Glomerular Disorders in Nephrotic Syndrome Lecture I PDF

Glomerular Disorders in Glomerulonephritis and Nephrotic Syndrome Lecture I Division of Anatomical Pathology University of the Witwatersrand  Introduction Learning topics: 1. Proteinuria and nephrotic syndrome 2. Common causes of proteinuria and n...

Glomerular Disorders in Glomerulonephritis and Nephrotic Syndrome Lecture I Division of Anatomical Pathology University of the Witwatersrand  Introduction Learning topics: 1. Proteinuria and nephrotic syndrome 2. Common causes of proteinuria and nephrotic syndrome 3. Immune mechanisms in glomerulonephritis and nephrotic syndrome 4. Basic morphology of the common causes of nephrotic syndrome 5. Chronic kidney disease  The Nephron Functional unit of the kidney is the Nephron The nephron consists of the following structures: Glomerulus with Bowman’s capsule Proximal convoluted tubules Loops of Henle Distal tubules Collecting ducts The nephron is responsible for the production of urine - which is the result of glomerular filtration, and tubular reabsorption & secretion. This normal glomerulus is stained with PAS to highlight basement membranes of glomerular capillary loops and tubular epithelium. The capillary loops of this normal glomerulus are well- defined and thin. The endothelial cells are seen in capillary loops. The mesangial regions are of normal size. Podocytes are present and forming the visceral epithelial surface. Bowman's space is seen along with parietal epithelial cells. Morphology of the glomerular tuft Note the relationship of the capillary loops to the mesangium. About 15% of glomerular filtration occurs through the mesangium, with the remainder through the fenestrated epithelium. The normal anionic charge barrier of slit pores in overlying podocyte cytoplasm prevents large protein molecules such as albumin from passing through the visceral epithelium. The normal mesangium contains about 2 to 4  TEM of a normal glomerulus Podocy te Podocyte foot processes Capillary loop Fenestrated Red blood epithelium cell GBM Transmission electron micrograph of a normal human glomerulus. The podocyte (P) cell body contains most of the organelles and resides within a trough formed by capillary loops. This podocyte extends cell processes to three capillary loops (CLs). (×5000) Proteinuria and Nephrotic syndrome Proteinuria: Protein within the urine > 30 milligrams / 24 hours - adults >100 milligrams / m2 / 24 hours - children Nephrotic syndrome: Heavy proteinuria (≥ 3.5 grams / 24 hours) Generalised oedema Hypoalbuminaemia Hyperlipidaemia  Glomerulonephritis Definition: Inflammation of the glomerulus (there are many pathologies that can cause this) Pathogenetic mechanisms: 1. Majority: Immune complex mediated Immune-complex formation and deposition (immune complexes form and deposit in the glomerulus leading to injury & inflammation of the glomerulus) 2. Minority: Non-immune complex mediated Cytokines, lymphokines (circulate in the blood and cause injury & inflammation in the glomerulus)  Glomerulonephritis GN can be classified according to the aetiology and the morphologic pattern Classification: 1. Aetiopathogenesis: Immunologic mechanisms 1.1 Immune complex medicated 1.2 Non-immune complex mediated Cytokines & lymphokines 2. Morphologic pattern of reaction 2.1 Focal / Diffuse 2.2 Segmental / Global 2.3 Non-proliferative 2.4 Proliferative 2.5 Crescentic  Morphologic patterns of reaction Morphologic pattern of reaction 2.1 Focal / Diffuse: 50% glomeruli are involved 2.2 Segmental / Global: 50% glomerular tufts are involved 2.3 Non-proliferative types Minimal change disease Focal Segmental Glomerulosclerosis with Hyalinosis (FSH / FSGS) Membranous glomerulonephritis 2.4 Proliferative types Membranoproliferative glomerulonephritis 2.5 Crescentic types  Glomerulopathies Renal involvement as part of a systemic disease process: Diabetes mellitus (DM) Systemic lupus erythematosus (SLE) Amyloidosis HIV Associated Nephropathy (HIVAN) / HIV Immune Complex Kidney disease (HIVICK)  Renal biopsy Renal biopsy is the method of choice for diagnosing glomerular pathology Techniques used to examine the biopsied specimen: Light microscopy(LM) Immunofluorescence microscopy(IMF) Electron microscopy(EM) Primary renal diseases resulting in Proteinuria / Nephrotic syndrome: Minimal change disease Focal segmental glomerulosclerosis (FSGS) Membranous GN Membranoproliferative GN  Minimal change disease Commonest cause of nephrotic syndrome in children: 2–6-year age group 27-77% of children with proteinuria or Nephrotic Syndrome (NS) 12-40% of adults with proteinuria or Nephrotic Syndrome (NS) Associations: Majority: nil Minority: infections immunization drugs e.g. NSAIDS neoplasia (lung, prostate)  Minimal change disease Aetiology: Unclear – now thought to be podocytopathy Immunologic: lymphokine / cytokine Not immune-complex mediated Clinical features: All age groups but more common in children; Caucasian > Black Males > Females Proteinuria / nephrotic syndrome Responsive to steroid therapy  Minimal change disease Pathology: LM: Normal IMF: Negative EM: Epithelial cell foot process effacement on ultrastructural examination Minimal change disease (MCD) is characterized by effacement of the epithelial cell (podocyte) foot processes and loss of the normal charge barrier such that albumin selectively leaks out and proteinuria ensues. In this electron micrograph, fenestrated endothelium is present, the basement membrane is normal, however, overlying epithelial cell foot processes are Minimal change disease Prognosis: Children: good majority resolve Adults: variable outcome small % progress to CRF Focal Segmental Glomerulosclerosis with Hyalinosis (FSH / FSGS) Incidence: 12-31% of children with proteinuria / NS 9-45% of adults with proteinuria / NS More prevalent in black patients Increasing incidence with HIV epidemic Pathogenesis: Unclear; podocytopathy Immunologic: lymphokine / cytokine Not immune-complex mediated Focal Segmental Glomerulosclerosis (FSGS) Pathology: LM: Focal lesions (