury depends on several factors, including: • the severity of renal damage • the nature and persistence of the antigens • the immune status, age, and genetic predisposition of the host. Clinical presentation Nephrotic syndrome Pathophysiology of nephrotic syndrome • Nephrotic syndrome is caused by a derangement in glomerular capillary walls resulting in increased permeability to plasma proteins. • The manifestations of the syndrome include: • Massive proteinuria, with the daily loss of 3.5 gm or more of protein (less in children) • Hypoalbuminemia, with plasma albumin levels less than 3 gm/dL • Generalized edema • Hyperlipidemia and lipiduria Cont. pathophysiology • A disturbance in the capillary walls of the glomeruli → ↑permeability to plasma proteins → ↓serum albumin → hypoalbuminemia → ↓ plasma colloid osmotic pressure and retention of salt and water by the kidney → generalized edema • The genesis of the hyperlipidemia: • Hypoalbuminemia → ↑synthesis of lipoproteins in the liver • The lipiduria reflects the increased permeability of the GBM to lipoproteins • Nephrotic patients are particularly vulnerable to infection, especially staphylococcal and pneumococcal infections, probably due to loss of immunoglobulins in the urine and vulnerable to thrombotic and thromboembolic complications Causes Membranous Nephropathy Pathophysiology of Membranous nephropathy MG • It is characterized by diffuse thickening of the glomerular capillary wall due to the accumulation of deposits containing Ig along the subepithelial side of the basement membrane. • The glomerular capillary wall become leaky due to a direct action of the membrane attack complex (MAC) • The MAC causes activation of mesangial cells and podocytes → liberate proteases and oxidants that can damage capillary walls 75% primary secondary drugs malignant tumors SLE Infections autoimmune disorders Morphology • light microscopy : • Exhibit uniform, diffuse thickening of the glomerular capillary wall • Basement membrane material is laid down between these deposits, appearing as irregular spikes protruding from the GBM. These spikes are best seen by silver stains Morphology • Electron microscopy: • Subepithelial deposits • mmunofluorescence microscopy: • Granular deposits Clinical course • Usually presents with the insidious onset of the nephrotic syndrome • 15% of patients present with non-nephrotic proteinuria. • Hematuria and mild hypertension are present in 15% to 35% of cases. • Rule out secondary causes Clinical course • Does not respond well to corticosteroid therapy. • Complete or partial remissions may occur in up to 40% of patients, even in some patients without therapy. • The disease recurs in up to 40% of patients who undergo transplantation for end-stage renal disease Minimal-Change Disease Pathophysiology • This relatively benign disorder is characterized by diffuse effacement of foot processes of visceral epithelial cells (podocytes), detectable only by electron microscopy, in glomeruli that appear virtually normal by light microscopy. Morphology • light microscopy: • The glomeruli are normal • electron microscopy • the GBM appears normal, and no electrondense material is deposited • uniform and diffuse effacement of foot processes • Immunofluorescence studies • show no Ig or complement deposits. Clinical features • The most frequent cause of the nephrotic syndrome in children • Usually response dramatically to corticosteroid therapy. • Most children (>90%) respond rapidly to this treatment. However, proteinuria may recur • Some patients may become steroid-dependent or resistant • Adults are slower to respond, their long term prognosis is also excellent. • Minimal-change disease in adults can be associated with Hodgkin lymphoma Focal Segmental Glomerulosclerosis (FSGS) Pathophysiology • The characteristic degeneration and focal disruption of visceral epithelial cells with effacement of foot processes resemble the diffuse epithelial cell change typical of minimal-change disease and other podocytopathies is the hallmark of FSGS • FSGS classified into: • primary (idiopathic) • secondary to other conditions Morphology • light microscopy • focal and segmental lesions may inolve only a minority of the glomeruli • In the sclerotic segments there is • collapse of capillary loops • increase in matrix • segmental deposition of plasma proteins along the capillary wall (hyalinosis) • Lipid deposition • electron microscopy : • both sclerotic and nonsclerotic areas show diffuse effacement of foot processes • immunofluorescence microscopy: • IgM and C3 may be present in the sclerotic areas and/or in the mesangium. Clinical features • Primary focal segmental glomerulosclerosis is the most common cause of nephrotic syndrome in adults in the United States • Accounts for 10% and 35% of cases of nephrotic syndrome in children and adults, respectively. • Is frequently manifest clinically by the acute or subacute onset of nephrotic syndrome or nonnephrotic proteinuria. • Hypertension, microscopic hematuria, and some degree of azotemia are commonly present when the disease is first clinically recognized. Cont. • Little tendency for spontaneous remission in idiopathic FSGS, and responses to corticosteroid therapy are variable. • Children have a better prognosis than adults do. • Progression to renal failure occurs at variable rates.