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GLOMERULONEPHROPATHIES Internal Medicine Lecture Series November 30, 2005 Julia Faller, D.O., PGY1 The Kidney Nephron Glomerulus Glomerulonephritis Glomerulonephritis Glomerulonephritis and glomerulopathy are used interchangeable to denote glomerular injury. The injury involves damage to the major components of the glomerulus: epithelium basement membrane capillary endothelium mesangium Primary versus Secondary Primary—pathology confined to the kidney -any systemic features are a direct consequence of glomerular dysfunction -usually idopathic Secondary—part of a multisystem disorder Acute, Subacute & Chronic Acute—injury occurring over days or weeks Subacute—rapidly progressive over weeks or months Chronic—months to years Focal versus diffuse Lesions are classifed as: Focal—involving less than 50% of glomeruli Diffuse—involving over 50% of glomeruli Focal versus Diffuse Segmental versus Global Segmental—involve part of the glomerular tuft Global—involve almost all of the glomerular tuft Segmental versus Global Intracapillary versus Extracapillary Intracapillary—refers to endothelial or mesangial cells Extracapillary—refers to Bowman’s space Other Descriptive Terms Proliferation—describes and increase in glomerular cell number Crescent—half-moon-shaped collection of cells in Bowman’s space, composed of proliferating parietal epithelial cells and infiltrating macrophages Sclerosis—an increase in the amount of nonfibrous extracellular material of similar composition to GBM and mesangium Fibrosis—depostition of collagens type I and III Classification Most glomerulopathies are classified according to their morphologic features 1. Nephritic syndrome (inflammatory) 2. Nephrotic syndrome 3. Deposition diseases Nephrotic and Nephritic Nephritic Syndrome 1. Focal proliferative glomerularnephritis 2. Diffuse proliferative glomerulonephritis 3. Crescentic glomerulonephritis Nephritic Syndrome Usually present with presence of RBC’s, red blood cell casts, leukocytes and sub nephrotic proteinuria of <3g/24hr Nephrotic Syndrome Affects glomerular filtration barrier for proteins 1. Membranous glomerulopathy 2. Minimal change disease 3. Focal and segmental glomerulosclerosis Nephrotic Syndrome Present with nephrotic range proteinuria of >3g/24 hr, few RBC’s, leukocytes, cellular casts Associated with hypoalbuminemia, edema, hyperlipidemia, and lipiduria and a prothombotic state Deposition Diseases Prominent extravascular depostion of a paraprotein or fibrillar material Can either trigger nephritic, nephrotic or combination Major Determinants of glomerular injury 1. The nature of the primary insult and secondary mediator systems it invokes 2. The site of injury within the glomerulus 3. The speed of onset, the extent, and intensity of disease Primary Insult 1. 2. 3. 4. 5. 6. 7. Immunologic Metabolic Hemodynamic Toxic Depostion Infectious Inherited Major Mechanismas of Glomerular injury 1. Inherited glomerular diseases 2. Immunologic glomerular injury 3. Nonimmunologic glomerular injurty 4. Final common pathways of injury in glomerular disease Clinical Manifestations of Glomerular Disease asymptomatic proteinuria nephrotic syndrome (proteinuria, hypoproteinemia, lyperlipidemia, edema) asymptomatic hematuria glomerulonephritis (hematuria, proteinuria, hypertension, renal failure) Clinical Manifestations of Glomerular Disease con’t acute glomerulonephritis (neprhitis with short term renal failure) crescentic glomerulonephritis (nephritis with rapidly progressive renal failure) chronic glomerulonephritis (chronic progression of renal failure) End Stage Renal Disease (irreversible renal failure) Case Presentation A 53 year old African American male with a history of hypertension and bipolar disorder that was treated with lithium presented to an emergency room complaining of "not feeling well". Lab Studies Evaluation revealed edema, proteinuria, creatinine 3.1 mg/dl and BUN 57 mg/dl. Four days later the creatinine was 5.3 mg/dl and BUN 74 mg/dl. He was hospitalized for further evaluation, which revealed BP 150/80, edema, 8.7 gm/24hr proteinuria, >20 RBC/hpf, serum albumin 1.5 g/dl, cholesterol 200 mg/dl, positive anti-nuclear antibody (ANA) at a titer of 1:320 and normal serum complement. Additional Information He gave no history of prior renal disease and had not taken nonsteroidal anti-inflammatory drugs. Over the next week his creatinine rose to 6.8 mg/dl. A renal biopsy was performed. Follow up The lithium was discontinued and the patient was treated with prednisone (60 mg/day). Five days after biopsy his creatinine was 6.1 mg/dl, and was 1.1 mg/dl one month later, at which time there was 1 g/24 hrs proteinuria. Within two months the proteinuria had disappeared and the serum albumin was 3.6 g/dl. Minimal change glomerulopathy with acute renal failure syndrome one of the most gratifying diagnoses that a renal pathologist can make prior to biopsy the patients are often thought to have either rapidly progressive glomerulonephritis or severe irreversible chronic glomerular disease Minimal change glomerulopathy with acute renal failure has a very good prognosis because the nephrosis usually responds to steroid treatment and the renal failure almost always resolves Case Presentation A 49 yr old man was well until 1 mos ago, when he developed dyspnea, fatigue, decreased appetite, and cough that produces blood tinged sputum. Three days ago, he had 3 episodes of frank hemoptysis. He has had no fever or chills. He has a 7 yr history of hypertension and has been a smoker for 15 years. He takes no medications. Physical Exam The patient is alert and in no distress but is pallid. BP 155/88, HR 90, resp 18, temp 98.6. Skin exam is normal. Optic funduscopy shows mild sclerosis and constriction. The carotids and thyroid are normal. The pharynx is clear. Lungs have coarse crackles in the right mid-lung field. CV NSR, no gallop. Abdomen is soft with no organomegaly. No redness or swelling of the joints are present. Lab Studies WBC 9.2, Hgb 8.7, hct 26%, platelet 443, creatinine 4.4 (was 1.3 1 mos earlier), Protein 6.3, Albumin 3.7 24hr protein 3.5 urinalysis: 4+ protein, 3+ hemoglobinuria, 25-50 RBC’s, 5-15 WBC’s, dysmorphic erythrocytes and casts Renal Biopsy Proliferative glomerulonephritis with 50% of glomeruli having crescents Immunofluorescence shows linear staining with IgG What do you think? 1. 2. 3. 4. Rapidly progressive glomerulonephritis Nephrotic syndrome Chronic renal failure Acute tubular necrosis Question 1 The most likely disease to have a nephritictype presentation is: 1. Minimal change glomerulonephropathy 2. Membranous glomerulonephropathy 3. Focal segmental glomerulosclerosis 4. Crescentic glomerulonephritis Question 2 The term focal in describing kidney disease means: 1. Only some of the glomerular tuft is affect 2. All of the glomerular tuft is affected 3. Less than 50% of the glomeruli are affected 4. Greater than 50% of the glomeruli are affected Question 3 Major Determinants of glomerular injury are: 1. The nature of the primary insult and secondary mediator systems it invokes 2. The site of injury within the glomeruli 3. The speed of onset, the extent, and intensity of disease 4. All of the above