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Flashcards in Pathology Deck (104):
1

Ischemia is most often due to what?

Coronary Atherosclerosis

2

Angina Pectoris

Substernal or precordial chest pain from transient myocardial ischemia lasting from 15 seconds to 15 minutes

3

Stable Angina

  • Most common variant
  • Angina w/ excercise, excitement, or other sudden increase in cardiac load
  • Associated w/ >70% chronic stable stenosis of a coronary artery (fixed plaque)
    • Not usually associated w/ plaque disruption

4

Unstable (Crescendo) Angina

  • Occurs w/ progessively lower levels of physical activity or at rest
  • Increases in frequency over time
  • Often prolonged duration
  • Usually caused by disruption of plaque and superimposed partial thrombosis
  • Infarct doesn't occur because of either fragmentation or fibrinolysis of the thrombi or subsiding of the vasospasm

5

Prinzmetal Angina

  • Episodic angina at rest due to intense coronary artery vasospasm
  • Attacks unrelated to exercise, HR, or BP
  • Generally responds to nitroglycerin or CCBs

6

Sequence of Events in Coronary Arterial Occlusion

  1. Sudden change in atheromatous plaque
    1. Hemorrhage, Erosion, Ulceration, Rupture, etc.
  2. Subendo collagen exposed, causing platelet adhesion, activation, and release of granule contents, then aggregation to form microthrombi
  3. Vasospasm is initiated by mediators from platelets
  4. Tissue factor activates the coagulation pathway (adding to size of thrombus)
  5. Thrombus evolves to partly or completely occlude the lumen, frequently within minutes
  6. Occlusion causes myocardial ischemia, dysfunction, and potentially myocyte death

7

Myocardial Response to Ischemia

  • Early response is cessation of aerobic metabolism (w/in seconds)
    • Rapidly leads to inadequate production of high-energy phosphates (ATP) and accumulation of noxious metabolites (lactic acid)
  • Loss of myocyte contractactility (w/in 60 seconds)
    • Can precipitate acute heart failure before myocardial cell death occurs
  • Changes potentially reversible w/ re-establishment of blood flow w/in 20-30 minutes
  • Prolonged ischemia for greater than 1 hour causes damage to cardiac microvasculature

8

What does myocyte necrosis result in pathologically that aids in diagnosis of myocardial infarction?

  • Disruption of sarcolemmal membrane
    • Allows intracellular macromolecules to leak out of cells into interstitium → ultimately into microvasculature and lymphatics
  • These macromolecules, once in the blood, can be detected by laboratory tests and used to diagnose

9

Effects of Repurfusion on Myocardial Viability and Function

  • Contractile function lost within 2 minutes viability begins to drop after about 20 minutes
  • If perfusion not restored nearly all myocardium in affected region suffers death
  • Flow restored then some necrosis is prevented, myocardium salvaged, and at least some function can return
  • BUT reperfusion may induce some damage and return of function may be delayed for hours to days (post-ischemic ventricular dysfunction or stunning)
    • Probably results from free radical damge to microvascular circulation
    • May extend beyond area of infarct
    • If another occlusion occurs, the reperfused area is already damaged and is more susceptible to a second MI

10

Progression of Myocardial Necrosis After Occlusion of Coronary Artery

  • Necrosis begins in small zone of myocardium beneath the endocardial surface in the center of the ischemic zone
  • Very narrow zone beneath endocardium is spared from necrosis because it can be oxygenated by gas diffusion from the ventricle

11

What is the most common cause of death in adults in the U.S?

Myocardial Infarction

12

What percentage of myocardial infarction occur in people under the age of 40?

10%

13

What percentage of MI's occur in people under the age of 65?

45%

14

Other than coronary artery occlusion what are other causes of MI's?

  • Vasospasm
    • Maybe in association w/ platelet aggregation
    • With or w/o visible coronary atherosclerosis
  • Emboli from L Atrium
    • A Fib
    • L Sided Mural Thrombus
    • Vegetations
    • Intracardiac Prosthetic Material
    • Paradoxical Emboli
  • Disorders of small, intramural coronary arteries
    • Vasculitis
    • Sickle Cell Disease
    • Amyloidosis
    • Vascular Dissection
    • Shock

15

What percentage of transmural MI cases occur in the absence of significant coronary artery disease?

About 10%

16

Transmural Infarct

  • ST Elevation Infarct
  • Most MI's
  • Ischemic necrosis involved the full or nearly full thickness of the ventricular wall in distribution of single coronary artery

17

Subendothelial Infarct

  • Non-ST Elevation Infarct
  • Ischemic necrosis is limited to the inner 1/3 to 1/2 of ventricular wall
  • May result from thrombus lysed before necrosis extends across the wall (Regional)
  • May also result from prolonged, severe hypotension (Global)
    • Myocardial damage is circumferential

18

Frequency of Coronary Artery Involvement w/ Corresponding Infarcts

  • LAD
    • 40-50%
    • Supplies:
      • Anterior wall of left ventricle near the apex
      • Anterior portion of ventricular septum
      • Apex circumferentially
  • RCA
    • 30-40%
    • Supplies:
      • Inferior/Posterior wall of L Ventricle
      • Posterior Portion of Ventricular Septum
      • Inferior/Posterior R Ventricular Free Wall in Some Cases
  • LCX
    • 15-20%
    • Supplies:
      • Lateral wall of L Ventricle EXCEPT at the apex

19

How long after severe ischemia is necrosis usually complete?

6 Hours

20

What does the location, size, and morpholgic features of an infarct depend on?

  1. Location, severity, and rate of development of the obstruction
  2. Size of vascular bed perfused by the obstructed vessels
  3. Duration of occlusion
  4. Metabolic/Oxygen needs of myocardium at risk
  5. Extent of collateral blood vessels
  6. Presence, site, and severity of coronary artery vasospasm
  7. Other Factors
    1. HR
    2. Cardiac Rhythm
    3. Blood Oxygenation

21

Morphological Changes In Infarction 30 Minutes to 4 Hours After

  • Gross
    • None
  • Microscopic
    • Usually None
    • Variable Waviness of Fibers at Border

22

Morphological Changes In Infarction 12-24 Hours After

  • Gross
    • Dark mottling of Infarct
  • Microscopic
    • Ongoing coagulation necrosis w/
      • Pyknosis of nuclei
      • Myocyte hypereosinophilia
      • Marginal contraction band necrosis
      • Early coagulative necrosis and wavy fibers
    • Widened spaces b/t dead fibers containg edema fluid and scattered neutrophils

23

Morphological Changes In Infarction 4-12 Hours After

  • Gross
    • Typically no visible changes
    • Occasional dark mottling
  • Microscopic
    • Early coagulation necrosis
    • Edema
    • Hemorrhage

24

Morphological Changes In Infarction 1-3 Days After

  • Gross
    • Mottling w/ pallor
    • Center of infarct yellow/tan
  • Microscopic
    • Coagulation necrosis w/
      • Loss of myocyte nuclei and striations
      • Interstitial infiltrate of abundant neutrophils
        • Lyse the dead myocytes

25

Morphological Changes In Infarction 3-7 Days After

  • Gross
    • Hyperemic border
    • Central yellow/tan softening
  • Microscopic
    • Beginning disintegration of dead myofibers w/
      • Dying neutrophils
    • Early phagocytosis of dead cells by macrophages at infarct border

26

Morphological Changes In Infarction 7-10 Days After

  • Gross
    • Maximally yellow/tan and soft w/ depressed red/tan infarct margins
  • Microscopic
    • Well-developed phagocytosis of dead cells
    • Granulation tissue at margins

27

Morphological Changes In Infarction 2-8 Weeks After

  • Gross
    • Gray/White Scar
      • Progressive from outer edge towards core of infarct
  • Microscopic
    • Increased collagen deposition w/ decreased cellularity and fewer capillaries

28

Morphological Changes In Infarction 10-14 Days After

  • Gross
    • Red/Gray depressed infarct borders
  • Microscopic
    • Trichrome-stained section showing well-established granulation tissue w/ new blood vessels (dark red) and collagen deposition (blue)

29

Morphological Changes In Infarction >8 Weeks After

  • Gross
    • Scarring Complete (White scar)
  • Microscopic
    • Trichrome stain of dense collagenous scar (blue) w/ surrounding surviving myocytes (red)

30

Lab Diagnosis of MI (Not Tested)

  • Total Creatinine Phosphokinase (CPK or CK)
    • CK-MB
      • Formerly "the gold standard" for diagnosis of MI
        • Levels rise w/in 2-4 Hours of MI
        • Peak about 24 Hours
        • Returns to Normal around 36 Hours
      • Sensitive BUT NOT specific for MI
      • Also found in skeletal muscle
      • Elevated in Many Conditions
        • Myocarditis
        • Polymyositis
        • Malignant Hyperthermia
        • Duchenne's
        • Cardiac Trauma
        • Skeletal Muscle Injury
        • Pulmonary Embolism
        • Hypothyroidism
        • Cryosurgery of Prostate
  • Troponins T and I
    • Most sensitive and specific biomarkers of myocardial damage
    • Early Phase:
      • Release of free cytosolic troponin
      • Detectable in serum 2-4 hours post-MI
    • Later Extended Phase:
      • After digestion and release of complex from contractile proteins
      • Level Peak at 48 Hours
      • Persist for 10-14 days post-MI

31

Potential Complications of MI

DARTH VADER

  • Death
  • Arrythmia
  • Rupture
  • Tamponade
  • Heart Failure
  • Valve Disease
  • Aneurysm of Ventricle
  • Dressler's Syndrome
  • Embolism
  • Recurrence/Regurgitation

32

Chronic Ischemic Heart Disease

Progressive congestive heart failure as a result of long-term ischemic damage to myocardium

AKA Ischemic Cardiomyopathy

  • Often a result of repeated ischemic events and repeated MI's
  • Account for nearly 1/2 of cardiac transplant recipients
  • Almost invariably there will be some degree of obstructive coronary artery atherosclerosis
  • Noncompliant myocardium and wall dysfunction promote mural thrombi w/ risk of thromboembolus

33

Morphological Changes of Chronic Ischemic Heart Disease

  • Gross
    • Often results in Cardiomegaly, L Ventricular Hypertrophy, and Ventricular Dilation
  • Microscopic
    • Interstitial Fibrosis
    • Often well-defined infarcts

34

Sudden Cardiac Death

Sudden death from cardiac causes in the absence of symptomatic heart disease or early after symptom onset

80-90% of Cases Marked Coronary Atheroscloris Exists

Most, however, are not associated w/ Acute MI

  • Are thought to result from ischemia-induced myocardial irritability that initiates dangerous arrythmias

10-20% are of Non-Atherosclerotic Causes

  • Hereditary or Acquired Cardiac Arrhythmias
  • Congenital Structural or Coronary Arterial Anomalies
  • Aortic Stenosis
  • Mitral Prolapse
  • Myocarditis
  • Dilated or Hypertrophic Cardiomyopathy
  • Pulmonary Hypertension
  • Conduction System Abnormalities 
  • Cardiac Hypertrophy of Any Cause
  • Severe Metabolic or Hemodynamic Disturbances, Catecholamines, Drugs of Abuse

35

Most Common Cause of Acute Renal Failure

Acute Tubular Injury

36

Acute Tubular Injury

  • Ischemic Type
    • Necrosis is patchy
    • Short lengths of tubules are affected and straight segments of proximal tubules and ascending loops of Henle are most vulnerable
  • Toxic Type
    • Extensive necrosis
    • Occurs along PCT segments, but also occurs along distal tubule, especially ascending loop of henle

37

Agents that cause toxic Acute Tubular Injury?

  • Mercuric Chloride - large acidophilic inclusions
  • Carbon Tetrachloride - accumulation of neutral lipids in injured cells
  • Ethylene Glycol - Marked ballooning and hydropic or vacuolar degeneration of proximal convoluted tubules. Calcium oxalate crystals also found in tubular lumens

38

Clinical Course of ATI

  • Initiation phase (about 36 hours)
    • Slight decline in urine output w/ rise in BUN
  • Maintenance Phase
    • Features of uremia
      • Metabolic Acidosis
      • Hyperkalemia
      • Rising BUN
      • Salt and Water Overload
      • Oliguria
  • Recovery Phase
    • Increase in UOP, up to 3L/day
    • Large amounts of Na, K, and Water lost in urine because tubules are damaged
    • Lab Values return to normal
    • Subtle tubular defects may persist for months

39

Tubulointerstitial Nephritis

  • Insidius onset, principal manifestation is azotemia
  • Presentation
    • Acute or Chronic, or both
    • Absence of nephritic or nephrotic syndromes
    • Defects in tubular function
      • Inability to concentrate urine
      • Salt wasting
      • Metabolic acidosis
      • Isolated defects in tubular reabsorption or secretion
  • Histological Features
    • Acute
      • Interstitial Edema
      • Leukocyte infiltration of interstitium and tubules
      • Tubular Injury
      • NO fibrosis or significant tubular atrophy
    • Chronic
      • Infiltration w/ mainly mononnuclear leukocytes
      • Promoninent interstitial fibrosis
      • Widespread Tubular Atrophy
      • NO edema, neutrophils, or eosinophils

40

Pyelonephritis and Urinary Tract Infection

  • Most common cause of acute kidney injury diseases of the kidney
  • Acute Pyelonephritis
    • Generally caused by bacteria associated w/ infections of other parts of UT
      • Ascending infections (Enterobacteriacaea, E. coli)
      • May also occur from seeding
    • Gross Morphology
      • Suppuration may occur
      • May involve one or both kidneys
    • Microscopic Features
      • Patchy interstitial suppurative inflammation
      • Intratubular aggregates of neutrophils
      • Neutrophilic tubulitis
      • Tubular Necrosis
    • Complications
      • Papillary Necrosis
        • Mainly in diabetes, sickle cell, and urinary obstruction. Also seen w/ NSAIDs
      • Pyonephrosis
        • Results when obstruction is complete or nearly so especially high in UT
        • Suppurative exudate cannot drain
      • Perinephric Abscess
        • Extension of suppurative inflammation through the renal capsule into perinephritic tissue
    • Polyomavirus
      • Emerging cause of acute pyelonphritis in renal allografts
      • Latent infection
      • Microscopic Appearance
        • Infection of tubular epithelial cell nuclei
        • Nuclear enlargement
        • Intranuclear inclusions visible by light microscopy
        • Interstitial mononuclear inflammatory response
  • Chronic Pyelonephritis
    • Predisposing factors
      • Vesicoureteral Reflux
      • Intrarenal Reflux
      • Obstruction
    • Gross Morphology
      • Coarse, discrete corticomedullary scars in irregular distribution, overlying dilated, blunted, or deformed calyces
      • Flattened papillae
      • Scars mostly in upper and lower poles
      • If bilateral, kidneys are asymmetric
    • Microscopic Findings
      • Tubules
        • Atrophy, Hypertrophy, or Dilation
        • Dilated tubules may be filled w/ casts resembling thyroid colloid
      • Interstitium
        • Chronic inflammation and fibrosis
      • Glomeruli may appear normal, unless other conditions present

41

Drug and Toxin-Induced Tubulointerstitial Nephritis

  • Second most common cause of acute kidney injury
  • Causes
    • Interstitial Immune Response
      • Occurs w/in 2-40 days after exposure
      • Clinical: fever, eosinophilia, rash, rising serum creatinine, oliguria
      • Morphology
        • Edema and infiltration of interstitium by mononuclear cells
    • Acute Tubular Injury
    • Subclinical but Cumulative Injury

42

Urate Nephropathy

  • Three types
    • Acute Uric Acid Nephropathy
      • Precipitation of Uric Acid Crystals in Renal Tubules and Development of Acute Renal Failure
      • Seen in leukemic patients undergoing chemo
    • Chronic Urate Nephropathy
      • Monosodium urates deposit in distal tubules and collecting ducts, interstitium, and form birefringent needle-like crystals
      • Seen in some patients w/ protracted forms of hyperuricemia
      • Crystals evoke a foreign body reaction w/ giant cells
    • Nephrolithiasis

43

Light Chain Cast Nephropathy (Myeloma Kidney)

  • Immunoglobulin light chains (Bence-Jones Proteins) are deposited in the kidney in plasma cell neoplasms (particularly myeloma)
    • Directly toxic to epithelial cells
    • Combine w/ Tamm-Horsfall protein to form tubular casts that obstruct the lumens and cause inflammatory reaction
    • Bence-Jones proteins are pink to blue amorphous masses on H&E stains and fill tubular lumens
    • Usually present is interstitial nephritis and somtimes fibrosis

44

Nephrosclerosis

  • Sclerosis of renal arterioles and small arteries, usually in setting of hypertension
  • Leads to glomerulosclerosis, chronic tubulointerstitial injury, and ultimately shrinking of the kidney
  • More likely in advanced age
  • Gross Morphology
    • Grain Leather
  • Microscopic Morphology
    • Narrowing of lumens
    • Subcapsular scars w/ sclerotic glomeruli and tubular dropout, alternating w/ better preserved perenchyma
    • Patchy ischemic atrophy w/ foci of tubular atrophy and interstitial fibrosis

45

Malignant Nephrosclerosis

  • Renal vascular disorder associated w/ malignant/accelerated hypertension
  • Fundamenta leasion is vascular injury that injures endothelium 
  • Gross Features
    • Variable kidney size
    • Petechial hemorrhages may be present on the kidney surface
  • Microscopic Features
    • Fibrinoid Necrosis of Arterioles
      • Smudgy, eosinophilic walls
      • Inflammation minimal/absent
    • Hyperplastic Arteriolitis
      • "Onion Skinning"
      •  

46

Renal Artery Stenosis

  • Unilateral renal artery stenosis causes about 2-5% of cases of hypertension, potentially curable by surgery
  • Pathogenesis
    • Increased production of renin from ischemic kidney induces hypertension
  • Two Main Causes
    • Atheromatous Plaque (MOST COMMON)
      • At origin of renal artery
      • Most commonly seen in elderly, is fairly common cause of renal insufficiency
      • Most commonly bilateral
      • Best diagnosed by angiography
      • Treatment is surgery
    • Fibromuscular Dysplasia
      • Thickening that may involve the arterial intima, media, and adventitia
      • More common in women

47

Thrombotic Microangiopathies (TMA)

  • Spectrum of diseases that includes the thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS)
  • Many insults may cause excessive activation of platelets, formation of platelet microthrombi in capillaries and arterioles in various vascular beds, and acute ischemic changes in affected tissues
  • Consumption of platlets leads to severe thrombocytopenia
  • Platelet microthrombi create flow abnormalities resulting in shearing of RBCs and formation of schistocytes

48

Atheroembolic Renal Disease

  • Embolization of fragments of atheromatous plaques from aorta or renal artery into intrarenal vessels
  • Precipitating Causes
    • Invasive Vascular Procedures (very common w/ AAA repairs)
    • CPR
    • Anticoagulant or Thrombolytic Therapy
    • Trauma
    • 1/4 are spontaneous
  • Clinical Consequences
    • Vary w/ number of emboli and pre-existing renal function
    • Sometimes asymptomatic, somtimes cause acute renal failure
  • Morphology
    • Emboli seen in lumens of arteries typically have cholesterol crystals
    • Acute lesions surrounded by fibrin, RBCs, and/or WBCs
    • Chronic lesions are embedded w/in intimal fibrosis
    • Multinucleated giant cells may be present

49

Cortical Infarcts

  • Infarcts result from localized disruption in vascular flow of sufficient severity and duration to result in death of cells in affected region
  • Tend to be wedge-shaped, and pale tan/yellow, w/ thin rim of viable subscapular cortex 
  • Microscopically
    • Tissue has preserved cellular outlines w/ loss of nuclei, and an inflammatory infiltrate (mainly neutrophils) in b/t necrotic tubules
  • Heal by scarring, as kidney does not regenerate

50

Diffuse Cortical Necrosis

  • Uncommon condition w/ numerous causes
    • Severe Obstetric Complications
    • Sepsis
    • Toxins
    • Extensive Surgery/Trauma
    • Many Others
  • Pathogenesis
    • Occurs w/ conditions that cause acute vascular damage and/or release of considerable tissue thromboplastin, activation of the coagulation cascade and platelets, and triggering an inflammatory response
    • Vasospasm and thrombosis of intrarenal vessels results in occlusion, ischemia, and tissue necrosis
    • Renal cortex has high metabolic demands, and is more susceptible to ischemic necrosis than is the medulla
  • Gross Morphology
    • Pale, ischemic, necrotic areas are confined to cortex and columns of Berlin
  • Microscopic
    • Thrombi are typically found in glomerular capillaries, arterioles, venules, and veins
    • Multifocal or diffuse coagulative necrosis of the cortex
    • Subscapular 1-2 mm of cortex, juxtamedullary cortex, and medulla are spared
    • Non-necrotic tubules may have acute tubular injury
    • Little interstitial inflammation is present; hemorrhage is usually seen at the edges

51

What is the major known cause of congenital heart disease?

Sporadic Genetic Abnormalities

52

Almost all congenital heart abnormalities predispose to what?

Bacterial Endocarditis

53

Congenital Disorders that Cause L to R Shunts

  1. Atrial Septal Defect
  2. Ventricular Septal Defect
  3. Patent Ductus Arteriosus
  4. Atrioventricular Septum Defect

54

Ventricular Septal Defect (VSD)

  • The most common congenital heart anomaly
  • Caused by incomplete closure of interventricular septum
  • Small VSDs are typically asymptomatic
  • Large defects may be manifested at birth or early in childhood by cyanosis and dyspnea
  • Frequently associated w/ other structural cardiac defects
  • Physical Exam Findings
    • Harsh holosystolic murmur is typical
      • Best heard at lower left sternal border
    • Small defects have the loudes murmurs because of turbulence
  • VSDs are classified according to their size and location, most are about the size of the aortic valve orifice
    • 90% involve region of membranous interventricular septum
    • Rest lie below the pulmonary valve or w/in the muscular septum
  • Treatment
    • Complete or partial spontaneous closure of small/moderate VSDs occurs in up to 50% of children by age 2
    • Surgical correction is recommended early for children w/ CHF or pulmonary vascular disease
  • Bacterial endocarditis may develop in patients w/ VSD w/ any size. Medical management includes prophylaxis for endocarditis for all patients w/ VSDs
  • Pressures are the same in both ventricles
  • Pressure hypertrophy of R Ventricle and Volume Hypertrophy of the L Ventricle are usually present

55

Atrial Septal Defect

  • Persistent opening in interatrial septum
  • Most common site is at the foramen ovale (ostium secundum ASD)
  • Most common congenital heart abnormality presenting in adulthood
  • Usually asymptomatic until after age 30
  • Detected by murmur
    • Usual.y from excessive flow through pulmonary valve
    • Mild systolic murmur is heard at the upper sternal border w/ secudum defect
  • Symptoms
    • Dyspnea on Exertion
    • Fatigue
    • Recurrent Lower Respiratory Infections
    • Adults may have palpitations due to R Atrial Enlargement
  • Treatment
    • Repair Hole

56

Patent Foramen Ovale

  • Small hole created by an open flap of tissue in the atrial septum at the oval fossa b/t the L and R Atria
  • Hole is forced shut at birth by increased blood pressure on the L side of the heart
    • Hole closes permanently in 80% of people
    • Remaining 20%, flap can open when R sided pressure increases from pulmonary hypertension, bowel movement, cough, or sneezes
  • Common Abnormality
    • Most people are asymptomatic, and unware of its presence
    • More common in people w/ uneplained stroke, or migraines w/ auras
  • Paradoxical emboli may arise due to R-L Shunting
    • From deep venous thromboses that, instead of going from the legs to the R heart, travel instead from R atrium through patent foramen ovale to L atrium and into systemic arterial ciruclation
    • May cause stroke, myocardial infarction, or infarcts of kidneys, pancreas, or other organs

57

Patent Ductus Arteriosus (PDA)

  • Persistent opening of ductus areteriosus after birth, w/ abnormal blood flow b/t aorta and pulmonary artery
  • Before birth, ductus arteriosus allows blood to bypass the baby's lungs by connecting the pulmonary arteries w/ the aorta 
    • Channel is kept open by the action of series E prostaglandins
    • Soon after the infant is born and the lungs fill w/ air, this blood vessel is no longer needed
    • It will usually close w/in a couple of days, as the levels of prostaglandins fall
    • Ductus arteriosus does not close, there will be abnormal blood circulation b/t heart and lungs
  • More common in girls than boys, premature infants, and in those w/ neonatal respiratory distress syndrome
  • 90% are an isolated finding
  • Usually asymptomatic at birth
  • Initially there is a L to R shunt w/ no cyanosis
    • Later may become R to L shunt,  due to pressure overload
  • "Machine Murmur" is usually heard on physical examination
  • Treatment
    • If small, Indomethacin or other NSAID
    • If large, surgery

58

Atrioventricular Septal Defect (AVSD)

  • Caused by abnormal development of AV canal, due to failure of the superior and inferior endocardial cushion to fuse
  • Can be partial or complete
    • Partial form: involves primarily the atria
    • Complete form: all four chambers can communicate freely, inducing volume hypertrophy in each
  • Greater than 1/3 of people w/ complete AVSD have Down Syndrome
  • Treatment: Surgical Repair

59

Pathophysiology of R to L Shunts

  • Unoxygenated blood from the R side of the circulation flows directly into the L side when the pressures are higher in the R heart than the left
  • Hypoxemia and cyanosis result because of the admixture of poorly oxygenated venous blood w/ systemic arterial blood (cyanotic congenital heart disease)
  • Emboli arising in peripheral veins can bypass the lungs and directly enter the systemic circulation and cause paradoxical embolism
  • Infarction and abcess in various organs are potential complications
  • Hypertrophic osteoarthropathy (clubbing of tips of fingers and toes) and polycythemia may also result

60

Congenital Anomalies Presenting w/ R to L Shunts

  • Tetralogy of Fallot
  • Transposition of the Great Arteries
  • Persistent Truncus Arteriosus
  • Tricuspid Atresia
  • Total Anomalous Pulmonary Venous Connection

61

Tetralogy of Fallot

  • Results from a single developmental defect: abnormal anterior and cephalad displacement of the infundibular (outflow tract) protion of the interventricular septum
  • 4 Findings
    • Overriding Aorta (Receives blood from both ventricles)
    • Pulmonic Stenosis (Which obstructs the R ventricular outflow tract)
    • VSD
    • Right Ventricular Hypertrophy
  • Most common form of cyanotic congenital heart disease after infancy
  • 5 of 10000 live births
  • Often associated w/ other defects
    • R Sided Aortic Arch
    • ASD
    • Anomalous Origin of L Coronary Artery
  • Boot Shaped Heart
  • Cyanosis worsens as stenosis worsens
  • Infants may turn blue during crying spells
  • Children often squat during exercise

62

Transposition of Great Arteries

  • Aorta comes off R Ventricle and Pulmonary Artery comes off L Ventricle
  • Comprises about 7% fo all congenital heart defects
  • Most common cause of cyanosis in neonatal period
  • Precise cause unknown
  • Must have patent forament ovale, ductus arteriosus or VSD to be compatible w/ life
  • Outlook depends on amout of "mixing" from VSD, PDA, or PFO
  • Cyanosis is usually present on day of birth
  • Medical Emergency
  • Maintian ductus arteriosus by prostaglandin infusion and use a balloon catheter to maintain intratrial communication until surgery can be performed
  • Treatment
    • Surgery
      • Arterial switch to proper position, coronary arteries then relocated to new aorta

63

Truncus Arteriosus

  • Aorta and Pulmonary Artery are merged as one vessel (due to failure of the embryologic truncus to split)
  • Underlying VSD is also present
  • If not corrected, pulmonary hypertension develops

64

Total Anomalous Pulmonary Venous Return

  • No pulmonary veins join the L Atrium
  • Embryologic systemic venous channels in the lung stay patent
  • Pulmonary venous drainage is into the left innominate vein or coronary sinus
  • Must have either a patent foramen ovale or an ASD to be compatible w/ life

65

Tricuspid Atresia

  • Complete occlusion of the tricuspid valve orifice due to abnormally developed or missing tricuspid valve
  • Results from unequal division of the AV Canal
  • Mitral valve is larger than normal 
  • R Ventricle is underdeveloped
  • Cyanosis present practically from birth
  • Mortality is high in the first few weeks of life
  • Treatment is complex w/ 3 stages:
    • Surgery immediately, at 4-6 months, and again b/t age 18 months and 4 years
  • Some large hospitals consider heart transplant a better alternative, but infant hearts are in short supply

66

Congenital Aortic Stenosis

  • Causes obstruction of blood flow from L Ventricle to Aorta
  • Most often caused by abnormal development of the valve (aortic valve stenosis), but may also be caused by muscular obstruction below the aortic valve, or aortic narrowing immediately above the valve
  • Most commonly bicuspid
    • 5/10000 live births
    • More common in males
    • 20% have additional abnormality
    • Valve leaflets are often thickened and less pliable than normal and the commissures are fused together to a variable degree
    • L Ventricle Hypertrophy
    • Turbulence cause chronic damage to valves and worsens stenosis
  • Physical Exam
    • Harsh, Crescendo-Decrescendo Systolic Murmur at Base of Heart, Radiating to the Neck, Present from Birth
    • Worsening stenosis leads to louder murmur
  • Treatment
    • Endocarditis prophylaxis 
    • Milder forms do not need surgical correction
    • More severe cases need surgical correction
      • Valvuloplasty in infancy is only palliative and additional revision is usually needed later

67

Congenital Pulmonic Stenosis

  • May involve pulmonic valve or the pulmonic artery
    • Valve stenosis seen in >90% of cases
  • May be an isolated defect or seen w/ another heart defect
  • Causes obstruction of R Ventricular Outflow w/ resulting R Ventricular Hypertrophy
  • Diagnosis is often made by finding a murmur on routine physical exam
  • Children w/ mild/moderate stenosis are asymptomatic
  • Mild pumlonic stenosis usually need NO treatment
  • Moderate/Severe Disease may by treated w/ balloon valvuloplasty

68

Coarctation of the Aorta

  • Discrete narrowing of aortic lumen
  • Incidence of 1/6000 live births
  • Often seen in Turner Syndrome
  • Accompanied by a bicuspid aortic valve in 50% of cases 
  • May also be associated w/ ASD, VSD, mitral regurgitation, or berry aneurysms of teh circle of Willis in the brain
  • May be classified according to location of the aortic narrowing relative to the ductus arteriosus
  • L Ventricle faces increased pressure load, w/ resulting hypertrophy
  • Blood flow to the head/neck is preserved because vessels supplying those areas branch off before obstruction
  • Flow to the descending aorta and lower extremities may be decreased
  • Affected children may have hypertension in upper body and hypotension in lower body
  • If coarctation occurs w/ a PDA cyanosis appears early
    • If NO PDA may not be noticed until adulthood
  • Older children and adults w/ this disorder have enlarged intercostal/internal mammary arteries and "notches" in the ribs from enlarged vessels
  • Resection and grafting is curative 

69

Agenesis of the Kidney

  • Bilateral agenesis is compatible w/ life
    • Often w/ other congenital abnormalities
  • Unilateral is uncommon, compatible w/ normal life, if there are no other abnormalities
    • Solitary kidney enlarges (compensatory hypertrophy)
    • Some develop progressive glomerular sclerosis, and eventually, chronic renal disease

70

Hypoplasia

  • Failure of kidneys to develop to normal size
  • May be seen in low birth weight infants and contributes to overall lifetime risk of chronic kidney disease
  • May be bilateral w/ renal failure in early childhood
  • More commonly is unilateral
  • True hypoplastic kidney has no scars and has reduced # of renal lobes and pyramids, whereas acquired diseases may have scarring and a normal number of renal lobes and pyramids

71

Horseshoe Kidneys

  • Fusion of upper (10%) or lower poles (90%) of kidneys
  • Produces a horseshoe-shape single kidney continuous across midline anterior to great vessels
  • Found in 1/500 - 1/1000 autopsies

72

Autosomal Dominant Polycystic Kidney Disease

  • Common hereditary disease 1/400 - 1/1000 live births
  • Characterized by multiple expanding cysts of both kidneys
  • Ultimately destroys kidneys and causes renal failure
  • Cysts are NOT present at birth, but develop gradually over years/decades
  • APKD causes 5-10% of cases of end stage renal disease requiring transplantation or dialysis
  • Inheritance
    • Autosomal Dominant w/ high penetrance 
    • Both alleles must be nonfunctional for development of the disease
    • Patients inherit one copy of mutated APKD gene, and mutation of the other allele results in APKD
  • Genetics
    • PKD1
    • PKD2
  • Pathogenesis
    • Not established, currently favored hypothesis is that the cilia-centrosome complex of tubular epithelial cells is critical in pathogenesis
  • Clinical Features
    • Cysts initially involve a minority of nephrons, so renal function is retained until about the 4th and 5th decade of life
    • Many people remain asymptomatic until renal insufficiency develops
    • Characterized by the insidious onset of hematuria (precedes other symptoms), followed by polyuria, and hypertension
      • Include urinary tract infection, concentrating defect, abdominal or flank pain, and nephrolithiasis
      • Proteinuria is typically absent, but not considered a major feature
    • Most reliable predictor of the development of renal failure is kidney size
      • Larger = higher likelihood of renal failure
    • Pateints w/ PKD2 mutations tend to have onset at older age and delayed development of renal failure, compared to those w/ PKD 1
    • Genetic and Environmental factors influence disease severity
    • Extrarenal Congenital Abnormalities associated w/ APKD
      • Polycystic Liver Disease (40%), usually asymptomatic
      • Cysts in spleen, pancreas, lungs less frequently (also asymptomatic)
      • Intracranial Berry Aneurysms arise in circle of Willis
        • Subarachnoid hemmorrhage may cause death in 4-10% of patients
      • Mitral Valve prolapse, and other heart valve abnormalities in 20-25%, mostly asymptomatic
      • Abdominal wall hernias
  • Gross Morphology
    • Kidneys are markedly enlarged bilaterally; may be enormous
    • Externally the kidney appears to be composed of a mass of cysts, each up to 3-4 cm diameter w/ no intervening renal perenchyma seen grossly
  • Microscopic Morphology
    • Functioning nephrons are interspersed b/t cysts
    • Cysts arise from tubule throughout the nephron, so lining epithelium is variable
      • Papillary epithelial formations and polyps may project into the lumen
    • Cysts are filled w/ clear, serous fluid or w/ turbid, red-brown fluid, or blood
    • Enlarging cysts encroach upon the calyces and pelvis to produce pressure defects

73

Autosomal Recessive (Childhood) Polycystic Disease (ARPKD)

  • Genetics
    • Caused by mutations in PKHD on chromosome 6
      • PKHD1 cause most cases of APRKD
    • Perinatal, neonatal, infantile, and juvenile subcategories exist
      • Perinatal and Neonatal MOST COMMON
  • Pathogenesis
    • PPKHD1 encodes fibrocystin protein, that is localized to the primary cilium of tubular cells, like polycystins 1 and 2 (function unknown)
    • "Ciliopathy"
  • Clinical Features
    • Broad w/ variable features and age of onset
    • Kidneys and Liver most commonly involved
      • Lungs may also be affected
    • About 1/3 of cases present before age 1
    • About 1/3 b/t ages 1-20
    • And about 1/3 after age 20
    • Homozygous truncating mutations in PKHD1 are associated w/ perinatal renal disease
      • Homozygous missense mutations present at a later age
    • Neonates often present w/ severe respiratory distress and pulmonary hypoplasia, +/- renal failure. Lethal in 30-40% of neonates
    • Hypertension present in almost all cases, at any age, typically developing before renal impairment is apparent
    • Other manifestations of cystic renal disease may also be present
      • Stones do not appear to be a significant finding
    • Patients who survive infancy may develop congenital hepatic fibrosis w/ periorbital fibrosis and proliferation of well differentiated biliary ductules
    • In older children and adults, the liver disease predominates, and patients may have portal hypertension and splenomegaly
      • May slo have renal insufficiency or concentrating defects
  • Gross Morphology
    • Neonates
      • Massively enlarged cystic kidneys w/ smooth external appearance
      • Bilateral Hypoplastic Lungs
    • Older Patients
      • Medulalry cysts +/- cortical cysts
      • Congenital hepatic fibrosis
    • Cut surface has numerous small cysts in cortex and medulla, giving it a sponge like appearance
    • Cysts are smaller than those of ADPKD, and are dilated, elongated channels at right angles to the cortical surface, completely replacing the medulla and cortex
  • Microscopic Morphology
    • Cylindrical or (less commonly) saccular dilation of all collecting ducts
    • Cytsts have a uniform lining of cuboidal cells, reflecting their origin from the collecting ducts
    • In almost all cases the liver also has cysts, associated portal fibrosis, and proliferation of portal bile ducts
    • In neonates, bile duct plate malformation is seen in the liver

74

Three Major Types of Cystic Diseases of Renal Medulla

  • Medullary Sponge Kidney
  • Nephronophthisis
  • Adult-Onset Medullary Cystic Disease

75

Medullary Sponge Kidney

  • Limited to conditions w/ tubular ectasia (dilation) of the collecting ducts and cystic formation confined to the medullary pyramids
  • Occurs in adults; usually discovered radiographically as an incidental finding
  • Genetics
    • Most cases are sporadic (No clear family transmission)
  • Clinical Presentation
    • Asymptomatic unless complicated by nephrolithiasis, hematuria, or infection
    • Symptoms (if present) are usually found in 4th and 5th decades
    • Renal function is usually normal
  • Pathogenesis unknown
  • Gross Morphology
    • Kidneys are usually normal in size, to slightly enlarged
    • Papillary ducts in the medulla are dilated and small cysts may be present
    • Cysts are limited to the medullary pyramids and papillae
      • Usually affect all pyramids in both kidneys
    • Cysts are lined by collecting duct epithelium and usually communicate w/ collecting tubules
    • Cortical scarring is absent, unless pyelonephritis exists
  • Microscopic Morphology
    • Cysts are lined by cuboidal epithelium, or sometimes by transitional epithelium, with no scarring

76

Nephronophthisis (NPHP)

 

  • MOST COMMON genetic cause of end-stage renal disease in children and young adults
  • Genetics and Pathogenesis
    • At least 16 responsible gene loci
    • Gene products present in primary cilia, basal bodies attached to these cilia, or the centrosome organelles form which the basal bodies originate
    • Pathogenesis still unknown "ciliopathy"
  • Three Main Types, Based on Inheritance
    • Sporadic, Nonfamilial
    • Familial Juvenile (MOST COMMON)
      • Autosomal Recessive Inheritance
      • Become clinically evident in childhood or adolescence
    • Renal-Retinal Dysplasia
  • Three Main Types, Based on Age at Clinical Presentation
    • Type I (Infantile), age at presentation <4 years
    • Type II (juvenile), age at presentation 13 years
    • Type III (adolescent), average age at presentation 19 years
  • Clinical Presentation
    • Polyuria and polydipsia, reflecting severe defect in concentrating ability of renal tubules, w/ sodium wasting and tubular acidosis
    • Fatigue and anemia typically develop during the disease course
    • Progression to ESRD typically occurs w/in 5-10 years
    • Several syndromic variants have associated extrarenal abnormalities (oculomotor or cerebellar abnormalities, retinal dystrophy, or liver fibrosis)
  • Gross Morphology
    • Corticomedullary and cortical cysts most prominent at corticomedullary junction
    • Kidney size varies w/ type
      • Infantile = large kidneys
      • Juvenile and Adolescent = Small or Normal
  • Microscopic Morphology
    • Cysts are lined by flattened or cuboidal epithelium and usually surrounded by either inflammation or fibrous tissue (interstitial fibrosis)
    • Cortex has widespread atrophy and thickening of the tubular basement membranes, and interstitial fibrosis
    • Glomerular structure is generally preserved

77

Adult-Onset Medullary Cystic Kidney Disease (MCKD)

  • Genetics
    • Autosomal dominant inheritance
    • Mutations in two genes are known to cause MCKD
      • MCKD1 on chromosome 1
      • MCKD2 on chromosome 16
  • Pathogenesis
    • Like the rest of the ciliopathies, unknown
  • Clinical Presentation
    • Typically presents in 3rd or 4th decade of life
    • Similar presentation to NPHP, w/ polydipsia, polyuria, but w/o growth retardation or anemia
    • May have hyperuricemia and gout, too
    • Not associated w/ any extrarenal manifestations
  • Gross Morphology
    • Kidneys are normal or moderately reduced in size
    • Small corticomedullary cysts are common, but may not always be grossly detected
  • Microscopic Morphology
    • Diffuse interstitial inflammation and fibrosis
    • Tubular atrophy interspersed w/ hypertrophied and dilated tubules

78

Multicystic Renal Dysplasia

  • Not associated w/ true dysplasia
  • Sporadic disorder that is almost always cystic
  • Involves the entire kidney 
  • Unilateral or Bilateral
  • Gross Morphology
    • Kidney is usually enlarged, extremely irregular, and multicystic
    • Cysts vary in size from several millimeters to several centimeters
  • Microscopic Morphology
    • Cysts are lined w/ flattened epithelium
    • Normal nephrons are present, but many have immature collecting ducts
    • Islands of undifferentiated mesenchyme, often w/ cartilage, and immature collecting ducts are histologic hallmarks
  • Most cases are associated w/ ureteropelvic obstruction, ureteral agenesis or atresia, and other anomalies of the lower urinary tract
  • When unilateral, it may mimic a cystic neoplasm, but renal function of the other, uninvolved kidney is normal
  • If bilateral, renal failure may result

79

Acquired Cystic Renal Disease (ACRD)

  • Initially reported in patients undergoing long-term dialysis
  • Similar changes may alos occur in uremic, nondialyed patients
  • Etiology has not been established, but may result from obstruction of the renal tubules by local fibrosis, oxalate deposition, or epithelial hyperplasia
  • Usually asymptomatic, but sometimes cysts may bleed, rupture, or become infected, causing hematuria, flank pain, and/or fever
  • Gross Morphology
    • Usually bilateral cysts, in both the renal cortex and medulla
    • Cysts numbers vary from a few subscapular cysts, to diffuse involvement of almost the entire kidney
    • Cysts are mainly smaller than 0.5 cm, but may be up to 2-3 cm
    • Cysts are filled w/ straw-colored or hemorrhagic fluid, often contain calcium oxalate crystals
  • Microscopic Morphology
    • Most cysts are lined by flattened epithelium, some are lined by hyperplastic cuboidal or columnar cells
      • Hyperplastic cysts may have papillary projections, which may occassionally develop atypia
    • Increased risk of renal cell carcinoma (12-18X), most commonly papillary type

80

Simple Cysts

  • MOST COMMON Cystic Abnormality of the Kidneys
  • Common postmortem finding w/o clinical significance
  • Usually asymptomatic, may occasionally hemorrhage, causing sudden distention and pain
  • Gross Morphology of Cysts
    • May be single or multiple, usually cortical. Rest of perenchyma normal
    • Measure 1-5 cm in size, may be larger
    • Cysts are translucent, lined by gray, glistening, smooth membrane
  • Microscopic Morphology
    • Cyst membran is composed of a single layer of cuboidal or flattened cuboidal epithelium, and lumen is filled w/ clear fluid
    • Calcification of the organizing hematoma may cuase abnormal radiographic findings
    • Main importance lies in distinction from cystic renal tumors
      • Simple cysts have smooth contours, are avascular, and give fluid signals on ultrasound (not solid)

81

Pathologic Responses of the Glomerulus to Injury

  • Hypercellularity
    • Proliferation of mesangial or endothelial cells
    • Infiltration of leukocytes
    • Formation of crests
      • Accumulations of proliferating glomerular epithelial cells (mainly parietal), and infiltrating leukocytes
      • Typically occurs after an immune/inflammatory injury involving capillary walls
  • Basement Membrane Thickening
    • Best seen in PAS-stained sections, this appears as thickening of capillary walls
    • Three forms
      • Deposition of amorphous, electron-dense material on endothelial or epithelial side of glomerular basement membrane, or w/in the GBM itself
      • Increased synthesis of protein components of GBM
      • Formation of additional layers of GBM matrices, mainly subendothelial
  • Hyalinosis and Sclerosis
    • Accumulation of hyalin, an amorphous material that, by light microscopy, appears homogenous and eosinophilic
      • Hyalin is composed of insudated plasma proteins that accumulate
    • Sclerosis is deposition of extracellular collagen matrix
      • May be confined to mesangial areas, or involve the capillary loops, or both

82

Pathogenesis of Glomerular Injury

  • Immune mechanisms underlie most forms of primary glomerulpathy, and many of the secondary glomerular disorders
  • Immunoglobulin deposition (directly or as antigen-antibody complexes), w/ activated complement and/or inflammatory cells are found in glomeruli of the majority of patients w/ glomerulonephritis
    • Usually detected by IF staining of renal biopsies, typically granular pattern
  • Two Main Forms of Antibody-Associated Injury
    • Injury by antibodies reacting in situ w/in the glomerulus, either by binding to insoluble intrinsic glomerular antigens, or to extrinsic molecules planted w/in the glomerulus 
      • Binding to intrinsic glomerular antigens
        • Primary membranous nephropathy caused by antibodies to endogenous tissue components
        • Secondary membranous nephropathy caused by drugs and graft-versus-host disease
        • Anti-GBM antibodies bind to GBM antigens in a homologous pattern
      • Binding to extrinsic antigens
        • Planted antigens include DNA nucleosomes, other nuclear proteins, bacterial, or other microbial products, drugs, etc.
    • Injury resulting from deposition of circulating antigen-antibody complexes in the glomerulus  
      • Antibodies have no affinity for glomerular antigens, but localize to glomeruli because of physiochemical properties and hemodynamic factors peculiar to the glomerulus
      • Probably not as common as in situ antibody binding
  • Mechanisms of injury of following immune complex formation
  • Cell-Mediated Immunity in Glomerulonphretis
  • Activation of Alternative Pathway
  • Mediators of Glomerular Injury
  • Epithelial Cell Injury
  • Mechanisms in Progression in Glomerular Disease
    • Two Major Histologic Features of Progressive Renal Damage
      • Focal Segmental Glomerulosclerosis
      • Tubulointerstitial Fibrosis

83

Clinical Manifestations of Glomerular Diseases

  • Nephritic Syndrome
    • Definition - glomerular injury mainly due to inflammation
    • Clinical Features - hematuria, RBC casts, azotemia, oliguria, mild/moderate hypertension, and proteinuria
    • May be characterized
      • Acute Glomerunephritis
      • Rapidly Progressive Glomerulonephritis
    • Lesions are characterized by proliferative changes and leukocyte infiltration
  • Nephrotic Syndrome
    • Derangement in glomerular capillary walls, resulting in increased permeability to plasma proteins, due to many different types of injury
    • Clinical Presentation
      • Massive proteinuria (>3.5 g/day), hypoalbuminemia (secondary to proteinuria), generalized edema, hyperlipidemia and lipiduria
      • Patients vulnerable to infection, likely due to loss of immunoglobulins
      • Loss of endogenous anticoagulants may result in thrombotic risk
    • Causes
      • In children, it is usually caused by diseases primary to kidney 
      • In adults it is usually to infection, likely due to loss of immunoglobulins
      • Less common: membranoproliferative glomerulonephritis, IgA nephropathy
  • Chronic Glomerulonephritis
    • Refers to end stage glomerular disease resulting from specific types of glomerulonephritis, or developing w/o any antecedent history of acute glomerulonephritis
    • Gross Morphology
      • Kidneys are symmetrically contracted (shrunken), w/ diffusely granular cortical surfaces
      • Cortex is thinned and peripelvic fat is increased
    • Microscopic Morphology
      • Varies w/ stage of disease and cause
      • In early cases, glomeruli may still have evidence of primary acute disease
      • Later, glomeruli may be obliterated transforming into acellular eosinophilic masses
        • Vascular sclerosis may be present in cases of hypertension

84

Acute Proliferative Glomerulonephritis

  • Cause of nephritic syndrome, mainly in children
  • Immune-mediated deposition of antigen/antibody complexes derived from bacterial antigens after infection
    • Infection is resolved; no organisms present
  • Morphology
    • Diffusue glomerulonephritis w/ global hypercellularity due to neutrophil and monocyte infiltration, and proliferation of endothelial, mesangial and epithelial cells
    • Immunofluorescence
      • Granular mesangial and GBM deposition of IgG, IgM, and C3
    • Electron Microscopy
      • Subepithelial humps
    • Clinical Course
      • Appears 1-4 weeks after Group A beta Streptococcus pharyngitis or other site of strep infections w/ nephritogenic strain
      • >95% of children recover quickly
      • Only about 60% of adults recover quickly
        • The rest develop rapidly progressive and chronic renal failure, or delayed resolution

85

Rapidly Progressive Glomerulonephritis

  • Rapid, progressive decline in renal function
  • Three Types based on cause, clinical features
    • Type I (anti-GBM antibody)
      • Linear IgG and C3 deposits in GBM
      • Antibodies may cross-react w/ pulmonary alveolar basement membranes to produce pulmonary hemorrhages
      • Genetic predisposition w/ environmental/infectious triggers
    • Type II (Immune Complex Mediated)
      • May be caused by an immune-complex nephritides
    • Type III (Pauci-immune)
      • Absence of anti-GBM antibodies or immune complexes. Patients instead have circulating antineutrophil cytoplasmic antibodies (ANCA), associated w/ systemic vasculitis
  • Gross Morphology
    • Kidneys enlarged and pale, often w/ petechial surface hemorrhages
  • Microscopic Morphology
    • Light Microscopy: crescents formed by parietal cell proliferation and inflammatory cell migration into Bowman space
      • Crescent may undergo sclerosis w/ time
    • Immunofluoresence
      • Linear staining in anti-GBM disease (type I)
      • Granular staining in immune-complex mediated (type II)
      • Little/No Staining in (type III)
    • Electron Microscope
      • Distinct ruptures in the GBM; subepithelial electron-dense deposits may also occur in type II disease
  • Clinical Course
    • Present w/ nephritic syndrome
    • Course is somewhat variable, depending upon type, but renal involvement is rapidly progressive over the course of a few weeks, culminating in severe oliguria 
    • Functional recovery may occur w/ intensive plasmapheresis + steroids and cytotoxic agents

86

Membranous Nephropathy

  • Common cause of adult nephrotic syndrome
  • Idiopathic in 85%; rest occur w/ malignancy, SLE, drugs, infections, autoimmune
  • Capillary leakiness results from complement activation that activates epithelial and mesangial cells to liberate damaging proteases and oxidants
  • Morphology
    • Light Microscopy
      • Shows diffuse thickening of capillary wall and interstitial chronic inflammation
      • Tubulary epithelial cells contain protein reabsorption droplets
      • W/ progressive disease, glomeruli will sclerose
    • Electron Microscope
      • Shows epithelial GBM deposits, eventually incorporated into the GBM to assume an intramembranous location
  • Clinical Features
    • Insidious onset of nephrotic syndrome
    • Course is variable, usually indolent

87

Minimal Change Disease

  • The major cause of nephrotic syndrome in children, usually b/t 2-6 years age
  • Occasionally follows respiratory infection or immunization, but also associated w/ atopic disorders and lymphoma/leukemias
  • Pathogenesis
    • Likely results from immune dysfunction and elaboration of circulating cytokines that affect visceral epithelial cells
    • Causes loss of glomerular polyanions that form part of normal permeability barrier, resulting in leakiness
  • Morphology
    • Light Microscopy - glomeruli look normal
    • Immunofluorescence - NO immune deposits
    • Electron Microscopic - Diffuse effacement of foot processes of visceral epithelial cells
  • Responds very well to corticosteroids
  • Long-term prognosis is excellent

88

Focal Segmental Glomerulosclerosis

  • Causes
    • Primary (idiopathic)
    • Secondary to IV drug abuse, HIV, sickle cell disease, obesity, other diseases
    • May occur after glomerular necrosis form other renal diseases (IgA Nephropathy)
    • May be an adaptive response to loss of renal tissue
    • May occure secondary to mutations of proteins that maintain glomerular filtration barrier (NPHS1, NPHS2, and others)
  • Pathogenesis
    • Primary glomerular lesion in FSGS from all causes in visceral epithelial damage in affected glomerular segments
    • Ensuing glomerular sclerosis and hyalinosis result from entrapment of plasma proteins, and increased matrix synthesis
  • Morphology
    • Light Microscopy
      • Sclerosis of some, but not all glomeruli (focal)
      • In affected glomeruli, only a portion of the capillary tuft is involve (segmental)
    • Immunofluorescence
      • IgM and C3 may be seen in sclerotic areas of mesangium
    • Electron Microscope
      • Diffuse foot process effacement w/ focal epithelial detachment, in both sclerotic and non-sclerotic 
  • Clinical Course
    • Nonselective proteinuria, hematuria, renal insufficiency, hypertension
    • In HIV-associated nephropathy, a severe collapsing glomerulopathy variant of FSGS may arise
      • It is not described because you will not need to know it

89

Membranoproliferative Glomerulonephritis

 

  • Accounts for up to 20% of nephrotic syndrome cases
  • Idiopathic or Secondary
  • Pathogenesis
    • Type I (Most Common)
      • Likely a consequence of antigen-antibody complex deposition and complement activation
      • Antigens may be from infection, autoimmue disease or malignancy
      • Usually source is unknown
    • Type II (Dense Deposit Disease)
      • Due to activation of alternate complement pathway
      • Most patients have C3 nephritic factor in the serum
  • Morphology
    • Light Microscopy
      • "TRAM TRACK"
    • EM
      • Type I
        • Subendothelial electron-dense deposits incorporated into the glomerular capillary wall b/t duplicated basement membranes and in mesangial regions
      • Type II
        • Characteristic laminar, ribbon-like, electron dense deposits in the GBM proper
  • Clinical Features
    • Most present in adolescence or young adulthood w/ nephrotic syndrome
    • Steroids may slow the progression, but about 50% of patients develop chronic renal failure w/in 10 years
    • High recurrence rate in renal transplant patients, especially w/ type II

90

IgA Nephropathy (Burger Disease)

  • The most common type of glomerulonephritis worldwide
  • Causes about 10% of cases of ESRD in many countries
  • More common in southern Europe, Asia, and in Native Americans
    • Less common in persons of African descent
  • Most common b/t ages 10-29 years, usually in males
  • Clinical Presentation
    • Recurrent hematuria after respiratory infection, but no systemic disease
    • Slowly progresses
      • 25-50% have renal failure at 20 years
    • Recurs in 20-60% of allografts
  • Morphology
    • Diffuse proliferation of mesangial cells and matrix w/o significant involvement of capillary walls or lumina
    • Prominent IgA deposits in mesangial regions
      • Electron dense on EM

91

Alport Syndrome

  • Heterogeneous groups of diseases due to defects in type IV collagen synthesis, affecting basement membranes
  • Inheritance is variable, depending on mutation
  • Genetics
    • Mutations in genes which code for important structural components of basement mebranes of kidney, inner ear, and eye
  • Clinical Presentation
    • Patients present w/ nephritis, subtle nerve deafness, eye disorders
    • Called hereditary nephritis if no hearing or vision defects are present
  • Morphology
    • Early lesions are only dectectable by EM
      • Diffuse GBM thickening and filling of interstitial cells w/ fats and mucopolysaccharides
    • As disease progresses
      • Morphological features of FSGS, tubular atrophy, and interstitial fibrosis may develop
    • In late stages
      • GBM is irregularly thickened w/ pronounced splitting of the lamina densa, often w/ a basket-weave appearance

92

Diabetic Neuropathy

  • Leading to ESRD occurs in about 40% of diabetics
  • Usually w/ glomerular disease leading to proteinuria, +/- nephrotic syndrome
  • Also causes hyalinizing arteriolosclerosis increasing susceptibility to pyelonephritis and papillary necrosis, and causes numerous tubular lesions
  • Morphology
    • Basement membrane thickening of tubules and glomerular capillaries
    • Diffuse mesangial sclerosis
    • Nodular glomerulosclerosis
  • Pathogenesis
    • Hyperglycemia and insulin deficiency lead to non-enzymatic glycosylation of proteins
    • Hydrodynamic changes in glomerulosclerosis

93

Nephroblastoma (Wilms Tumor)

  • Tumor arising from nephrogenic bastema cells that differentiate along several lines to include blatemal, epithelial, and stromal features
  • Most common genitourinary cancer in children (comprises 80% of GU neoplasms in patients under age 15 years)
  • Epidemiology
    • Usually affects young children (peak incidence 2-3 years) but usually not neonates or young infants
    • 98% diagnosed before age 10
    • Affects males and females equally
  • Clinical Manifestations
    • Abdominal mass, occassionally pain, hematuria, hypertension, and symptoms related to rupture (acute abdomen)
  • Gross Morphology
    • Solitary tumor, round w/ sharply defined border (encapsulated or pseudocapsule)
    • Cut surface is usually soft, friable, gray to tan, and bulges from surface
    • Foci of hemmorrhage and necrosis often present; rarely a dominant feature
    • Tumors tend to be firm, and have a whorled appearance on cut section, if have mostly mature elements
    • Often have a distinctly lobulated appearance as a result of fibrous septae
    • 7% are multicentric and 5% are bilateral
    • Adhesions to adjacent organs are often present
    • Tumor often extends into the renal vein, and metastasizes to regional lymph nodes
  • Microscopic Morphology
    • Triphasic tumors most characteristic (biphasic and monophasic also found)
      • Blastemal
        • Almost always present
        • Small densely packed, mitotically active, w/ little evidence of differentiation into recognizable epithelial or stromal structures
        • Arranged into diffuse, serpentine, nodular and/or basaloid patterns
      • Epithelioid Component
        • Resemble developing collecting ducts, nephrons, and glomeruli in the fetal kidney
      • Stromal Component
        • Spindle cells that resemble embryonic mesenchyme w/in myxoid background are present in almost all nephroblastomas
          • Skeletal muscle (most common)
    • Anaplasia may be present
  • Molecular Alterations
    • Deletion in chromosome 11p13 is found in children w/ WAGR syndrome and Denys-Drash syndrome
    • 11p15.5 alterations may be seen in Beckwith-Wiedemann Syndrome
    • Other abnormalities of chromosomes 1p, 12, and 8, 16q
  • Prognosis
    • Varies w/ age at diagnosis, stage, and degree of differentiation/anaplasia
      • Anaplastic cells are most resistant to chemotherapy
    • Overall survival is >90% w/ proper therapy
  • Disease Associations
    • WAGR syndrome
      • Increased susceptibility to Wilms tumor, aniridia, genital anomaly, retardation
    • Denys-Drash Syndrome
      • Glomerulonephritis, ambiguous genitalia, streak gonads, and increased susceptibility to Wilms tumor
    • Beckwith-Wiedemann Syndrome
      • Enlargement of body organs, hemihypertrophy, renal medually cysts, and abnormal large cells in adrenal cortex (cytomegaly)

94

Renal Papillary Adenoma

  • Small, discrete benign tumors arising from the renal tubular epithelium
  • Clinical
    • Common neoplasm
    • Found incidentally in 7-22% of persons at autopsy
  • Gross Morphology
    • Small, usually less than 0.5 cm
    • Found invariably w/in the cortex as pale yellow, discrete, well-circumscribed nodules
  • Microscopic Morphology
    • Composed of complex, branching papillary structures w/ numerous complex fronds
    • Cells may also grow as tubules, glands, cords, and sheets of cells
    • Cells are cuboidal to polygonal in shape, w/ regular small central nuclei and scant cytoplasm, w/ no significant atypia

95

Renal Oncocytoma

  • Neoplasm formed of "oncocytes," large eosinophilic cells that have granular cytoplasm due to the presence of many mitochondria (best demonstrated by EM)
    • Cells are thought to arise from the intercalated cells of collecting ducts
  • Epidemiology
    • 5-15% of all renal neoplasms
    • Most common in men
    • Usually found in adults older than age 50
    • May coexist w/ renal cell carcinoma
  • Clinical
    • Usually incidental finding, unless associated w/ Birt-Hogg-Dube syndrome
  • Genetics
    • No association w/ 3p abnormalities 
  • Gross Morphology
    • Well-encapsulated, usually solitary tumor
    • Tan to mahogany brown w/ relatively homogenous appearance
    • Central stellate scar in 1/3 of cases
    • May grow quite large, up to 12 cm
  • Microscopic Morphology
    • Comprised of abundant acidophilic, granular cytoplasm that grow in a nested pattern or tubular pattern
    • Nuclei are usually small, round and regular, but focal nuclear pleomorphism may be seen 
    • Tumors should NOT have papillary areas, clear cells, or necrosis

96

Angiomyolipoma

  • Neoplasm originating from perivascular epithelioid cells
  • Composed of vessels, smooth muscle, and fat; originating from perivascular epithelioid cells (PEC, PEComa)
  • Epidemiology
    • Usually diagnosed in adults
    • Uncommon, <1% of all renal tumors
    • May be sporadic, but is associated w/ tuberous sclerosis, and w/ TSC2/PDK1 contiguous gene syndrome
      • Tuberous sclerosis
        • Autosomal dominant neurocutaneous disorder
        • Characterized by hemartomas/tumors of brain, retina, skin, heart, bone, lung, and kidney; mental retardation and infantile/childhood seizures
        • Caused by alterations of TSC1 gene (hemartin) and TSC2 gene (tuberin)
        • Most cases are sporadic
        • About 80% of people w/ tuberous sclerosis develop angiomyolipomas w/ loss of heterzygosity of TSC2
      • TSC2/PKD1 Contiguous Gene Syndrome
        • Both kidneys are enlarged and cystic, w/ classic angiomyolipomas
  • Clinical Presentation
    • Almost always considered benign, but may be complicated by hemorrhage, or contiguous involvement of other organs
    • Retroperitoneal hemorrhage may be massive and sometimes fatal
  • Gross Morphology
    • Circumscribed, non-encapsulated, w/ pushing border 
    • Cut surface
      • red, pale tan-white, or yellow appearance
    • Size ranges from 0.5-25 cm
    • Usually unilateral and single tumors
    • If bilateral/multiple tumors suggest tuberous sclerosis
    • Even though benign, it may invade renal vein, regional lymph nodes, and adjacent organs
  • Microscopic Morphology
    • Triphasic tumor, w/ variable admixture of abnormal thick-walled blood vessels w/out elastic lamina, islands of mature adipose tissue, and spindle-shaped smooth muscle cells

97

Renal Cell Carcinoma (RCC)

  • Epidemiology
    • About 3% of all newly diagnosed cancers in US
    • Comprise of 85% of all renal cancers in adults
    • Men affected 2X more often than women
    • Most often occurs in older adults; mean age at presentation is 60 years
  • Clinical Manifestations
    • Most remain clinically occult for most of their lifespan
    • W/ Advanced Disease, some manifest "classic triad"
      • Hematuria
      • Flank Pain
      • Palpable Flank Mass
    • Other Symptoms 
      • Fever, weight loss, fatigue, nausea and vomiting, neuropathy, and muscle tenderness
    • Clinical symptoms usually do not seem related to kidney
    • Syndromes associated w/ RCC include hypercalcemia, polycythmia, hypertension, hepatic dysfunction, feminization or masculinization, Cushing syndrome, eosinophilia, leukemoid reactions, and amyloidosis
    • 30% present w/ signs of metastatic disease
    • 5-year survival is about 70% 
  • Risk Factors
    • Tobacco Use
    • Obesity
    • Unopposed estrogen therapy
    • Hypertension
    • Exposure to asbestos, petroleum products, and heavy metals
    • ESRD, CKD, Acquired Cystic Disease, and Tuberous Sclerosis
  • Genetics
    • Most cases sporadic
    • Familial Syndromes
      • Von Hippel-Lindau Syndrome
        • VHL gene
      • Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome
        • Autosomal dominant mutations in FH gene
      • Hereditary Papillary Carcinoma
        • Multiple, bilateral, papillary renal cell carcinomas
        • Mutations in MET proto-oncogene
      • Birt-Hogg-Dube Syndrome
        • Mutations involving BHD gene

98

Papillary Renal Cell Carcinoma

  • Type of RCC w/ predominant or exclusively papillary growth pattern
  • Second Most Common Type
  • Molecular Genetics
    • Sporadic Form
      • Trisomy 17
      • Trisomy 7
      • Loss of Y Chromosome in Males
    • Familial Form
      • Trisomy 7
    • NOT associated w/ abnormalities of chromosome 3p 
  • Gross Morphology
    • Usually well-circumscribed and eccentrically located in the renal cortex
      • May fibrous pseudocapsule
      • Cut surface is usually yellow, due to lipid-laden stromal macrophages
      • Most have regions of hemorrhage and necrosis
  • Microscopic Morphology
    • Papillary architecture in most cases
    • Neoplastic cells are arranged as a single layer on fibrovascular stalks, that may be expanded by lipid-laden macrophages
    • Psammoma bodies are often abundant 

99

Chromophobe Renal Cell Carcinoma

  • Thought to arise from intercalated cells of renal cortex, similar to oncocytoma
  • Clinical
    • Third Most Common Type
    • Usually in middle-aged and older adults
    • Slight male predominance
  • Molecular Genetics
    • Many different mutations found
    • Loss of one copy of chromosomes 1, 2, 6, 10, 13, and 17 seen in >85% of cases
  • Gross Morphology
    • Usually large tumors, usually unilateral
    • Almost always well circumscribed and solitary
    • Cut surface is usually solid brown, w/o hemorrhage or necrosis
  • Microscopic Morphology
    • Predominantly solid growth pattern, w/ groups of cells separated by incomplete fibrovascular septae
    • Most tumors have an admixture of pale cells w/ finely reticulated cytoplasm and brightly eosinophilic cells w/ densely granular cytoplasm
    • Cell membranes prominent due to displacement of other cell organelles by abundant microvesicles
    • Nuclei tend to be coarsely granular w/ wrinkled nuclear membrane and perinuclear halos, w/ occasional prominent nucleoli
    • Differential is Clear Cell RCC

100

Clear Cell RCC

  • Comprised of cells w/ clear cytoplasm, and do not form papilllary configurations
  • MOST COMMON TYPE
  • Prognosis
    • 5-Year Survival 75%; 10-Year Survival 62%
  • Microscopic Appearance
    • Well differentiated = uniform pattern mainly alveolar or acinar
    • Poorly differentiated = solid sheets of neoplastic cells w/ zones of hemorrhage, necrosis, and fibrosis
  • Gross Appearance
    • Tumor typically protrudes form renal cortex as round, well-circumscribe golden yellow mass
  • Molecular Genetics
    • 98% have loss of sequences on chromosome 3p, causing loss of theVHL gene
    • 95% sporadic

101

Collecting Duct (Bellini Duct) Carcinoma

  • Genetics
    • Several genetic abnormalities have been described, but none are characteristic
  • Gross Morphology
    • Infiltrative firm gray or white mass, centered in medulla
      • Sometime multinodular
    • Hemorrhage, necrosis, and cystic change are common
  • Microscopic Morphology
    • Infiltrative neoplasm
    • Pleomorphic cells w/ large nuclei, prominent nuceoli, coarse chromatin, and numerous mitoses
    • Tumor often looks like high grade adenocarcinoma
  • Prognosis
    • POOR

102

Renal Medullary Carcinoma

  • Rare, aggressive tumor arising in medulla, believed to arise from renal papillae or calyceal epithelium
  • Almost always arise in young patients w/ sickle cell trait, rarely sickle cell anemia, possibly triggered by chronic hypoxia
  • Clinical Features
    • Hematuria, flank pain, and weight loss in almost all patients
    • Often symptoms of metastatic disease
    • May have fever, nausea/vomiting, and palpable abdominal mass
  • Gross Morphology
    • Poorly circumscribed, lobulated, rubbery gray tumor in medulla, w/ hemorrhage and necrosis
    • 4-12 cm size
    • Usually extends into pelvis and calyces
  • Microscopic Morphology
    • Pleomorphic tumor cells w/ large dark nuclei, prominent nucleoli, and eosinophilic cytoplasm
    • Sickle RBC often seen in sections
  • Prognosis
    • Grim

103

Prognosis of types of RCC (Best to Worse)

Chromophobe > Papillary > Clear Cell > Collecting Duct and Medullary

104

Urothelial Carcinoma of the Renal Pelvis

  • Tumors arising from cells of the lining urothelium of the renal pelvis, not the renal parenchyma
  • Risk Factors
    • Increased incidence in Lynch Syndrome, tobacco use, and exposure to some industrial chemicals
    • Questionable link to analgesic nephropathy
  • Clinical Presentation
    • Almost invariably are small when discovered because hematuria
    • May block urinary outflow causing hydronephrosis
  • Gross and Microscopic Morphology
    • Similar to that for the bladder
  • Prognosis
    • Not good, despite small size at presentation, as invasion of the wall of renal pelvis and calyces is common
    • 5-Year Survival Rates
      • Low-Grade, Noninvasive Lesions: varies from 50-100%
      • High-Grade, Invasive Tumors 10%