Nephrotic Syndrome PDF

NEPHROTIC SYNDROME PROF DR SUZAN KATO PROFESSOR OF PATHOLOGY  Normal and abnormal proteinuria Normal urine contains Low molecular weight proteins filtered across the GCW and not reabsorbed by tubular cells Tamm–Horsfall protein secreted by tubular cells, 2/3 of the initial resp...

NEPHROTIC SYNDROME PROF DR SUZAN KATO PROFESSOR OF PATHOLOGY  Normal and abnormal proteinuria Normal urine contains Low molecular weight proteins filtered across the GCW and not reabsorbed by tubular cells Tamm–Horsfall protein secreted by tubular cells, 2/3 of the initial responders < 5% develop chronic kidney disease. Focal segmental glomerulosclerosis (FSGS) FSGS is characterized by sclerosis of some (but not all) glomeruli that involves only a part of each affected glomerulus. FSGS may be primary (idiopathic) or secondary Primary (idiopathic) disorder The most common cause of adult NS Accounts for 20-30% of all cases. It is common in adults and a frequent cause in children.  Secondary to Mutations of proteins that ▪ Heroin abuse, HIV infection, maintain the glomerular filtration sickle cell disease, obesity. barrier. ▪ After glomerular necrosis due to other Inherited AD forms associated causes (IgA nephropathy). with Mutations in cytoskeletal ▪ As an adaptive response to loss of proteins and podocin, both of renal tissue (chronic reflux, which are required for the analgesic abuse, or unilateral renal integrity of podocytes. agenesis). Pathogenesis 1. Visceral epithelial damage (effacement or detachment Injury to podocytes) in affected segments. 2. Deposition of hyaline in the glomeruli is caused by the entrapment of plasma proteins and lipids in foci of injury where sclerosis develops. 3. The recurrence of proteinuria in patients undergoing renal transplantation for FSGS, sometimes within 24 hours of transplantation, supports the idea that a circulating mediator leads to podocyte damage in some cases.  Morphology Light microscopy The affected glomeruli exhibit Increased mesangial matrix, Obliterated capillary lumina, Deposition of hyaline (hyalinosis) Foamy (lipid-laden) macrophages. Immunofluorescence microscopy Nonspecific trapping of Igs (IgM), and complement in the areas of hyalinosis. Electron microscopy The podocytes exhibit effacement of foot processes, as in minimal- change disease. Clinical picture and prognosis Hematuria and hypertension Nonselective proteinuria Poor response to corticosteroid therapy At least 50% develop end-stage renal disease within 10 years  Membranous glomerulonephritis - Chronic immune complex GN induced by antibodies reacting in situ to endogenous or planted glomerular antigens. - Adults between the ages of 30 and 60 years - follows an indolent and slowly progressive course. Etiology Primary; Up to 80% of cases, caused by autoantibodies against podocyte antigens. Secondary to - Infections (chronic hepatitis B, syphilis, schistosomiasis, malaria), - Malignant neoplasms, (carcinoma of the lung and colon and melanoma) - Autoimmune diseases (SLE) - Exposure to inorganic salts (gold, mercury) - Drugs (penicillamine, captopril, nonsteroidal anti-inflammatory agents). Pathogenesis - Subepithelial Ig-containing deposits along the GBM → complement activation → membrane attack complex (C5-C9) , that causes podocyte injury and proteinuria  Morphology Light microscopy: Diffuse thickening of the capillary wall on H&E. Electron microscopy Global uniformly dense subepithelial electron- dense immune complex deposits along glomerular basement membranes. separated by spikelike protrusions of GBM matrix (spike and dome pattern). As the disease progresses, these spikes close over the deposits, incorporating them into the GBM. The podocytes show effacement of foot processes. Electron microscopy shows spikes (black arrows) surrounding immune complex deposits in the glomerular basement membrane.  Clinical picture - Sudden onset as full-blown NS, usually without antecedent illness. - Nonselective proteinuria - fails to respond to corticosteroid therapy. - It follows a variable and often indolent course. - Prognosis - Proteinuria persists in greater than 60% of patients, - 40% progress to renal failure in 2 to 20 years. - 10-30% of cases have partial or complete remission of proteinuria.  Membranoproliferative glomerulonephritis Characterized by mesangial cell proliferation and structural changes in glomerular capillary walls. It accounts for 5-10% of idiopathic NS in children and adults. Type I MPGN caused by deposition of immune complexes (circulating or in situ) against an unknown antigen. Type II, “Dense deposit disease”, Type II MPGN is an autoimmune disease in which patients have IgG autoantibody (C3 nephritic factor).  Morphology Light microscopy: Large glomeruli, have an accentuated lobular appearance Proliferation of mesangial and endothelial cells Infiltrating leukocytes. The GBM is thickened. Membranoproliferative GN. Note the lobulated appearance, the increased cellularity, and the thickening of the capillary walls. Electron microscopy: ▪ The GBM is thickened. ▪ “Splitting” of the GBM with double contour, or “tram track,” appearance, due to extension of processes of mesangial and inflammatory cells into the peripheral capillary loops and deposition of mesangial matrix ▪ Subendothelial immune complexes. Membranoproliferative GN. Note the double contours Immunofluorescence microscopy C3 is deposited in an irregular granular pattern IgG and early complement components (C1q and C4) are present, indicative of an immune complex pathogenesis. Clinical picture NS in 50% of cases. It may begin as acute nephritis or mild proteinuria. Prognosis is poor, 40% progressed to end-stage renal failure, 30% had variable degrees of renal insufficiency. Complications of NS ANY QUESTIONS