Kidney Introduction Pathogenesis of glomerular diseases

Objectives By the end of this session the student should be able to: List the major clinical presentation of disorders of the kidney. Describe the anatomical components of the kidney and list the major diseases of each. List and describe the types of immune mechanisms in glomerular diseases.

Introduction Kidney function Components of Blood RBC WBC Plasma (water, electrolytes, protein) Anatomical/Histological components: Glomeruli Tubules Interstitium vessels

Diseases of the kidney Glomeruli Tubulointerstitium Vessels Glomerulonephritis Primary Secondary Chronic Tubulointerstitium Acute tubular necrosis Pyelonephritis Acute chronic Vessels Nephrosclerosis Benign Malignant Urinary obstruction Stones Hydronephrosis Cystic diseases of the kidney Tumors

Renal dysfunction Urea, creatinine Azotemia (high urea, creatinine) Pre renal Renal Post renal Uremia (azotemia+ clinical features) Features of uremia

Major clinical presentations Acute nephritic syndrome Gross hematuria, mild-moderate proteinuria, hypertension, azotemia, edema Nephrotic syndrome Heavy proteinuria (>3.5g/day), hypoalbuminemia, edema, hyperlipidemia, lipiduria Asyptomatic hematuria or proteinuria

Major clinical presentations Rapidly progressive glomerulonephritis Acute renal failure Chronic renal failure UTI urinary tract infection Renal colic (stones) Obstruction Mass lesion

Kidney Biopsy

Kidney Biopsy Send fresh Routine processing Immunoflourescence (IF) Electron microscopy (EM) Light microscopy (formaline fixed)

Case Presentation

A 47-year-old black male truck driver presents to the emergency room with intractable nausea and vomiting, dyspnea on exertion, and dizziness. The nausea began about two weeks prior to admission; vomiting has occurred within the last few days. The chest pain has been present for only 2-3 days and is described as retrosternal, burning, and worse on inspiration. There is no history of medication or toxin exposure. His past medical history is positive for hypertension diagnosed 14 years ago with no follow-up. He has smoked 1 ppd for 27 years.

On physical examination, he is a thin, black man in moderate distress On physical examination, he is a thin, black man in moderate distress. His blood pressure is 160/120, temperature 36.7°C, pulse 100 (nl 60-100/min). His skin is pale with numerous areas of bruising. Lung exam reveals bilateral rales to the mid lung fields, and cardiac exam reveals muffled heart sounds, a friction rub, and a I/VI systolic ejection murmur. Chest x-ray shows moderate cardiomegaly with increased pulmonary vascular markings and hazy obliteration of the lower lung bases. Abdominal ultrasound examination shows a right kidney size of 7 cm (nl approx. 10 cm) and a left kidney size of 6.8 cm without evidence of pelvicalyceal dilation.

Urinalysis: protein - 1+ blood - 1+ glucose - neg casts - neg bacteria - neg

WBC: 6,700/mm3 Platelets: 250,000/mm3 Hematocrit: 26% Creatinine: 200 mmol/L (high, normal <120) BUN: 215 mg/dL (high, normal <25) Calcium: 6.2 mg/dL (low, normal 8-10mg/dl) Uric Acid: 16.5 mg/dL (high, normal 5-7) Cardiac markers of MI: negative

An echocardiogram reveals a moderate amount of fluid around the heart An echocardiogram reveals a moderate amount of fluid around the heart. A pericardiocentesis is performed, and 250 cc of serosanguineous fluid is removed. An urgent request for hemodialysis is made, and the patient is dialyzed with some relief in his breathing and chest pain. However, the next morning, the patient complains of abdominal pain and passes several melanotic stools, followed by gross blood. Hypotension and arrhythmias follow, and death supervenes. An autopsy is performed.

What are the possible causes of this appearance of the kidneys?

Hypertension, D.M., Chronic glomerulonephritis

Describe the four compartments (glomeruli, tubules, interstitium, and vasculature)

Describe the abnormality

What is the abnormality?

What is the abnormality?

Colon mucosa: What is the abnormality?

Four parathyroid glands

Discussion Hypertension Chronic Renal Failure Uremia Urinalysis Blood work Kidney findings Secondary hyper parathyroidism

Glomerular diseases

Glomerulus Structure Filtering membrane 1. Endothelial cells 2. GBM glomerular basement membrane 3. Visceral epithelium GFR: glomerular filtration rate Mesangium Permeablility Water, albumin Size, charge

Glomerular disease Primary Seconday Hereditary

Membranoproliferative GN Diffuse proliferative GN Crescentic GN Glomerular disease Primary Minimal change GN Membranous GN Focal segmental GS Membranoproliferative GN Diffuse proliferative GN Crescentic GN Seconday SLE, DM, Amyloidosis, Goodpasture, vasculitis Hereditary Albort syndrome

Pathogenesis of Glomerular Disease Immune disorder Kidney involvement Injury by inflammation and other mediators Glomerular dysfunction

Pathogenesis of Glomerular Disease Immune disorder Circulating immune complex Immune complex formation Cell-mediated Glomerular dysfunction

Pathogenesis 1. Circulating Immune complex nephritis (type III hypersensitivity) Antigen is not glomerular origin Intrinsic- SLE Extrinsic- Poststreptococcal GN, HepB, Malaria Ag-Ab complex is trapped in glomeruli Complement activation injury

Pathogenesis 1. Circulating Immune complex nephritis (type III hypersensitivity) Morphology: IF: deposits (glomerular) EM: electron-dense deposits (mesangial, subendothelial, subepithelial) Proliferative: leukocytes, endothelial, mesangial, epithelial

Pathogenesis 1. Circulating Immune complex nephritis (type III hypersensitivity) What happen Short lived Ag-Ab complex---- Recovery Repeated Ag-Ab complex------- chronic GN

Pathogenesis of Glomerular Disease Immune disorder Circulating immune complex In-situ Immune complex formation Cell-mediated Glomerular dysfunction

Pathogenesis 2. In-situ Immune complex nephritis In-situ Intrinsic Extrinsic/planted

Pathogenesis 2. In-situ Immune complex nephritis Anti-GBM Goodpasture syndorme In human: auto antibodies Pathology: Severe glomerular damage Cresentic GN Ag: alpha3 chain of collagen type IV (Rabbits Masugi Nephritis) injury to rats by antibodies of rabbit IF: linear deposits

Pathogenesis 2. In-situ Immune complex nephritis Haymann Nephritis: Immunizing rats to proximal tubular brush border IF: granular deposits of Ig and complement along the GBM Ag (megalin) on visceral epithelial cells Result in membranous GN

Pathogenesis 2. In-situ Immune complex nephritis Planted antigen DNA Bacterial products (groupA strep) IgG/complex IF: granular pattern

Pathogenesis of Glomerular Disease Immune disorder Circulating immune complex In-situ Immune complex formation Cell-mediated Glomerular dysfunction

Pathogenesis Cell mediated Immune GN Sensitized T cells suspected

Pathogenesis of Glomerular Disease Immune disorder Circulating immune complex In situ Immune complex formation Cell-mediated Glomerular dysfunction

Pathogenesis of Glomerular Disease Immune disorder Kidney involvement Injury by inflammation and other mediators Glomerular dysfunction

Mediators of Immune Injury Cells Plasma products

Mediators of Immune Injury Cells Neutrophils Proteases, oxygen free radicals Monocytes Platelets Epithelial cells Plasma products

Mediators of Immune Injury Cells Plasma products Direct cytotoxicity by Ab Fibrin related products Complement activiation C5-C9 membrane attack complex

Epithelial cell injury Ab to visceral epithelium Toxins Cytokins Loss of foot processes, vacuolization, detachment proteinuria

Pathogenesis of Glomerular Disease Immune disorder Kidney involvement Injury by inflammation and other mediators Glomerular dysfunction

Renal ablation glomerulopathy Any disease resulting in decrease GFR to 30-50% Progress to end-stage renal failure glomerulosclerosis

Renal ablation glomerulopathy Glomerulosclerosis—hypertrophy—increase in single nephron GRF—increase blood flow—capillary hypertension—endothelial/epithelial inury—protein/fibrin/lipid deposition—capillary collapse—lyaline degeneration—proliferation of mesangial cells—increase mesangial matrix—sclerosis.

Objectives By the end of this session the student should be able to: List the major clinical presentation of disorders of the kidney. Describe the anatomical components of the kidney and list the major diseases of each. List and describe the types of immune mechanisms in glomerular diseases.