Pbl Exam 7 Case 2

Front 1

1.. What are the three types of arteries?

Back 1

1. Large or elastic arteries
2. Medium-sized or muscular arteries
3. Small arteries and arterioles

*The relative amount and configuration of the basic consitutents vary along the arterial system owing to local adaptations to mechanical or metabolic needs.

Front 2

2. What are the principal points of physiologic resistance to blood flow in the body?

Back 2

The arterioles are the principal points of physiologic resistance to blood flow.

Front 3

3. Where does vascular leakage and leukocyte exudation occur in many types of inflammation?

Back 3

In the postcapillary venules.

Front 4

4. Which are more prone to irregular dilation, compression, degeneration, and vascular invasion - arteries or veins?

Back 4

B/c of their poor support, veins are predisposed to irregular dilation, compression, degeneration, and vascular invasion.

Front 5

5. What are 8 functions of endothelial cells?

Back 5

1. Maintenance of permeability barrier
2. Elaboration of anticoagulant, antithrombotic, fibrinolytic regulators
3. Elaboration of prothrombotic molecules
4. ECM production (collagen, proteoglycans)
5. Modulation of blood flow and vascular reactivity
6. Regulation of inflammation and immunity
7. Regulation of cell growth
8. Oxidation of LDL

Front 6

6. What are the three physiologic responses to vascular injury?

Back 6

1. Smooth muscle cells migrate from the media to the intima
2. Smooth muscle cell mitosis
3. Synthesize and deposit ECM

Front 7

7. What are arteriovenous fistulas?

Back 7

These are rare, usually small, abnormal communications between arteries and veins. They arise as developmental defects, but can also be produced from rupture of an arterial aneurysm into the adjacent vein, from penetrating injuries that pierce the walls of artery and vein, or from inflammatory necrosis of adjacent vessels.

These may be of clinical significance b/c they short-circuit blood from the arterial to the venous side, thereby causing the heart to pump additional volume; sometimes high-output cardiac failure ensues.

Front 8

8. What is atherosclerosis?

Back 8

Atherosclerosis is a slowly progressive disease of large to medium sized muscular and large elastic arteries.

It is characterized by elevated intimal-based fibrofatty plaques composed of lipids, proliferating smooth muscles cells, and increased ECM.

Lesions are initially focal, with patchy vessel involvement both circumferentially and longitudinally.

Front 9

9. What are the common locations for atherosclerosis to occur (in decreasing order)?

Back 9

In decreasing order:

1. Abdominal aorta
2. Coronary arteries
3. Popliteal arteries
4. Descending thoracic aorta
5. Internal carotid arteries
6. Circle of Willis

Front 10

10. What is the morphology of an atheromatous plaque?

Back 10

The characteristic atheromatous plaque is a raised white-yellow intimal based lesion, protruding into the vessel lumen.

Histologically, plaques are composed of superficial fibrous caps containing SMCs, leukocytes, and dense connective tissue ECM overlying necrotic cores, containing dead cells, lipid, cholesterol clefts, lipid-laden foam cells, and plasma proteins; small blood vessels proliferate at the intimal medial interface.

Front 11

11. What are the two common variants of atheromatous plaques?

Back 11

1. Fatty streaks
2. Complicated plaques

Front 12

12. What are fatty streaks?

Back 12

Fatty streaks are early lesions composed of intimal collections of lipid-laden macrophages and SMCs in patients as young as 1 y/o. They start as multiple yellow, flat spots less than 1mm in diameter that coalesce into elongated streaks, 1 cm or longer. They contain T lymphocytes and extracellular lipid in smaller amts than in plaques.

A causal relationship between fatty streaks and atheromatous plaques is suspected but remains unproved.

Front 13

13. What are complicated plaques?

Back 13

Complicated plaques are calcified, hemorrhagic, fissured, or ulcerated atheromas, predisposing to local thrombosis, medial thinning, cholesterol microemboli and aneurysmal dilation.

Front 14

14. What are the three principal components of atherosclerotic plaques?

Back 14

1. Cells, including SMCs, macrophages, and other leukocytes

2. ECM, including collagen, elastic fibers, and proteoglycans

3. Intracellular and extracellular lipid

Front 15

15. What are the major consequences of atherosclerotic disease?

Back 15

Most often involves the arteries supplying the heart, brain, kidneys, and lower extremities.

1. MI
2. Cerebral infarction
3. Aortic aneurysms
4. Peripheral vascular disease (gangrene of leg)
5. Sudden cardiac death
6. Chronic, ischemic heart disease
7. Thrombosis

Front 16

16. What are the four pathological changes that have clinical significance in atherosclerosis?

Back 16

1. Focal rupture, ulceration, or erosion of the luminal surface of the plaque may result in thrombus formation

2. Hemorrhage into a plaque, especially in the coronary arteries, may be initiated by rupture of the fibrous cap.

3. Superimposed thrombosis, which may partially or completely occlude the lumen.

4. Aneurysmal dilation may result from ATH-induced atrophy of the media, with loss of elastic tissue causing weakness and potential rupture.

Front 17

17. What are some other factors that can lead to atherosclerosis besides the obvious?

How are multiple risk factors for atherosclerosis calculated?

Back 17

1. Homocystinuria
2. Lipoprotein A
3. Type A personality

Front 18

18. What are the non-modifiable risk factors for atherosclerosis?

Back 18

1. Increasing age
2. Male gender
3. Family history
4. Genetic abnormalities
5. Obesity
6. Physical inactivity
7. Stress
8. Postmenopausal estrogen deficiency
9. High carbohydrate intake

Front 19

19. What are the potentially controllable risk factors for atherosclerosis?

Back 19

1. Hyperlipidemia
2. Hypertension
3. Cigarette smoking
4. Diabetes
5. EtOH
6. LipoproteinA
7. Hardened (trans) unsaturated fat intake
8. Chlamydia pneumoniae

Front 20

20. What is the pathogenesis of atherosclerosis?

Back 20

The contemporary view is the response to injury hypothesis, which considered atherosclerosis to be a chronic inflammatory response of the arterial wall initiated by injury to the endothelium.

Moreover, lesion progression is sustained by interaction between modified lipoprotein, monocyte-derived macrophages, T lymphocytes, and the normal cellular constituents of the arterial wall.

Front 21

21. What are the eight factors that are central to the contemporary view of atherosclerosis?

Back 21

1. Chronic endothelial injury
2. Accumulation of lipoproteins, mainly LDL, with its high cholesterol content, in the vessel wall
3. Modification of lesional lipoproteins by oxidation
4. Adhesion of blood monocytes to the endothelium, followed by the migration and transformation into macrophages and foam cells
5. Adhesion of platelets
6. Release of factors from activated platelets, macrophages, or vascular cells that cause migration of SMCs from media into the intima
7. Proliferation of SMCs in the intima, and elaboration of ECM, leading to accumulation of collagen and proteoglycans
8. Enhanced accumulation of lipids both within cells and extracellularly

Front 22

22. What is the cornerstone of the response to injury hypothesis?

Back 22

Chronic or repetitive endothelial injury is the cornerstone of the response to injury hypothesis.

Front 23

23. What are the two most important determinants of endothelial alterations?

Back 23

1. Hemodynamic disturbances that accompany normal circulatory function

2. Adverse effects of hypercholesterolemia.

Front 24

24. What do macrophages produce that increase the adhesion of leukocytes?

Back 24

Macrophages produce IL-1 and TNF, which increase adhesion of leukocytes.

Several chemokines generated by macrophages, including monocyte chemotactic protein-1, may recruit more leukocytes into the plaque.

Front 25

25. What do T lymphocytes encounter that stimulate macrophages as well as vascular endothelial cells and SMCs?

Back 25

They encounter IFN-γ and lymphotoxin, which in turn stimulate macrophages as well as vascular endothelial cells and SMCs.

Front 26

26. What three things are implicated in hypercholesterolemia in the genesis of atherosclerosis?

Back 26

1. The major lipids in atheromatous plaques are plasma-derived cholesterol and cholesterol esters.

2. Oxidized LDL is observed in macrophages in arteries at sites of fatty streaks. Antioxidant treatment protects against the development of atherosclerosis in hypercholesterolemic experimental animals.

3. Genetic defects in lipoprotein metabolism causing hyperlipoproteinemia are associated with accelerated atherosclerosis

Front 27

27. What are the three mechanisms by which hyperlipidemia contributes to atherogenesis?

Back 27

1. Chronic hyperlipidemia, particularly hypercholesterolemia, may directly impair EC function through increased production of oxygen free radicals that deactivate NO, the major endothelial relaxing factor.

2. With chronic hyperlipidemia, lipoproteins accumulate within the intima at sites of increased endothelial permeability.

3. Chemical change of lipid induced by free radicals generated in macrophages or ECs in the arterial wall yields oxidized LDL.

Front 28

28. What are four properties of oxidized LDLs?

Back 28

1. Oxidized LDL is ingested by macrophages through the scavenger receptor, distinct from the LDL receptor, thus forming foam cells.
2. Increases monocyte accumulation in lesions
3. Stimulates release of growth factors and cytokines
4. Is cytotoxic to ECs and SMCs

Front 29

29. What is the role of SMCs in the formation of atherosclerosis?

Back 29

SMCs migrate from the media to the intima, where they proliferate and deposit ECM components, converting a fatty streak into a mature fibrofatty atheroma, and contribute to the progressive growth of atherosclerotic lesions.

With progression, the atheroma is modified by SMC-synthesized collagen and proteoglycans.

Front 30

30. What is oligoclonality of atherogenic lesions?

Back 30

The monoclonal hypothesis of atherogenesis was based on observation that some human plaques are monoclonal or at most oligoclonal.

A recent study showed that clonal patches exist and are often greater than 4 mm in size in not only atherosclerotic but also normal arteries, consistent with the possibility that atherosclerotic plaques could arise in a pre-existing clonal patch.

Front 31

31. What two types of infections can contribute to atherosclerosis?

Back 31

Chlamydia pneumoniae and cytomegalovirus.

Evidence for C. pneumoniae is strongest, which includes direct detection of bacterial components in atherosclerotic lesions.

In addition, infectious organisms might potentiate the complications of existing lesions.

Front 32

32. Summary of the six mechanisms that contribute to plaque formation and progression

Back 32

1. Endothelial dysfunction
2. Monocyte adhesion and infiltration
3. Lipid accumulation and oxidation
4. SMC proliferation
5. ECM deposition
6. Thrombosis

Front 33

33. Clinical features of atherosclerosis can result from what four mechanisms?

Back 33

1. Insidious narrowing of vascular lumens
2. Plaque rupture or superficial erosion followed by superimposed thrombus causing sudden luminal occlusion
3. Vessel wall weakening followed by aneurysm formation and possible rupture.
4. Providing a source of thromboemboli

Front 34

34. What are the clinical features of atherosclerosis?

Back 34

Approximately 1/3 of all deaths in the US result from atherosclerosis, which is significant in causing MI, or sudden cardiac death, strokes, aneurysm rupture, mesenteric occlusion, and extremity gangrene.

Front 35

35. What is hypertensive vascular disease?

Back 35

Hypertension is the single most important risk factor in both coronary heart disease and strokes and can also directly cause congestive heart failure, renal failure, and aortic dissection.

Front 36

36. What causes 95% of the hypertension in most patients?

Back 36

In about 90% of cases hypertension has no known cause (primary or essential hypertension).

The remainder are mostly secondary to renal disease or (less often) to renal artery stenosis (renovascular hypertension), endocrine abnormalities, vascular malformations, or neurogenic disorders.

Front 37

37. What causes the bottom 5% of the hypertension in most patients?

Back 37

A small percentage of hypertensive persons show a rapidly rising blood pressure that if untreated, leads to death within a year or two.

This is called accelerated or malignant hypertension (systolic over 200 and diastolic over 120.

It may develop in previously normotensive persons but more often is superimposed on pre-existing benign hypertension, either essential or secondary.

Front 38

38. What are the characteristics of malignant hypertension?

Back 38

1. Severe hypertension (systolic over 200 and diastolic over 120)
2. Renal failure
3. Retinal hemorrhages and exudates with or without papilledema.

Front 39

39. When does arterial hypertension occur?

Back 39

Arterial hypertension occurs when the relationship between cardiac output and total peripheral resistance is altered.

Front 40

40. In what two ways does the renal artery stenosis cause increased BP?

Back 40

1. The decreased GFR induces renin secretion, initiating angiotensin II mediate vasoconstriction and increased peripheral resistance.

2. The resultant increases sodium reabsorption and therefore blood volume through the aldosterone mechanism.

Front 41

41. What determines BP?

Back 41

Blood pressure is proportional to cardiac output and peripheral vascular resistance.

BP = CO x TPR

The BP level is a complex trait that is determined by the interaction of multiple genetic, environmental and demographic factors that influence cardiac output and vascular resistance

Front 42

42. What are the four main things that regulate BP?

Back 42

1. Sodium load, mineracorticoids, and natriuretic factors

2. Vasoconstriction increases vascular resistance:
-includes angiotensin II, catecholamines, thromboxane, leukotrienes, and endothelin

3. Vasodilation decreases vascular resistance
-includes kinins, prostaglandins, nitric oxide, and adenosine

4. Regional autoregulation, wherein increased blood flow leads to vasocontriction (and vice versa).

Front 43

43. How do the kidneys regulate blood pressure?

Back 43

Through the renin-angiotensin system - angiotensin II raises BP by increasing both peripheral resistance and blood volume

When the blood volume is reduced, the GFR falls, leading to increased reabsorption of Na by proximal tubules and thereby conserving sodium and expanding blood volume

The kidneys respond to natriuretic factors by inhibiting sodium reabsorption is distal tubules and thereby cause sodium excretion and diuresis.

When renal excretory function is impaired, increased arterial pressure is a compensatory mechanism that helps restore fluid and electrolyte imbalance.

Front 44

44. What are the mechanisms of essential hypertension?

What are the two systems that can have abnormalities in essential hypertension?

Back 44

Essential hypertension is caused by increased blood volume (due to reduced renal sodium excretion) or increased peripheral resistance (due to increased release of vasocontrictor agents), or both.

Two systems that can have abnormalities in essential hypertension:
1. The renin-angiotensin system
2. Sodium homeostasis

Front 45

45. What genetic disorders cause hypertension?

For instance, what is Liddle syndrome?

Back 45

1. Gene defects in enzymes involved in aldosterone metabolism (e.g. aldosterone synthase, 11β-hydroxylase, 17α-hydroxylase). These lead to an adaptive increase in secretion of aldosterone, increased salt and water resorption, plasma volume expansion, and hypertension.

2. Mutations in proteins that affect sodium reabsorption. For example, the moderately severe form of salt-sensitive hypertension, called Liddle syndrome, is caused by mutations in an ENaC protein that lead to increased distal tubular reabsorption of sodium induced by aldosterone.

Front 46

46. What is the vascular pathology in hypertension?

Back 46

Hypertension accelerates atherogenesis and causes structural changes that potentiate both aortic dissection and cerebrovascular hemorrhage.

In addition, hypertension is associated with arteriolosclerosis, primarily affecting arterioles and small arteries, particularly in the kidney.

Front 47

47. What are the two types of arteriosclerosis?

Back 47

1. Hyaline arteriolosclerosis
2. Hyperplastic arteriolosclerosis

Front 48

48. What is hyaline arteriolosclerosis?

Back 48

Hyaline arteriolosclerosis is a major morphologic characteristic of benign nephrosclerosis.

It typically occurs in elder people, particularly those with mild hypertension and mild diabetes. The lesion probably reflects EC injury, with subsequent plasma leakage into the arteriolar walls and ECM synthesis by SMCs.

Microscopically, there is diffuse, pink, hyaline arteriolar thickening.

Front 49

49. What is hyperplastic arteriolosclerosis?

Back 49

Hyperplastic arteriolosclerosis is characteristic of malignant hypertension.

There is concentric laminated (onion-skin) arteriolar thickening with reduplicated basement membrane and SMC proliferation, frequently associated with fibrin deposition and acute necrosis of the vessel walls, so-called necrotizing arteriololitis, particularly in the kidney.

Front 50

50. What is an aneurysm?

What is a true aneurysm vs. a false aneurysm?

Back 50

An aneurysm is a localized abnormal dilation of blood vessel or the wall of the heart.

When an aneurysm is bounded by arterial wall components or the attenuated wall of the heart, it is called a true aneurysm.

In contrast, a false aneurysm is a breach in the vascular wall leading to an extravascular hematoma that freely communicates w/the intravascular space ("pulsating hematoma").

Front 51

51. What are examples of true aneurysms?

False aneurysms?

Back 51

Atherosclerotic, syphilitic, and congenital vascular aneurysms and the left ventricular aneurysm that can follow a MI are of the true aneurysm type.

The most common false aneurysm is a post MI rupture that has been contained by a pericardial adhesion, or a leak at the junction (anastomosis) of a vascular graft w/a natural artery.

*Both true and false aneurysms can rupture.

Front 52

52. What are the two most important causes of aortic aneurysms?

Back 52

1. Atherosclerosis
2. Cystic medial degeneration of the arterial media

Front 53

53. What is a mycotic aneurysm?

What are the three ways in which they may originate?

Back 53

Infection of a major artery that weakens its wall gives rise to mycotic aneurysm.

They may originate either (1) from embolization and arrest of a septic embolus at some point w/in a vessel, usually as a complication of infective endocarditis; (2) as an extension of an adjacent suppurative process; or (3) by circulating organisms directly infecting the arterial wall.

Front 54

54. What are saccular aneurysms?

What are fusiform aneurysms?

Back 54

Saccular aneurysms are essentially spherical and vary in size from 5-20 cm in diameter, often partially or completely filled by thrombus.

Alternatively, aneurysms may be fusiform (involving a long segment). Fusiform aneurysms vary in diameter (up to 20 cm) and in length; many involve the entire ascending and transverse portions of the aortic arch, whereas others may involve large segments of the abdominal aorta or even the iliacs.

Front 55

55. Where do atherosclerotic aneurysms occur most frequently?

Back 55

Atherosclerotic aneurysms occur most freq in the abdominal aorta (AAA), but the common iliac arteries, the arch, and descending parts of the thoracic aorta can be involved.

Front 56

56. What is the morphology of AAA?

Back 56

Usually positioned below the renal arteries and above the bifurcation of the aorta, AAAs are saccular or fusiform, sometimes up to 15 cm in greatest diameter and of various length.

The aneurysm and the nearby aorta often contain atheromatous ulcers covered by granular mural thrombi, prime sites for the formation of atheroemboli that may lodge in the vessels of the kidneys or lower extremities. Additionally, a thrombus freq fill at least part of the dilated segment.

Not infrequently, AAAs are accompanied by smaller fusiform or saccular dilations of the iliac arteries.

Front 57

57. What is the inflammatory AAA variant?

Back 57

Inflammatory AAAs are characterized by dense periaortic fibrosis containing an abundant, inflammatory reaction rich in lymphocytes and plasma cells w/many macrophages and often giant cells.

Their cause is uncertain.

Front 58

58. What is the mycotic AAA variant?

Back 58

Mycotic AAAs are atherosclerotic AAAs that have become infected by lodgment of circulating organisms in the wall, particularly in bactermeia from a primary Salmonella gastroenteritis.

In such cases, suppuration can further destroy the media, potentiating rapid dilation and rupture.

Front 59

59. What is the pathogenesis of AAAs?

Back 59

Atherosclerosis is a major cause of AAAs, but other factors may contribute. They rarely develop before age 50 and are more common in men. There is a genetic susceptibility to AAAs in that altered collagen or its remodeling could provide a susceptible substrate on which atherosclerosis or hypertension could act to weaken the aortic wall.

In this regard, the MMPs have been implicated in the development of AAAs thru increased proteolysis of ECM proteins. MMPs are expressed in aortic aneurysms at elevated levels compared w/normal vessel wall. Also, a decreased level of tissue inhibitor of MMPs has been reported in AAA.

Front 60

60. What is the clinical course of AAAs?

Back 60

Risk of rupture increases w/the max diameter of the AAA; minimal risk if smaller than 5 cm but a risk of 5-10% annually when greater than 5 cm.

Operative mortality rate is 5% of unruptured aneurysm but more than 50% after rupture.

B/c aortic atherosclerosis is usually accompanied by severe coronary atherosclerosis, patients w/AAA have a high incidence of ischemic heart disease.

Front 61

61. What are syphilitic (leutic) aneurysms?

What do most patients with this die from?

Back 61

The obliterative endarteritis characteristic of the tertiary stage of syphilis (lues) shows a predilection for small vessels, w/complications especially in the aorta and nervous system.

Syphilitic involvement of the vasa vasorum of the thoracic aorta van lead to aneurysmal dilation that can include the aortic annulus.

*Most patients w/syphilitic aneurysms die of heart failure induced by aortic valvular incompetence.

Front 62

62. What is the morphology of syphilitic aneurysms?

Back 62

Inflammatory involvement begins in the aortic adventitia, particularly involving the vasa vasorum, inducing obliterative endartertis rimmed by an infiltrate of lymphocytes and plasma cells (sphilitic aortitis). The narrowing of the lumina causes ischemic injury of the aortic media.

W/destruction of the media, the aorta loses its elastic recoil and may become dilated, producing a syphilitic aneurysm. Contraction of fibrous scars may lead to wrinkling of intervening segments of aortic intima, called "tree-barking".

*Luetic involvement of the aorta favors the development of superimposed atheromatosis of the aortic root, which can envelop and occlude the coronary ostia.

Front 63

63. What is a complication of leutic aortitis?

What is cor bovinum?

Back 63

Luetic aortitis may also cause aortic valve ring dilation, resulting in valvular insufficiency thru circumferential stretching of the valve cusps, widening of the commissures btwn the cusps, and turbulence-induced thickening and rolling of the free margins.

Owing to aortic insufficiency, the left ventricular wall can undergo massive volume overload hypertrophy and be referred to as "cor bovinum" (cow's heart).

Front 64

64. What are the 7 complications of thoracic aneurysms?

Back 64

1. Encroachment on mediastinal structures
2. Respiratory difficulties due to encroachment on the lungs and airways
3. Difficulty in swallowing due to compression of the esophagus
4. Persistent cough due to irritation of or pressure on the recurrent laryngeal nerves
5. Pain caused by erosion of bone
6. Cardiac disease as the aortic aneurysm leads to aortic valve dilation and insufficiency
7. Rupture

Front 65

65. What is an aortic dissection (dissecting hematoma)?

Back 65

Aortic dissection is a catastrophic illness characterized by dissection of blood between and along the laminar planes of the media, with the formation of a blood-filled channel, within the aortic wall, which often ruptures outward, causing massive hemorrhage.

*May or may not be associated w/marked dilation of the aorta.

Front 66

66. What is the prevalence of aortic dissection?

Back 66

Aortic dissection occurs in two groups of people:

1. Men between the ages of 40-60 with antecedent hypertension (90%)
2. Usually younger group that has a systemic or localized abnormality of connective tissue defects that affects the aorta (e.g., Marfan syndrome)

Front 67

67. What is the morphology of aortic dissection?

1/2

Back 67

In spontaneous dissection, an intimal tear that is presumably the origin extends into but not thru the media of the ascending aorta, usually w/in 10 cm of the aortic valve. These tears are transverse or oblique, 1-5 cm in length and have sharp, jagged edges.

The dissection can extend proximally toward the heart as well as distally all the way into the iliac and femoral arteries.

The dissecting hematoma spreads characteristically along the laminar planes of the aorta, usually between the middle and outer thirds.

Front 68

68. What is the morphology of aortic dissection?

2/2

Back 68

In some instances, the blood reruptures into the lumen of the aorta, producing a second or distal intimal tear and a new vascular channel within the media of the aortic wall (to produce a "double-barreled aorta" with a false channel).

In the course of time, false channels may become endothelialized ("chronic dissection")

Front 69

69. What is the most frequent preexisting histologically detectable lesion in aortic dissection?

Back 69

Medial degeneration (AKA cystic medial degeneration).

Medial degeneration is characterized by elastic tissue fragmentation and separation of the elastic and fibromuscular elements of the tunica media by small cleftlike spaces where the normal elastic tissue is lost; these areas are filled with amorphous ECM of connective tissue and resembles cysts.

*Medial degeneration of the aorta frequently accompanies Marfan syndrome.

Front 70

70. What is the pathogenesis of aortic dissection?

Back 70

Hypertension is clearly the major risk factor. Some dissections are related to inherited connective tissue disorders, most prominently Marfan syndrome.

Regardless of etiology, the trigger for the intimal tear and intramural aortic hemorrhage is unknown in most cases. Once the tear has occurred, increases systemic BP fosters progression of the medial hematoma.

Front 71

71. What is the clinical course of aortic dissections?

What is the most common cause of death?

Back 71

The classic symptoms are the sudden onset of excruciating pain, usually beginning in the anterior chest, radiating to the back, and moving downward as the dissection progresses. This pain can be readily confused with that of an acute MI.

The most common cause of death is rupture of the dissection outward into any of the three body cavities. This can then lead to cardiac tamponade, aortic insufficiency, and MI.

The prognosis has markedly improved; surgical repair and early treatment w/antihypertensive meds permit salvage of 65-75% of pts w/dissections.

Front 72

72. What determines the clinical course of aortic dissection?

Back 72

The risk and nature of complications depend on the level of the aorta affected, w/the most serious complications occurring from the aortic valve to the arch.

There are two types of aortic dissections:
1. Type A - the more common (and serious or potentially damaging) proximal lesions, involving either the ascending portion only or both the ascending and the descending aorta.
2. Type B - distal lesions not involving the ascending part and usually beginning distal to the subclavian artery.

Front 73

73. What is vasculitis?

Back 73

Inflammation fo the walls of vessels, called vasculitis, is encounted in diverse clinical settings. Clinical manifestations often include constitutional signs and symptoms such as fever, myalgias, arthralgias, and malaise, or local manifestations of downstream tissue ischemia.

Front 74

74. What are the two most common mechanisms of vasculitis?

Back 74

1. Direct invasion of vascular walls by infectious pathogens
2. Immune mediated mechanisms

Front 75

75. What are the three main immunologic mechanisms that initiate noninfectious vasculitis?

Back 75

1. Immune complex deposition
2. Antineutrophil cytoplasma antibodies
3. Anti-endothelial cell antibodies

Front 76

76. What is the evidence for immune complexes in noninfectious vasculitis?

Back 76

1. The vascular lesions resemble those found in the Arthus phenomenon and serum sickness. Immune reactants and complement can be detected in the serum or vessels of patients with vasculitis.
2. Hypersensitivity to drugs causes approx 10% of vasculitic skin lesions, largely thru vascular deposits of immune complexes.
3. In vasculitis associated w/viral infection, immune complexes can be found in the serum and in the vascular lesions of some pts, particularly in the cases of polyarteritis nodosa (for example, HBsAg-anti-HbsAg in hepatitis induced vasculitis).

Front 77

77. What are antineutrophil cytoplasmic antibodies (ANCAs)?

Back 77

ANCA are a heterogeneous group of autoantibodies directed against enzymes mainly found within the azurophil or primary granules in neutrophils, in the lysosome of monocytes, and in ECs.

Two main patterns are recognized, those in the cytoplasm (c-ANCA with the most common target proteinase-3 - PR3) and those in the perinucleus (p-ANCA) and is usually specific for myeloperoxidase - MPO.

Front 78

78. In what disorders is c-ANCA typically found?

p-ANCA?

Back 78

c-ANCA is typically found in Wegener granulomatosis and p-ANCA is found in most cases of microscopic polyangiitis and Churg-Strause syndrome.

Front 79

79. How are ANCAs useful?

Back 79

They serve as useful quantitative diagnostic markers for ANA-associated vasculitis, and their levels may reflect the degree of inflammatory activity.

ANCAs rise in episodes of recurrence, and thus are useful in management. In addition, the close association btwn ANCA titers and disease activity suggests they may be important in the pathogenesis of this disease.

Front 80

80. What is a hypothesis for the causative role of ANCAs in vasculitis?

Back 80

1. An underlying disorder (infection) elicits pro-inflammatory cytokines such as TNF and GMCSF, and endotoxin, which together cause neutrophils and other inflammatory cells to express PR3 and MPO on their surfaces.
2. These stimulate the formation of ANCAs
3. ANCAs react w/circulating cytokine primed neutrophils and cause them to degranulate
4. PMNs activated by ANCA cause endothelial cell toxicity and other direct tissue injury.

Front 81

81. What are anti-endothelial cell antibodies?

Back 81

Antibodies, to ECs, perhaps induced by defects in immune regulation, may predispose to certain vasculitides, such as those associated w/SLE and Kawasaki disease.

Front 82

82. What is giant cell (temporal) arteritis?

Back 82

Giant cell arteritis, the most common form of systemic vasculittis in adults, is an acute and chronic, often granulomatous, inflammation of arteries of large to small size.

It principally affects the arteries in the head, especially the temporal, vertebral, and ophthalmic arteries. Ophthalmic arterial involvement may lead to permanent blindness. Therefore, visual loss caused by giant cell arteritis is a medical emergency.

Front 83

83. What is the morphology of giant cell (temporal) arteritis?

Back 83

Characteristically, segments of affected arteries develop nodular thickenings w/reduction of the lumen and may become thrombosed. In the more common variant there is granulomatous inflammation of the inner half of the media centered on the internal elastic membrane marked by a mononuclear infiltrate, multinucleate giant cells, and fragmentation of the internal elastic lamina.

The healed stage reveals collagenous thickening of the vessel wall; organization of the luminal thrombus sometimes transforms the artery into a fibrous cord.

Front 84

84. What is the pathogenesis of giant cell arteritis?

Back 84

The granulomatous nature of the inflammation, association w/certain HLA-DR haplotypes, and the response to corticosteroid therapy are consistent w/T-cell mediated and antigen-driven injury.

Striking features of the disorder are the rarity of the disease in persons younger than 50, the predilection for the superficial temporal arteries, and the high incidence in populations of Nordic origins.

Front 85

85. What are the clinical features of giant cell arteritis?

Back 85

Rare before age 50. Temporal arteritis typically presents w/headache and facial pain; 50% of patients have systemic symptoms, including a flu-like syndrome w/myalgias, arthralgias, and fever, called polymyalgia rheumatica.

It may cause visual disturbances (diplopia) and even blindness (an acute emergency). It responds well to corticosteroids.

Front 86

86. What is Takayasu arteritis?

Back 86

This granulomatous vasculitis of mediuma nd larger arteries is characterized principally by ocular disturbances and marked weakening of the pulses in the upper extremities (pulseless disease)

The pathologic findings that account for the clinical picture are vasculitis and subsequent fibrous thickening of the aorta, particularly the aortic arch and its branches, w/narrowing or virtual obliteration of the origins or more distant portions.

Front 87

87. What is the prevalence of Takayasu arteritis?

Back 87

The illness is seen predominantly in females younger than 40. The cause and pathogenesis are unknown, although autoimmune mechanisms are suspected.

A high frequency of the HLA-A24-B52-DR2 has been found in Japanese patients but not in other populations.

Front 88

88. What is the morphology of Takayasu arteritis?

1/2

Back 88

Takayasu arteritis classically involves the aortic arch, but in 1/3 of cases it also affects the remainder of the aorta and its branches. In 1/2 the cases it affects the pulmonary arteries.

*The gross morphologic changes include irregular thickening of the aortic or branch vessel wall w/intimal wrinkling.

Histologically, the changes range from an adventitial mononuclear infiltrate w/perivascular cuffing of the vasa vasorum to intense mononuclear inflammation of the media.

Front 89

89. What is the morphology of Takayasu arteritis?

2/2

Back 89

Granulomatous inflammation, replete w/giant cells and patchy necrosis of the media in some cases may be indistinguishable from those in giant cell arteritis.

Thus, distinctions among active giant cell lesions of the aorta are based largely on the age of the patient, and most giant cell lesions of the aorta in young patients are designated Takayasu arteritis.

Front 90

90. What are the clinical features of Takayasu arteritis?

Back 90

The salient clinical features include markedly lower BP and weaker pulses in the upper extremities with coldness or numbness of the fingers; ocular disturbances, including visual defects, retinal hemorrhages and total blindness; hypertension, and neurological deficits.

Involvement of the more distal aorta may lead to claudication of the legs; that of pulmonary arteries may lead to pulmonary hypertension.

Front 91

91. What is polyarteritis nodosa (PAN)?

Back 91

PAN is a systemic vasculitits of small or medium-sized muscular arteries (but not arterioles, capillaries, or venules), typically involving renal and visceral vessels but sparing the pulmonary circulation. Clinical manifestations result from ischemia and infarction of affected tissues and organs.

Front 92

92. What is the morphology of PAN?

Back 92

Classic PAN occurs as segmental transmural necrotizing inflammation of arteries of medium to small size, in any organ w/the possible exception of the lung, and most freq kidneys, heart, liver, and GI tract. Segmental erosion w/weakening of the arterial wall due to the inflammatory process may cause aneurysmal dilation or localized rupture. Impairment of perfusion, causing ulcerations, infarcts, ischemic atrophy, or hemorrhages in the area supplied by these vessels may provide the first clue to the existence of the underlying disorder.

Front 93

93. What are the histologic characteristics of PAN?

Back 93

The histologic picture during the acute phase is characterized by transmural inflammation of the arterial wall w/neutrophils, eosinophils, and mononuclear cells, freq accompanied by fibrinous necrosis. The lumen may become thrombosed.

Later, the acute inflammatory infiltrate infiltrate disappears and is replaced by fibrous thickening of the vessel wall that may extend into the adventitia. Firm nodularity sometimes marks the lesions.

Particularly characteristic of PAN is that all stages of activity may coexist in different vessels or even within the same vessel.

Front 94

94. What is the clinical course of PAN?

Back 94

PAN is largely a disease of young adults, w/protean and nonospecific clinical presentation related to whatever tissue is involved (e.g., hematuria, albuminuria, and hypertension [kidneys]; abdominal pain and melena [GI tract]; diffuse myalgias; and peripheral neuritis.

The most common systemic manifestations include fever, malaise, and weight loss.

PAN may be associated w/HBV antigenemia, and deposited immune complexes may play a role in pathogenesis. Untreated, the disease is generally fatal, but a 90% remission rate is achieved w/immunosuppressive therapy.

Front 95

95. What is Kawasaki disease (mucocutaneous lymph node syndrome)?

Back 95

Kawasaki disease is an arteritis that often involves the coronary arteries, usually in young children and infants (80% of cases are <4 y/o), and is the leading cause of acquired heart disease in children in the US and Japan.

It is associated w/the mucocutaneous lymph node syndrome, an acute but usually self-limited illness manifested by fever, conjunctival and oral erythema and erosion, edema of the hands and feet, erythema of the palms and soles, a skin rash often w/desquamation, and enlargement of the cervical lymph nodes.

Front 96

96. What is the pathogenesis of Kawasaki disease?

Back 96

The cause is uncertain, but there is evidence that the vasculitis results from an immune reaction characterized by T-cell and macrophage activation to an unknown antigen, secretion of cytokines, polyclonal B-cell hyperactivity, and the formation of autoantibodies to endothelial cells and SMC, leading to acute vasculitis.

Front 97

97. What is the morphology of Kawasaki disease?

Back 97

The vasculitis is PAN like, with necrosis and pronounced inflammation affecting the entire thickenss of the vessel wall, but fibrinoid necrosis is usually less prominent in Kawasaki disease.

Although the acute vasculitis subsides spontaneously or in response to treatment, it can be complicated by aneurysm formation, thrombosis, and/or MI. As w/other causes of arteritis, healed lesions may cause obstructive intimal thickening.

Front 98

98. What is the clinical course of Kawasaki disease?

Back 98

Approx 20% of pts develop cardiovascular sequelae, ranging in severity from asymptomatic vasculitis of the coronary arteries, coronary artery ectasia, or aneurysm with rupture or thrombosis, MI, or sudden death.

Acute fatalities occur in approx 1% of pts. Pathologic changes outside the cardiovascular system are rarely significant.

The use of aspirin and IV IgG has had a significant effect on lower the rate of coronary artery aneurysms and death from the disease.

Front 99

99. What is microscopic polyangiitis?

Back 99

This type of necrotizing vaculitis generally affects arterioles, capillaries, and venules - vessels smaller than those involved in PAN.

In contrast to PAN, all lesions tend to be of the same age. It typically presents as "palpable purpura" involving the skin, or invovlement of the mucous membranes, lungs, brain, heart, GI tract, kidneys, and muscle. Skin biopsy is often diagnostic.

In contrast to PAN, necrotizing GN and pulmonary capiillaritis are particularly common.

Front 100

100. What are the major clinical features of microscopic polyangiitis?

Back 100

The major clinical features are hemoptysis, arthralgia, abdominal pain, hematuria, proteinuria, hemorrhage, and muscle pain or weakness. In many cases, an immunologic reaction to an antigen such as drugs (i.e. penicillin), microorganisms (streptococci), heterologous proteins, and tumor antigens are the precipitating cause.

*in 70% of pts, p-ANCAs are present.

Front 101

101. What is the morphology of microscopic polyangiitis?

Back 101

The lesions of microscopic polyangiitis are often histologically similar to those of PAN. In contrast to PAN, muscular and large arteries are usually spared; thus, macroscopic infarcts similar to those seen in PAN are uncommon.

Granulomatous inflammation is absent.

Histologically, segmental fibrinoid necrosis of the media may be present, but some lesions have changes limited to infiltration w/neutrophils, which become fragmented as they follow the vessel wall (leukocytoclasia).

The term leukocytoclastic angiitis (LCA) is given to such lesions, most commonly found in postcapillary venules.

Ig's and complement are often present in the vascular lesions of the skin; they is a paucity of Ig demonstrable via pauci-immune injury.

Front 102

102. What is the clinical course of microscopic polyangiitis?

Back 102

W/the exception of those who develop widespread renal or brain involvement, most pts respond well simply to removal of the offending agent.

Disseminated vascular lesions of hypersensitivity angiitis may also appear in Henoch-Schonlein purpura, essential mixed cryoglobulinemia, vasculitis associated w/some of the CT disorder, and vasculitis associated w/malignancy.

Front 103

103. What is allergic granulomatosis and angiitis (Churg-Strauss syndrome)?

Back 103

In Churg-Strauss syndrome, vascular lesions may be histologically similar to those of classic PAN or microscopic polyangiitis, but they characteristically have necrotizing vasculitis accompanied by granulomas w/eosinophilic necrosis. p-ANCAs are present in 1/2 of pts.

Coronary arteritis and myocarditis are the principal causes of morbidity and mortality.

Front 104

104. What is the pathogenesis of Churg-Strauss syndrome?

Back 104

There is a strong association w/allergic rhinitis, bronchial asthma, and eosinophilia.

The disorder is thought to result from hyperresponsiveness to an allergic stimulus; in asthmatics, cysteinyl leukotriene receptor type 1 antagonists are reported to trigger it.

Front 105

105. What is Wegener granulomatosis?

Back 105

Wegener granulomatosis is a necrotizing vasculitis characterized by the triad of: (1) acute necrotizing granulomas of the upper respiratory tract (ENT), the lower respiratory tract (lung), or both; (2) necrotizing or granulomatous vasculitis affecting small to medium-sized vessels (e.g., capillaries, venules, arterioles, and arteries), most prominent in the lungs and upper airways; and (3) renal disease in the form of focal necrotizing, often crecentic, glomerulitis.

Patients who do not manifest the full triad are said to have "limited" Wegener granulomatosis, in which the involvement is restricted to the respiratory tract.

Front 106

106. What is the morphology of Wegener granulomatosis?

Back 106

Vascular lesions resemble those of acute PAN (sharply circumscribed arterial fibrinoid necrosis, w/associated neutrophilic infiltrates that may extend to the adventitia), but they are frequently accompanied by granuloma formation.

Front 107

107. What is the pathogenesis of Wegener granulomatosis?

Back 107

The resemblance to PAN and serum sickness suggest that Wegener granulomatosis may represent some form of hypersensitivity, possibly to an inhaled infectious or other environmental agent.

Immune complexes have been seen in the glomeruli and vessel walls in occasional patients.

Front 108

108. What are the clinical features of Wegener granulomatosis?

Back 108

Peak incidence is from ages 40-50 years. Typical symptoms include persistent pneumonitis w/bilateral nodular and vacitary infiltrates, chronic sinusitis, mucosal ulcerations of the naspharynx, and evidence of renal disease.

W/o treatment, 80% of pts die w/in 1 year; in contrast 90% respond to immunosuppression, particularly w/cyclophosphamide.

c-ANCA is present in more than 90% of pts w/active disease, and is a good marker of disease activity.

Front 109

109. What is lymphomatoid granulomatosis?

Back 109

Lymphomatoid granulomatosis is characterized by pulmonary nodules of lymphoid and plasmacytoid cells, often w/cellular atypia. It probably represents an evolving lymphoproliferative disorder, b/c up to 1/2 of pts develop a lymphoid malignancy, most commonly non-Hodgkin lymphoma.

This condition is sometimes difficult to differentiate from Wegener granulomatosis.

Front 110

110. What is thromboangiitis obliterans (Buerger disease)?

Back 110

Thromboangiitis obliterans is a distinctive disease that often leads to vascular insufficiency, and is characterized by segmental, thrombosing, acute and chronic inflammation of medium and small arteries, principally the tibial and radial arteries and sometimes secondarily extending to veins and nerves of the extremities.

*This disease is highly associated w/cigarette smoking; there is an increased prevalence of HLA-A9 and HLA-B5 in these pts.

Front 111

111. What is the morphology of thromboangiitis obliterans (Buerger disease)?

Back 111

Thomboangiitis obliterans is characterized by sharply segmental acute and chronic vasculitis of medium-sized an small arteries, mostly of the upper and lower extremities.

Microscopically, acute and chronic inflammation permeates the arterial walls, accompanied by thrombosis of the lumen, which may undergo organization and recanalization. Typically, the thrombus contains small microabscesses w/a central focus of neutrophils surrounded by grnulomatous inflammation.

Front 112

112. What are the complications of thromboangiitis obliterans (Buerger disease)?

Back 112

Later complications are chronic ulcerations of the toes, feet or fingers, and frank gangrene in some pts. In contrast to atherosclerosis, Buerger disease involves smaller arteries and is accompanied by severe pain, even at rest, related to the neural involvement.

Abstinence from cigarette smoking in the early stages of the disease often prevents further attacks.

Front 113

113. What is infectious arteritis?

Back 113

Localized arteritis may be caused by the direct invasion of infectious agents, usually bacteria or fungi, particularly Aspergillus and murcomycosis.

Vascular infections may weaken the arterial wall to result in a mycotic aneurysm or induce thrombosis and infarction.

Front 114

114. What is Raynaud phenomenon?

Back 114

Raynaud phenomenon refers to paroxysmal pallor or cyanosis of the digits of the hands or feet and, infrequently, the tips of the nose or ears (acral parts) owing to cold-induced vasoconstriction of the digital arteries, precapillary arterioles, and cutaneous AV shunts.

Front 115

115. What are the clinical features of Raynauds?

Back 115

Characteristically, the fingers change color in the sequence white-blue-red.

Raynauds reflects an exaggeration of normal central and local vasomotor responses to cold or emotion. It mostly affects young, otherwise healthy women.

Front 116

116. What is secondary Raynaud phenomenon?

Back 116

Secondary Raynauds refers to arterial insufficiency of the extremities caused by various conditions, including SLE, scleroderma, atherosclerosis, or Buerger disease.

Features suggestive of secondary Raynaud phenomenon include age of onset > 30 years, more severe episodes, associated skin lesions, and clinical features of CT disease.

Front 117

117. What is the morphology of varicose veins?

Back 117

Veins with varicosities are dilated, tortuous, elongated, and scarred, with thinning at the points of maximal dilation.

Intrluminal thrombosis and valvular deformities (thickening, rolling, and shortening of the cusps) are freq discovered when the vessels are opened.

Frequently there is elastic tissue degradation and spotty calcifications within the media (phlebosclerosis).

Front 118

118. What is the clinical course of varicose veins?

Back 118

Vein dilation or deformation renders the valves incompetent, w/consequent stasis, persistent edema, and trophic skin changes, ultimately resulting in stasis dermatitis and ulceration (varicose ulcers).

Affected tissues may have impaired circulation and poor healing.

Front 119

119. Are embolisms common in varicose veins?

Back 119

No, embolism or other serious complication is very rare. This is in sharp contrast to the relatively frequent thromboembolism that arise from DVT.

Front 120

120. What is thrombophlebitis and phlebothrombosis?

Back 120

The deep leg veins account for more than 90% of cases for thrombophlebitis and phlebothrombosis, two designations for inflammation and venous thrombosis.

Predisposing factors for DVT include CHF, neoplasia, pregnancy, postoperative state, prolonged immobilization or local infection. Although 90% occur in deep leg veins, periprostatic plexus in men and ovarian and pelvic veins in women are other important site.

DVT are common sources of pulmonary emboli.

Front 121

121. What is migratory thrombophlebitis (Trousseau sign)?

Back 121

Migratory thrombophlebitis (Trousseau sign) is an entity consisting of multiple evanescent venous thrombi cropping up sporadically in multiple sites.

It is attributed to malignancy-associated hypercoagulability (particularly adenocarcinomas), and may be associated w/nonbacterial thrombotic endocarditis.

Front 122

122. What is plegmasia alba dolens (painful white leg)?

Back 122

This is a special variant of primary phlebothrombosis and refers to iliofemoral venous thrombosis occurring in pregnant women prior to or following delivery.

It is postulated that the thrombus initiates phlebitis, and the perivenous inflammatory response induces lymphatic blockage w/painful swelling.

Front 123

123. What is SVC syndrome?

Back 123

The SVC syndrome is usually caused by neoplasms compressing or invading the SVC (e.g., primary bronchogenic CA or mediastinal lymphoma). The resulting obstruction produces a distinctive complex manifested by dusky cyanosis and marked dilation of head, neck, and arm veins.

Front 124

124. What is IVC syndrome?

Back 124

The IVC syndrome is caused by similar processes. Moreover, certain neoplasms, particular HCC and renal cell CA, show a striking tendency to grow within veins, extending into the IVC and occasionally up to the heart.

IVC obstruction induces marked leg edema, distention of the lower abdominal superficial collateral veins, and when renal veins are involved - massive proteinuria.

Front 125

125. What is lymphatitis?

Back 125

Bacterial infections may spread into and thru the lymphatics to create acute inflammatory involvement in these channels (lymphangitis).

The most common etiologic agents are the group A beta-hemolytic stroptococci.

Lymphagitis presents as painful subcutaneous red streaks along involved lymphatics, with regional lymphadenopathy.

Front 126

126. What is obstructive lymphedema?

Back 126

Occlusion of lymphatic drainage is followed by the abnormal acculumulation of interstitial fluid in the affected part, called obstructive lymphedema.

Front 127

127. What are the five causes of secondary lymphatic blockage?

Back 127

1. Spread of malignant tumors obstructing either the lymphatic channels or the regional lymph nodes
2. Radical surgical procedures w/removal of regional groups of lymph nodes
3. Postirradiation fibrosis
4. Filariasis
5. Postinflammatory thrombosis and scarring

Front 128

128. What causes primary lymphedema?

Back 128

In contrast, primary lymphedema may occur as an isolated congential defect or as the familial Milroy disease (heredofamilial congenital lymphoma).

A third form of primary lymphedema, AKA lymphedema praecox, appears btwn the ages 10-25 years, usually in females. Of unknown cause, the edema begins in the feet and slowly accumulates thru life.

Front 129

129. What are the consequences of chronic lymphedema in the subcutaneous tissue?

Back 129

Lymphedema leads to increased subcutaneous interstitial fibrous tissue, w/consequent enlargement of the affected part, brawny induration, "peau d'orange" appearance of the skin, and skin ulcers?

Front 130

130. What is bacillary angiomatosis?

Back 130

These are non-neoplastic reactive vascular proliferations.

Front 131

131. Where do most neoplasms of the blood and lymphatic vessels occur?

Back 131

Most lesions occur in soft tissues and viscera. Primary tumors of the large vessels (aorta, pulmonary artery, and vena cava) are extremely rare, most being connective tissue sarcomas.

Front 132

132. What are the two main differences between benign and malignant neoplasms in the blood vessels?

Back 132

1. Benign tumors produce readily recognized vascular channels filled w/blood cells or lymphatics w/transudate; these channels are lined by a layer of normal endothelial cells, w/o atypia.

2. Malignant tumors are more solidly cellular, w/cytologic anaplasia, including mitotic figures, and usually do not form well-organized vessels.

Front 133

133. What is a hemangioma?

Back 133

Hemangiomas are most commonly localized; however, some involve large segments of the body such as an entire extremity (agiomatosis). The majority are superficial lesions, often of the head or neck, but they may occur internally, w/nearly 1/3rd in the liver.

Front 134

134. What is a capillary hemangioma?

Back 134

Capillary hemangiomas are the most common type of vascular tumor; they occur primarily in skin or mucous membranes, but also in viscera. Tumors range from 1-2 mm to several cm in diameter.

All are well defined, unencapsulated lesions composed of closely packed aggregates of capillary-sized, thin-walled vessels. They may be partially or completely thrombosed.

Front 135

135. What are juvenile capillary (strawberry) hemangiomas?

Back 135

Juvenile capillary (strawberry) hemangiomas are a speicfic variant that are present at birth, grow rapidly for a few months, and begin regressing at age 1-3 years. Almost all disappear by age 7.

Front 136

136. What is the morphology of capillary hemangiomas?

Back 136

Varying in size from a few mm to several cm, hemangiomas are bright red to blue and are level w/the surface of the skin or slightly elevated.

Histologically, they are usually lobulated but unencapsulated aggregates of closely packed, thin-wall capillaries, usually blood filled and lined by a flattened endothelium, separated by scant connective tissue stroma.

Rupture of vessels causes scarring and accounts for the hemosiderin pigment occasionally found.

Front 137

137. What are cavernous hemangiomas?

Back 137

Less common than the capillary variety, cavernous hemangiomas share age and anatomic distribution, but they are usually larger, less well circumscribed, and more frequently involve deep structures than do capillary hemangiomas.

As they may be locally destructive and show no tendency to regress, many require surgery.

*Those in the brain are most threatening - in von Hippel-Lindau disease, they occur in the brain, cerebellum, and eye.

Front 138

138. What is the morphology of cavernous hemangiomas?

Back 138

Grossly, the usual cavernous hemangioma is a red-blue, soft, spongy mass 1-2 cm in diameter. Rarely, giant forms occur that affect large subcutaneous areas of the face, extremities, or other regions.

Histologically, the mass is sharply defined, but not encapsulated, and is made up of large, cavernous vascular spaces, partly or completely filled w/blood separated by a scant connective tissue stroma.

Intravascular thrombosis w/associated dystrophic calcification is common.

Front 139

139. What is a pyogenic granuloma (lobular capillary hemangioma)?

Back 139

This polypoid form of capillary hemangioma occurs as a rapidly growing exophytic red nodule attached by a stalk to the skin and gingival or oral mucosa. The lesions bleeds easily and is often ulcerated. Approx 1/3 of lesions develop after trauma. The proliferating capillaries are often accompanied by extensive edema and acute and chronic inflammatory infiltrate.

They have a striking resemblance to exuberant granulation tissue. Recurrence occurs infrequently as a solitary nodule or as satellite nodules.

Front 140

140. What is granuloma gravidarum?

Back 140

Granuloma gravidarum is a pyogenic granuloma that occurs in the gingiva or 1% of pregnant women and regresses after delivery.

These lesions, like the spider telangiectasias, highly the role of estrogen in vascular growth and proliferation.

Front 141

141. What is lymphangioma circumscriptum (capillary lymphangioma)?

Back 141

These lesions are composed of small lymphatic channels; they are typically 1-2 cm in diameter, exudate filled blister-like blebs, w/a predilection for head, neck and axillary subcutaneous tissue.

Histologically, they are composed of a network of endothelium-lined lymph spaces beneath the epidermis and **can be distinguished from capillary channels only by the absence of blood cells.**

Front 142

142. What is a cavernous lymphangioma (cystic hygroma)?

Back 142

Cavernous lymphangiomas occur in children in the neck or axilla and rarely retroperitoneally. They occasionally achieve considerable size, up to 15 cm in diameter, and may fill the axilla or produce gross deformities in the neck area. These lesions are not well encapsulated, and complete surgical resection can be difficult.

Microscopically, they are composed of highly dilated cystic spaces lined by endothelium w/scant stroma.

*Cystic hygromas of the neck occur in Turner syndrome

Front 143

143. What is a glomus tumor?

Where are they most commonly found?

Back 143

A glomus tumor is a biologically benign but often exquisitely painful tumor that arises from the modified smooth muscle cells of the glomus body, a specialized AV anastomosis that is involved in thermoregulation.

Glomus tumors are most commonly found in the distal portion of the digits, especially under the fingernails.

Front 144

144. What is the morphology of a glomus tumor?

Back 144

Grossly, the tumors are less than 1 cm in diameter, slightly elevated, rounded, red-blue, and firm, and may be pinpoint under the nail.

***Histologically, there are branching vascular channels separated by a connective tissue stroma that contains aggregates, nests, and masses of the specialized glomus cells that typically are arranged around vessels.*** Individual cells are usually small, regular in size, and round or cuboidal, w/scant cytoplasm and features very similar to SMC.

Front 145

145. What does telangiectasis mean?

Back 145

Telangiectasis designates a congenital anomaly or an acquired exaggeration of preformed vessels, composed of prominent capillaries, venules, and arterioles that creates a small focal red lesion, usually in the skin or mucous membranes.

Front 146

146. What is nevus flammeus?

Back 146

(Birthmark) This most common form of ectasia characteristically forms on the head and neck, is flat, and ranges in color from light pink to deep purple.

Histologically, these lesions show only dilation of vessels in the dermis.

Front 147

147. What is a port-wine stain?

Back 147

A special form of birthmark, this type may grow proportionately w/a child, thicken the skin surface, become unsightly, and demonstrate no tendency to fade.

Front 148

148. What is Sturge-Weber syndrome (AKA encephalotrigeminal angiomatosis)?

Back 148

Port-wine stains in the distribution of the trigeminal nerve may be associated w/Sturge-Weber syndrome, an extremely uncommon congenital disorder attributed to the faulty development of certain mesodermal and ectodermal elements.

Front 149

149. What are the clinical characteristics of Sturge-Weber syndrome?

Back 149

Sturge-Weber syndrome is characterized by venous angiomatous masses in the leptomeninges over the cortex and by ispilateral port-wine nevi of the face. It is associated w/mental retardation, seizures, hemiplegia, and radiopacities in the skull.

Thus, a large vascular malformation in the face may indicate the presence of more extensive vascular malformation in a child who exhibits some evidence of mental deficiency.

Front 150

150. What are spider telangiectasias?

Back 150

This non-neoplastic vascular lesion is a more or less radial and often pulsatile array of dilated subcutaneous arteries or arterioles about a central core that blanches when pressure is applied to its center.

These lesions tend to be on the face, neck. or upper chest and are most frequent in pregnant women and in patients w/cirrhosis. The hyperestrinism found in these two settings is believed to play a role in their development.

Front 151

151. What is Osler-Weber-Rendu disease?

Back 151

In the autosomal dominant Osler-Weber-Rendu disease, telangiectases are genetic malformations consisting of dilated capillaries and veins. They are present from birth and distributed widely over the skin and mucous membranes of the oral cavity, lips, and respiratory, GI, and urinary tracts. Rupture may occur, causing serious nosebleeds, bleeding into the gut, or hematuria.

Front 152

152. What is bacillary angiomatosis?

Back 152

Bacillary angiomatosis is an opportunistic infection in immunocompromised persons and manifests as vascular proliferations that clinically resemble tumors and involve skin, bone, brain, and other organs.

It is caused by infection with gram-negative bacilli of the Bartonella family, particularly Bartonella henselae, the organism that causes cat-scratch disease in immunocompetent person, and B. quintana, the cause of trench fever.

Front 153

153. What is the morphology of bacillary angiomatosis?

Back 153

Grossly, skin lesions have one or more red papules or nodular subcutaneous masses. Microscopically, these are tumor-like capillary proliferations composed of atypical ECs.

In contrast to pyogenic granuloma, Kaposi sarcoma, or angiosarcoma, there are also numerous neutrophils, nuclear dust, and purplish granular material (bacteria).

Tx is w/erythromycin.

Front 154

154. What are the four forms of Kaposi sarcoma?

Back 154

1. Chronic, or classic KS
2. Lymphadenopathic, or African KS
3. Transplant-associated KS
4. AIDS associated KS

Front 155

155. What is chronic or classic KS?

Back 155

Occurs primarily (90%)of older men in Eastern European descent (Ashkenazi Jews). This form is not associated w/HIV, but homosexual men may be at increased risk.

Clinically, chronic KS commences w/multiple red to purple skin plaques or nodules, primarily on the arms or legs, slowly increasing in size and number, spreading to more proximal sites and often becoming confluent.

The tumors freq remain asymptomatic and localized to the skin and subcutaneous tissues but are locally persistent, w/an erratic course of lapses and remissions.

Front 156

156. What is lymphadenopathic (African or edemic) KS?

Back 156

This form is common in portions of Africa and is common among young Bantu children of S. Africa. (Same regions of Burkitt lymphoma) They present w/generalized lymphadenopathy. Skin lesions are sparse.

W/the high prevalence of HIV-associate disease in Africa and the association with AIDS with KS, KS in HIV-negative and HIV-positive patients is now the most frequently occurring tumor in Central Africa.

Front 157

157. What is transplant associated KS?

Back 157

Transplant associated KS occurs typically several months to a few years postoperatively in organ transplant recipients who receive high doses of immunosuppressants.

This type of KS tends to be aggressive, involving lymph nodes, mucosa, and visceral organs in 1/2 of pts, and skin lesions may be absent.

Organ and internal involvement is usually fatal.

Front 158

158. What is AIDS-associated KS?

Back 158

KS is the msot common AIDS-associated cancer in the US.

W/the use of HAART, KS incidence has declined.

AIDS-associated KS lesions have no site of preference, but involvement of lymph nodes and the gut and wide dissemination tend to occur early in the course.

Front 159

159. What is the morphology of KS?

Back 159

Three stages can be identified: patch, plaque, and nodule.

The pathces are pink to red to purple solitary or multiple macules that are usually confined to the distal lower extremities or feet.

OVer times, lesiosn spread proximally, and usually convert into larger, violaceous raised plaques that reveal dermal, dilated, jagged, vascular channels lined by plump spindle cells.

A still later stage, the lesions may become nodular and neoplastic and may be composed of sheets of plump proliferating spindle cells.

Front 160

160. What are the characteristics of the nodular stage of KS?

Back 160

Particularly characteristic in this cellular background are scattered small vessels and slit-like spaces that often contain row of red cells and hyaline droplets.

Marked hemorrhage, hemosiderin pigment, lymphocytes, and occasional macrophages may be mixed with this cellular background.

The nodular stage is often accompanied by involvement of lymph nodes and of viscera, particular in the African and AIDS-associated KS.

Front 161

161. What is the pathogenesis of KS?

Back 161

Nearly all KS lesions are infected w/human herpesvirus 8, AKA KS-associated herpesvirus (KSHV).

This agent is both necessary and sufficient for KS development, although immunosupression is an important cofactor in disease pathogenesis and clinical expression.

*KSHV proteins may disrupt cellular control by inhibiting p53 and making a viral homologue of cyclin D67.

Front 162

162. What are hemangioendotheliomas?

Back 162

This term is used to denote a wide spectrum of vascular neoplasms showing histologic features and clinical behavior intermediate between the benign, well differentiated hemangiomas and the frankly malignant angiosarcomas.

Front 163

163. What is an epithelioid hemangioendothelioma?

Back 163

This a unique vascular tumor occurring around medium sized and large veins in the soft tissue of adults.

In such tumors, well-defined vascular channels are inconspicuous and the tumor cells are plump and often cuboidal, thus resembling epithelial cells.

The differential Dx includes metastatic CA, melanoma, and those sarcomas that assume an epithelioid appearance.

Front 164

164. What is an angiosarcoma?

Back 164

Angiosarcomas are malignant endothelial neoplasms w/structure varying from highly differentiated tumors that resemble hemangiomas (hemangiosarcoma) to whose whose anaplasia makes them difficult to distinguish from malignant neoplasms.

They occur in both sexes, more often in older adults, anywhere in the body but most commonly in the skin, soft tissue, breast, and liver.

Front 165

165. What are hepatic angiosarcomas?

Back 165

The rare hepatic angiosarcomas are associated w/distinct carcinogens (arsenic, Thorotrast, and PVC).

With all three agents, there is a very long latent period of many years btwn exposure and the development of tumors.

Front 166

166. What is the morphology of angiosarcomas?

Back 166

Grossly, cutaneous angiosarcoma may begin as small, well-demarcated red nodules evolving into large, fleshy, gray-white soft tissue masses.

*Microscopically, all degrees of differentiation of these tumors may be found.

EC derivation is demonstrated by staining for CD31, CD34, or vWF.

Front 167

167. What is a hemangiopericytoma?

Back 167

Hemangiopericytoma is a tumor of pericytes, most commonly arising on the lower extremities (especially the thigh) or in the retroperitoneum.

50% metastasize. Most are small, but can grow up to 8 cm. Microscopically, they are composed of numerous capillary channels encased by nests and masses of spindle-shaped to round cells extrinsic to the EC basement membrane (resembling pericytes).

Front 168

168. What are the key elements of luminal expansion in angioplasty?

Back 168

1. Plaque rupture
2. Medial dissection
3. Stretching of the media of the dissected segment.

Front 169

169. What is proliferative restenosis?

Back 169

The long-term success of angioplasty is limited by the development of proliferative restenosis, which results from intimal thickening and occurs in approx 30-50% of pts w/in the first 4-6 mos following angioplasty.

The factors causing restenosis probably relate to muscle cell injury, elaboration of cytokines and growth factors from the inflammatory cells in the plaque, local thrombosis, and elastic recoil of the dilated segment.

Front 170

170. What are the most widely used small vessel replacement?

Failing of the small vessel prostheses is due to...?

Back 170

Aulogous saphenous vein (pt's own vein) and expanded polytetrafluoroethylene (a spongy Teflon fabric).

Failing of the small diameter prostheses are frequently due to thrombotic occlusion, intimal fibrous hyperplasia, or occasionally atherosclerosis.

Front 171

171. CABG surgery grafts are done with what prostheses?

Back 171

Bypasses are done using grafts of either reversed autologous saphenous vein, or internal mammary artery (usually the left internal mammary artery, owing to proximity to the heart).

Internal mammary artery grafts have a greater than 90% patency at 10 years, vs. only 50% patency with saphenous vein grafts.

Front 172

172. What is acute tubular necrosis?

Back 172

ATN is a clinicopathologic entity characterized morphologically by destruction of tubular epithelial cells and clinically by acute diminution or loss of renal function.

*It is the most common cause of acute renal failure, which signifies rapid reduction of renal function and urine flow, falling w/in 24 hours to less than 400 mL per day.

Front 173

173. What are the five conditions that can cause ATN?

Back 173

1. Ischemia, due to decreased or interrupted blood flow (polyarteritis nodosa, malignant hypertension, HUS, etc...)
2. Direct toxic injury to the tubules via drugs, radiocontrast, HGB, radiation
3. Acute tubulointerstitial nephritis, most commonly occurring as a hypersensitivity reaction to drugs
4. DIC
5. Urinary obstruction by tumors, BPH, or blood clots

Front 174

174. What is ischemic ATN?

Back 174

Most ATN lesions arise in a variety of clinical settings. Most of these, ranging from severe trauma to acute pancreatitis, have in common a period of inadequate blood flow, usually accompanied by marked hypotension and shock.

This pattern of ATN is called ischemic ATN.

Also, mismatched blood transfusions and other hemolytic crises cuasing hemoglobinuria and skeletal muscle injuries causing myoglobinuria also produce a picture resembling ischemic ATN

Front 175

175. What is nephrotoxic ATN?

Back 175

Nephrotoxic ATN is caused by a multitude of drugs, such as gentamicin and other antibiotics; radiographic contrast agents; poisons, including heavy metals, and organic solvents.

Front 176

176. What are the two critical events in both ischemic and nephrotoxic ATN?

Back 176

1. Tubular injury
2. Persistent and severe disturbances in blood flow.

Front 177

177. What does tubular injury result in?

Back 177

Results in loss of polarity due to redistribution in membranes and increased sodium delivery to distal tubules. The latter incites tubuloglomerular feedback. There is also increased expression of ICAM-1.

In time, injured cells detach from the basement membranes and cause limited tubule obstruction, increased intratubular pressure, and decreased GFR.

Front 178

178. What are the four main events leading to diminished renal function?

Back 178

1. Arteriolar vasoconstriction (w/tubuloglomerular feedback involving the renin-angiotensin system and endothelial dysfunction) leading to increased endothelin and decreased NO and PGI₂
2. Tubular obstruction by casts derived from necrotic and apoptotic epithelial cells and proteinaceous material
3. Back-leak of tubular fluids
4. Altered glomerular ultrafiltration

Front 179

179. What is the morphology of ischemic ATN?

Back 179

Ischemic ATN is characterized by focal tubular epithelial necrosis at multiple points along the nephron, with large skip areas in between, often accomapnied by rupture of basement membranes (tubulorrhexis) and occlusion of tubular lumens by casts. Tubular cell injury typically involve the proximal tubular straight segments and thick ascending loop of Henle.

Paradoxically, the clinical syndrome of ATN is not manifest by overt tubular necrosis, but often lesser degrees of tubular injury.

Front 180

180. What type of casts are present in the distal tubules and collecting ducts in ischemic ATN?

Back 180

Eosinophilic hyaline casts, as well as pigmented granular casts, are common, particularly in the distal tubules and collecting ducts.

These casts consist principally of Tamm-Horsfall protein (a urinary glycoprotein normally secreted by the cells of ascending thick limb and distal tubules) in conjunction with other plasma proteins.

Also, flattened epithelial cells w/hyperchromatic nuclei and mitotic figures are often present.

Front 181

181. What is the morphology of nephrotoxic ATN?

Back 181

Toxic ATN is manifested by acute tubular injury most obvious in the proximal convoluted tubules.

The type of injury may be distinctive in poisoning with certain agents.

Front 182

182. What is the injury like with mercuric chloride?

Back 182

With mercuric chloride, severely injured cells that are not yet dead might contain large acidophilic inclusions. Later these cells become totally necrotic, are desquamated into the lumen, and may undergo calcification.

Front 183

183. What is the injury like with CCl₄?

Back 183

With CCl₄ poisoning, there is an accumulation of neutral lipids in injured cells, and such fatty change is followed by necrosis.

Front 184

184. What is the injury like with ethylene glycol poisoning?

Back 184

Ethylene glycol produces marked ballooning and hydropic or vacuolar degeneration of proximal convoluted tubules.

Calcium oxalate crystals are often found in the tubular lumens in such poisoning.

Front 185

185. What are the three clinical phases of ATN?

Back 185

1. Initiation
2. Maintenance
3. Recovery

Front 186

186. What occurs in the initiation phase?

Back 186

The initiation phase, lasting for about 36 hrs, is dominated by the inciting medical, surgical, or obstetric event in the ischemic form of ATN. The only indication of renal involvement is a slight decline in urine output w/a rise in BUN.

At this point, oliguria could be explained on the basis of a transient decrease in blood flow to the kidneys

Front 187

187. What occurs in the maintenance phase?

Back 187

The maintenance phase is characterized by sustained decreases in urine output to btwn 40 and 400 mL/day with salt and water overload, rising BUN concentrations, hyperkalemia, metabolic acidosis, and other manifestations of uremia.

With appropriate attention to the balance of water and blood electrolytes, including dialysis, the pt can be carried over this oliguric crisis.

Front 188

188. What occurs in the recovery phase?

Back 188

The recovery phase is ushered in by a steady increase in urine volume that may reach up to 3 L/day. The tubules are still damaged, so large amts of water, sodium, and potassium are lost in the urinary flood.

*Hypokalemia, rather than hyperkalemia, becomes a clinical problem.

There is also an increased vulnerability to infection at this stage. Eventually renal tubular function is restored and BUN and creatinine levels begin to return to normal.

Front 189

189. What is the clinical course of ATN?

Back 189

It depends on the type of ATN. With modern methods of care, 95% of those who do not succumb to the precipitating cause have a chance of recovery. Conversely, in shock related to sepsis, extensive burns, or other causes of multiorgan failure, the mortality rate can rise to more than 50%.

*Up to 50% of patients with ATN might not have oliguria and might in fact have increased urine volumes. This so-called nonoliguric ATN occurs particularly often with nephrotoxins, and it generally follows a more benign clinical course.

Front 190

190. What is acute tubulointerstitial nephritis?

Back 190

Can be acute or chronic. Acute TIN has a rapid clinical onset and is characterized by interstitial edema, often accompanied by leukocytic infiltration of the interstitium and tubules, and focal tubular necrosis.

Front 191

191. What is chronic tubulointerstitial nephritis

Back 191

In chronic TIN, there is infiltration with predominantly mononuclear leukocytes, prominent interstitial fibrosis, and widespread tubular atrophy.

Front 192

192. What are the morphologic differences btwn acute and chronic tubulointerstitial nephritis?

Back 192

Edema, and when present, eosinophils and neutrophils occur in the acute form.

Fibrosis and tubular atrophy are in the chronic form.

Front 193

193. How are tubulointerstitial diseases distinguished from glomerular diseases on clinical grounds?

Back 193

The conditions are distinguished from glomerular disease by the absence, in early stages, of such hallmarks of glomerular injury as nephritic or nephrotic syndromes and by the presence of defects in tubular function.

The latter may be subtle and include impaired ability to concentrate urine, evidenced clinically by polyuria or nocturia; salt wasting; diminished ability to excrete acids (metabolic acidosis), and isolated defects in tubular reabsorption or secretion.

Front 194

194. What are the most common agents in UTIs?

Back 194

By far the most common are the gram-negative bacilli that are normal inhabitants of the intestinal tract. These are E.coli, followed by Proteus, Klebsiella, and Enterobacter.

Streptococcus faecalis, also of enteric origin, staphylococci, and virtually every other bacterial and fungal agent can also cause lower UTI and renal infection.

Front 195

195. What is the most common cause of clinical pyelonephritis?

Back 195

Ascending infection is the most common cause of clinical pyelonephritis.

This requires:
1. Colonization of the distal urethra and introitus (in the female ) by coliform bacteria).
2. Spread from the urethra to the bladder
3. Multiplication in the bladder
4. Vesicoureteral reflux; it is incompetence of the vesicoureteral valve that allows bacteria to ascend into the renal pelvis
5. Intrarenal reflux

Front 196

196. What causes incompetence of the vesicoureteral valve?

Back 196

Reflux is most often due to congenital absence or shortening of the intravesical portion of the ureter.

In addition, bladder infection can cause or accentuate vesicoureteral reflux, esp in children.

Acquired vesicoureteral reflux in adults can result from persistent bladder atony caused by spinal cord injury.

Front 197

197. Where is intrarenal reflux most common?

Back 197

Vesicoureteral reflux can propel urine up to the renal pelvis and deep into the renal parenchyma thru open ducts at the tips of the papillae.

Intrarenal reflux is most common in the upper and lower poles of the kidney, where papillae tend to have flattened or concave tips rather than the convex pointed type present in the midzones of the kidney.

Front 198

198. What are the hallmarks of acute pyelonephritis?

Back 198

Patchy interstitial suppurative inflammation, intratubular aggregates of neutrophils, and tubular necrosis.

In pyelonephritis associates w/reflux, damage occurs most commonly in the lower and upper poles.

Front 199

199. What are three potential complications of acute pyelonephritis?

Back 199

1. Papillary necrosis (seen mainly in diabetics and those w/urinary tract obstruction) - the necrotic tissue shows characteristic coagulative necrosis with preservation of outlines of tubules.

2. Pyonephrosis - suppurative exudate is unable to drain and thus fills the renal pelvis, calyces, and ureter.

3. Perinprhic abscess (extension of suppurative inflammation thru the renal capsule into the peripnephric tissue.

Front 200

200. What happens after the acute phase of pyelonephritis?

Back 200

After the acute phase, healing occurs. The neutrophilic infiltrate is replaced by one that is predominantly mononuclear, with macrophages, plasma cells, and lymphocytes.

The inflammatory foci are replaced by scars that can be seen on the cortical surface as fibrous depressions.

***However, the pyelonephritic scar is almost always associated w/inflammation, fibrosis, and deformation of the underlying calyx and pelvis, reflecting the role of ascending infection and vesicoureteral reflux in the pathogenesis of the disease.

Front 201

201. What are the eight conditions that predispose to acute pyelonephritis?

Back 201

1. Urinary tract obstruction
2. Instrumentation of the urinary tract (catheterization)
3. Vesicoureteral reflux
4. Pregnancy
5. Patients' sex and age (more freq in females until after 40 - then it becomes equal between males and females)
6. Preexisting renal lesions
7. DM
8. Immunosuppression

Front 202

202. What is the clinical course of acute pyelonephritis?

Back 202

When clinically apparent, the onset is usually sudden, w/pain at the costovertebral angle and systemic evidence of infection, such as fever and malaise. There are usually indications of bladder and urethral irritation, such as dysuria, frequency, and urgency. The urine contains many leukocytes (pyuria) derived from the inflammatory infiltrate, but pyuria does not differentiate upper from lower UTI.

The finding of leukocyte casts, typically filled w/neutrophils (pus casts) indicates renal involvement, b/c casts are formed only in tubules.

Front 203

203. What is an emerging viral pathogen causing pyelonephritis in kidney allografts?

Back 203

Polyoma virus - latent infection w/polyoma virus is widespread in the general population, but immunosuppression of the allograft recipient can lead to reactivation of the latent infection and the development of a nephropathy resulting in allograft failure in up to 1-5% of kidney transplant recipients.

Front 204

204. What is the morphology of polyoma virus pyelonephritis?

Back 204

This form is characterized by viral infection of tubular epithelial cell nuclei, leading to nuclear enlargement and intranuclear inclusions visible by light microscopy (viral cytopathic effect).

The inclusions are composed of viral structures arrayed in distinctive crystalline-like lattices when visualized by electron microscopy.

Front 205

205. What is chronic pyelonephritis?

Back 205

Chronic pyelonephritis is a chronic tubulointerstitial renal disorder in which chronic tubulointerstitial inflammation and renal scarring are associated w/pathologic involvement of the calyces and pelvis.

Chronic pyelonephritis is an important cause of end-stage kidney disease.

It has two forms : chronic reflux associated and chronic obstructive

Front 206

206. What is chronic reflux pyelonephritis?

Back 206

This is the more common form of chronic pyelonephritis scarring.

It begins in childhood, as a result of infections superimposed on congenital vesicoureteral reflux and intrarenal reflux. Reflux nephropathy may have a silent, insidious onset, sometimes presenting w/hypertension or evidence of renal dysfunction in the absence of persisting infection.

Front 207

207. What is chronic obstructive pyelonephritis?

Back 207

In obstructive chronic pyelonephritis, chronic obstruction predisposes the kidney to infections, and multiple recurrences over time produce chronic pyelonephritis. It is usually caused by enteric bacteria.

Front 208

208. What is the morphology of chronic pyelonephritis?

Back 208

The kidneys are usually scarred; if bilateral, the involvement is asymmetric.

The hallmark of chronic pyelonephritis is the coarse, discrete, corticomedullary scar overlying a dilated, blunted, or deformed calyx. Most are in the upper and lower poles, consistent w/the freq of reflux in these sites.

There is often fibrosis around the calyceal epithelium as well as a marked chronic inflammatory infiltrate.

Front 209

209. What is xanthogranulomatous pyelonephritis?

Back 209

Xanthogranulomatous pyelonephritis is an unusual and relatively rare form of chronic pyelonephritis characterized by accumulation of foamy macrophages intermingled w/plasma cells, lymphocytes, polymorphonuclear leukocytes, and occasional giant cells.

Often associated w/Proteus infections and obstruction, the lesions sometimes produce large, yellowish orange nodules that may be confused w/renal cell CA.

Front 210

210. What is the clinical course of chronic pyelonephritis?

Back 210

May be insidious in onset or may present w/clinical manifestations of acute recurrent pyelonephritis w/back pain, fever, frequent pyuria, and bacteriuria. Chronic pyelonephritis associated w/reflux may have a silent onset. These pts come to clinical attention b/c of renal insufficiency and hypertension or the discovery of pyuria or bacteriuria on routine exam.

Front 211

211. What does focal segmental glomerulosclerosis have to do with chronic pyelonephritis?

Back 211

Some patients w/pyelonephritic scars develop focal segmental glomerulosclerosis with significant proteinuria, even in the nephrotic range, usually several years after the scarring has occurred and often in the absence of continued infection or persistent vesicoureteral reflux.

The appearance of proteinuria and FSGS is a poor prognostic sign.

Front 212

212. What are the three ways in which toxins and drugs can produce renal injury?

Back 212

1. They may trigger an interstitial immunologic reaction (methicillin)
2. They may cause acute renal failure
3. They may cause subtle but cumulative injury to tubules that takes years to become manifest, resulting in chronic renal insufficiency

Front 213

213. What is acute drug-induced interstitial nephritis?

Back 213

Acute drug-induced interstitial nephritis is an adverse hypersensitivity reaction to a variety of drugs. It begins 2 to 40 days after exposure. The disorder is immune-mediate; the offending agents act as immunizing haptens.

During tubular secretion, the drugs covalently bind to cytoplasmic or extracellular matrix components, become immunogenic, and induce antibody (IgE) (Type I Hypersensitivity reaction) and T cell-mediated immune reactions (Type IV Hypersensitivity reaction).

Front 214

214. What are the clinical features of acute drug-induced interstitial nephritis?

Back 214

Fever, eosinophilia, skin rash, hematuria, mild proteinuria, sterile pyuria, azotemia, and acute renal failure can all be variably present.

Drug withdrawal usually leads to full recovery.

Front 215

215. What is the morphology of acute drug-induced interstitial nephritis?

Back 215

On histologic exam, the abnormalities are in the interstitium, which shows variable but freq pronounced edema and infiltration by mononuclear cells, principally lymphocytes and macrophages.

With some drugs (e.g., methicillin, thiazides), interstitial granulomas w/giant cells may be seen. "Tubulitis", the infiltration of tubules by lymphocytes, is common.

Front 216

216. What is analgesic nephropathy?

Back 216

This is a form of chronic renal disease caused by excessive intake of analgesic mixtures and characterized morphologically by chronic tubulointerstitial nephritis w/renal papillary necrosis.

Most pts with this disease usually ingest at least two antipyretic analgesics (phenacetin-containing mixtures).

*The drugs act synergistically to cause papillary necrosis first, and then cortical tubulointerstitial nephritis is a secondary phenomenon.

Front 217

217. How do the analgesics this shitstorm?

Back 217

The phenacetin metabolite acetaminophen injures cells by both covalent binding and oxidative damage.

Aspirin induces its potentiating effect by inhibiting the vasodilatory effects of prostaglandin, predisposing the papillae to ischemia.

Thus, the papillary damage may be due to a combo of direct toxic effects and ischemic injury to both tubular cells and vessels.

Front 218

218. What is the morphology of analgesic nephropathy?

1/2

Back 218

In gross appearance, the kidneys are either normal or slightly reduced in size, and the cortex exhibits depressed and raised areas; the depressed areas represent cortical atrophy overlying necrotic papillae.

The papillae show various stages of necrosis, calcification, fragmentation, and sloughing.

Front 219

219. What is the morphology of analgesic nephropathy?

2/2

Back 219

On microscopic exam, the papillary changes may take one of several forms.

In early cases, there is patchy necrosis; but in the advanced form, the entire papilla is necrotic, often remaining in place as a structureless mass w/ghosts of tubules and foci of dystrophic calcification. Segments of entire portions of the papilla may then be sloughed and excreted into the urine.

Cortical changes consist of loss and atrophy of tubules and interstitial fibrosis and inflammation.

Front 220

220. What is the clinical course of analgesic nephropathy?

Back 220

Patients may have polyuria, headaches, anemia, GI symptoms, pyuria, UTIs, and hypertension. *The anemia, in particular, is out of proportion to the renal insufficiency, owing to damage to RBCs by the phenacetin metabolites.

These pts have an increased incidence of transitional cell CA of the renal pelvis. Chronic renal failure can result, but drug withdrawal often stabilizes renal function.

Renal papillary necrosis can be Dx radiologically, although it is not specific for analgesic nephropathy.

Front 221

221. What are some NSAID associated renal syndrome?

Back 221

1. Hemodynamically induced acute renal failure, due to the inhibition of vasodilatory prostaglandin synthesis by NSAIDs
2. Acute hypersensitivity interstitial nephritis
3. Acute interstitial nephritis and minimal change disease
4. Membranous glomerulonephritis, w/the nephrotic syndrome

Front 222

222. What is acute uric acid nephropathy?

Back 222

Caused by the precipitation of uric acid crystals in the renal tubules, principally in the collecting ducts, lead into obstruction of nephrons and the development of acute renal failure.

This type is particularly likely to occur in pts w/leukemias and lymphomas who are undergoing chemo.

Front 223

223. What is chronic urate nephropathy?

Back 223

AKA gouty nephropathy, this occurs in patients w/more protracted forms of hyperuricemia.

The lesions are ascribed to the deposition of monosodium urate crystals in the acidic milieu of the distal tubules and collecting ducts as well as in the interstitium.

These deposits have a distinct histologic appearance and may form birefringent needle-like crystals either in the tubular lumina or in the interstitium.

Front 224

224. What is the earliest functional defect in the kidney?

Back 224

The inability to elaborate a concentrated urine.

Other tubular defects, such as tubular acidosis and salt-losing nephritis may also occur.

Front 225

225. What is multiple myeloma?

Back 225

Renal involvement is a sometimes ominous manifestation of multiple myeloma; overt renal insufficiency occurs in half of patients w/this disease.

Front 226

226. What is the main cause of renal dysfunction in multiple myeloma?

What is Bence Jones proteinuria?

Back 226

Bence Jones proteinuria and cast nephropathy - some light chains are directly toxic to epithelial cells. In addition, Bence Jones proteins combine with the urinary glycoproteins (Tamm-Horsfall protein) under acidic conditions to form large, histologically distinct tubular casts that obstruct the tubular lumens and induce a peritubular inflammatory reaction (cast nephropathy).

Front 227

227. How is amyloidosis associated with myelomas?

Back 227

Amyloidosis, formed by accumulations of light chains w/a predisposition to form amyloid fibrils, which occurs in 6-24% of pts w/myelomas.

Front 228

228. What is the morphology of the kidneys in multiple myeloma?

Back 228

The tubulointerstitial changes are fairly characteristic.

The Bence Jones tubular casts appear as pink to blue amorphous masses, sometimes concentrically laminated, often w/a fractured appearance, filling and distending the tubular lumens. Some of the casts are surrounded by multinuclear giant cells that are derived from mononuclear phagocytes.

The histologic features of amyloidosis, light chain deposition disease, and nephrocalcinosis and infection may also be present.

Front 229

229. What is the clinical course of the renal manifestations of multiple myeloma?

Back 229

In the most common form, chronic renal failure develops and usually progresses slowly during a period of several months to years.

Another form occurs suddenly and is manifested by acute renal failure w/oliguria. Precipitating factors in these patients include dehydration, hypercalcemia, acute infection, and treatment with nephrotoxic antibiotics.

Front 230

230. What is benign nephrosclerosis?

Back 230

Benign nephrosclerosis is the term used for the renal pathology associated with sclerosis of renal arterioles and small arteries. The resultant effect is focal ischemia of parenchyma supplied by vessels with thickened walls and consequent narrowed lumens.

Some degree of nephrosclerosis is present at autopsy with increasing age, preceding or in the absence of hypertension.

Hypertension and DM, however, increase the incidence and severity of the lesions.

Front 231

231. What are the two processes that participate in inducing the arterial lesions in benign nephrosclerosis?

Back 231

1. Medial and intimal thickening, as a response to hemodynamic changes, aging, genetic defects, or some combination of these

2. Hyaline deposition in arterioles, caused partly by extravasation of plasma proteins through injured endothelium and partly by increased deposition of basement membrane matrix.

Front 232

232. What is the morphology of benign nephrosclerosis?

1/2

Back 232

In gross appearance, the kidneys are either normal or moderately reduced in size. The cortical surfaces have a fine, even granularity that sesembles grain leather.

On histologic exam, there is narrowing of the lumens of arterioles and small arteries caused by thickening and hyalinization of the wall (hyaline arteriolosclerosis).

Larger muscular arteries show fibroelastic hyperplasia, with both medial and intimal thickening.

Front 233

233. What is the morphology of benign nephrosclerosis?

2/2

Back 233

The vascular lesions cause diffuse ischemic atrophy of nephrons; as a result, the kidneys are relatively small and exhibit diffuse granular surfaces due to scarring and contraction of individual glomeruli.

There patchy ischemic atrophy consists of (1) foci of tubular atrophy and interstitial fibrosis and (2) a variety of glomerular alterations.

Front 234

234. What is the clinical course of benign nephrosclerosis?

What three groups are at highest risk of benign nephrosclerosis?

Back 234

Benign nephrosclerosis rarely causes renal failure, but can cause mild proteinuria.

Three groups of patients are at increased risk of developing renal failure:
1. Blacks
2. Patients with more severe BP elevations
3. Patients with a second underlying disease, especially diabetes

In these groups, renal insufficiency may supervene after prolonged benign hypertension, but more rapid renal failure results from development of the malignant hypertension.

Front 235

235. What is malignant nephrosclerosis?

Back 235

Malignant nephrosclerosis is the form of renal disease associated with the malignant or accelerated phase of hypertension.

Although occasionally developing in previously normotensive people, most cases are superimposed on preexisting benign essential hypertension, chronic renal disease, or scleroderma.

For instance, it is also a frequent cause of death from uremia in patients with scleroderma.

Front 236

236. What is the pathogenesis of malignant hypertension?

Back 236

The initial insult appears to be some form of vascular damage to the kidneys. This might result from long-standing benign hypertension, with eventual injury to the arteriolar walls, or the initiating injury may spring de novo from arteritis or a coagulopathy or some injury causing acute exacerbation of the hypertension.

In any case, the result is increased permeability of the small vessels to fibrinogen and other plasma proteins, endothelial injury, focal death of cells of the vascular wall, and platelet deposition.

*This leads to the appearance of fibrinoid necrosis of arterioles and small arteries, swelling of the vascular intima, and intravascular thrombosis.

Front 237

237. What happens to the kidneys in malignant hypertension?

Back 237

These changes cause ischemia, with stimulation of the renin-angiotensin and other vasoconstrictive systems, perpetuating an ever-increasing cycle of escalating blood pressures.

Front 238

238. In patients with malignant hypertension, what substance is elevated in their plasma?

Back 238

Patients with malignant hypertension have markedly elevated levels of plasma renin.

Aldosterone levels are also elevated, and salt retention undoubtedly contributes to the elevation in BP.

Front 239

239. What is the morphology of malignant hypertension?

Back 239

The kidney has a "flea bitten" appearance due to small, pinpoint petechial hemorrhages on the cortical surface.

Pathologic changes include fibrinoid necrosis of arterioles, *hyperplastic arteriolopathy* (*onion-skinning*); and necrotizing glomerulitis, and a glomerular thrombotic microangiopathy.

In addition, sometimes the arteriolar and arterial lesions result in considerable narrowing of all vascular lumens, with ischemic atrophy and at time infarction distal to the abnormal vessels.

Front 240

240. What is the clinical course in malignant hypertension?

Back 240

Patients have a diastolic BP greater than 130 mm Hg, marked proteinuria, hematuria, papilledema, encephalopathy, cardiovascular abnormalities, and eventually renal failure.

There are marked increases in plasma renin, angiotensin, and aldosterone.

With current interventions, about 75% of patients will survive 5 years, and 50% survive with pre-crisis renal function.

Front 241

241. What is renal artery stenosis?

What causes it?

Back 241

Unilateral renal artery stenosis accounts for 2-5% of cases of renal hypertension, resulting from excessive renin secretion by the involved kidney.

*A large proportion of patients with renovascular hypertension have elevated plasma or renal vein pressure levels, and almost all show a reduction of BP when given competitive antagonists of angiotensin II.

Front 242

242. What is the morphology of renal artery stenosis?

What are the two types of lesions that lead to stenosis?

Back 242

The most common cause of renal artery stenosis (70% of cases) is occlusion by an atheromatous plaque at the origin of the renal artery. This lesion occurs more freq in men, and the incidence increases w/advancing age and DM.

The plaque is usually concentrically placed, and superimposed thrombosis often occurs.

The second type of lesion leading to stenosis is so called fibromuscular dysplasia of the renal artery, which is characterized by nonarteriosclerotic intimal, medial, or adventitial thickening. These stenoses, as a whole, are more common in women and then to occur in younger age groups.

Front 243

243. What happens to the kidneys in renal artery stenosis?

Back 243

The ischemic kidney is usually reduced in size and shows signs of diffuse ischemic atrophy, with crowded glomeruli, atrophic tubules, interstitial fibrosis, and focal inflammatory infiltrates.

The arterioles in the ischemic kidney are usually protected from the effects of high pressure, thus showing only mild arteriolosclerosis. In contrast, the contralateral nonischemic kidney may exhibit more severe arteriolosclerosis, depending on the severity of the hypertension.

Front 244

244. What is the clinical course in renal artery stenosis?

Back 244

On occasion, a bruit can be heard on auscultation of the kidneys.

Elevated plasma or renal vein renin, response to ACE inhibitors, renal scans, and IV pyelography may aid with Dx, but artiography is required to localize the stenotic lesion.

The cure rate after surgery is 70-80% in well selected cases.

Front 245

245. What are the four overlapping clinical manifestations in thrombotic microangiopathies?

Back 245

The overlapping symptoms are:
1. Thrombosis in capillaries and arterioles throughout the body
2. Microangiopathic hemolytic anemia
3. Thrombocytopenia
4. Renal failure in certain conditions

Front 246

246. What are the thrombotic microangiopathic diseases?

Back 246

1. Classic hemolytic-uremic syndrome (HUS)
2. Adult HUS associated with infection, antiphospholipid antibodies, contraceptives, complications of pregnancy, certain drugs, radiation, and scleroderma.
3. Familial HUS
4. Idiopathic HUS and thrombotic thrombocytocenic purpura (TTP)

Front 247

247. What are the shared pathogenetic mechanisms in thrombotic microangiopathies?

Back 247

(1) Endothelial injury and (2) Intravascular platelet aggregation and coagulation appear to be shared pathogenetic mechanisms.

Both of these events cause vascular obstruction and vasoconstriction and thus precipitate distal ischemia.

Front 248

248. What is the morphology of thrombotic microangiopathies?

Back 248

They are characterized morphologically by thromboses in the interlobular arteries, afferent arterioles, and glomeruli, together with necrosis and thickening of the vessel walls.

The morphologic changes are similar to those in malignant hypertension, but the changes can precede the development of hypertension or be seen in its absence.

Front 249

249. How is endothelial injury related to thrombotic microangiopathies?

Back 249

The triggers for endothelial injury and activation can be bacterial endotoxins and cytotoxins, cytokines, viruses, drugs, antiendothelial antibodies, and abnormal multimers or inhibitors of the vWF coagulation factor.

In childhood HUS associated with diarrheal infections, verocytotoxin is clearly the culprit. But in many cases, the proximate endothelial toxin is unknown.

Front 250

250. How is platelet aggregation related to thrombotic microangiopathies?

Back 250

Because many thrombi in HUS/TTP are composed largely of aggregated platelets with scant fibrin, serum factors causing platelet aggregation have been sought.

These include unusually large vWF factor multimers that are secreted by endothelial cells. Normally, they are degraded into smaller multimers by the action of ADAMTS-12, a vWF cleaving metalloprotease.

With congenital or acquired loss of ADAMTS-13 activity, very large vWF multimers persist in the circulation and induce aggregation by activating platelet surface glycoproteins.

Front 251

251. What is classic (childhood) HUS?

Back 251

This is the most well characterized of the HUS syndromes, since as many as 75% of cases occur in children after intestinal infection with verocytotoxin producing E. coli.

This disease is one of the main causes of acute renal failure in children.

Front 252

252. What are the symptoms of classic HUS?

Back 252

1. Sudden onset, usually after a GI or influenza like prodromal episode
2. Bleeding manifestations (especially hematemesis and melena)
3. Severe oliguria
4. Hematuria
5. Microangiopathic hemolytic anemia
6. In some patients, prominent neurologic change.

Hypertension is present in about half the patients.

Front 253

253. What is the pathogenesis of classic HUS?

Back 253

The pathogenesis of this syndrome is clearly related to the Shiga-like toxin. The toxin has a variety of effects on endothelium, causing increased adhesion of leukocytes, increased endothelin production and loss of endothelial NO; and in the presence of cytokines, such as TNF, endothelial lysis.

The resultant endothelial effects enhance both thrombosis and vasoconstriction, resulting in the characteristic microangiopathy. Verocytotoxin also binds to platelets and can directly activate them.

Front 254

254. What is the morphology of classic HUS?

Back 254

In gross appearance, the kidneys may show patchy or diffuse renal cortical necrosis. On micro exam, the glomeruli show thickening and sometimes splitting of capillary walls, due largely to endothelial and subendothelial swelling, and deposits of fibrin-related materials in the capillary lumens, subendothelially, and in the mesangium.

Mesangiolysis is a common finding. Interlobular and afferent arterioles show fibrinoid necrosis and intimal hyperplasia and are often occluded by thrombi.

Front 255

255. Now that we know what causes classic HUS, what causes adult HUS?

Back 255

1. In association with infection, such as typhoid fever, E. coli septicemia, viral infections, and shigellosis.
2. In the antiphospholipid syndrome, either primary or secondary to SLE.
3. Related to complications of pregnancy (placental hemorrhage) or the postpartum period. So called postpartum renal failure usually occurs after an uneventful pregnancy.
4. Associated with vascular renal diseases, such as systemic sclerosis and malignant hypertension.
5. In patients treated with chemotherapeutic and immunosuppressive drugs, such as mitomycin, cyclosporine, bleomycin, cisplatin, and radiation.

Front 256

256. What is postpartum renal failure?

Back 256

So called postpartum renal failure usually occurs after an uneventful pregnancy, 1 day to several months after delivery, and is characterized by microangiopathic hemolytic anemia, oliguria, anuria, and initially mild hypertension.

The condition has a grave prognosis, although recovery can occur in milder cases.

Front 257

257. What is familial HUS?

Back 257

About 5-10% of cases of HUS present with recurrent thromboses, and have a much higher mortality rate (about 50%) than classical childhood HUS (less than 5%).

Most patients with familial HUS have an inherited deficiency of the complement regulatory protein Factor H, which normally breaks down the alternative pathway C3 convertase and protects cells from damage by uncontrolled complement activation.

Front 258

258. What is idiopathic TTP?

Back 258

Idiopathic TTP is manifested by fever, neurologic symptoms, hemolytic anemia, TTP, and the presence of thrombi in glomerular capillaries and afferent arterioles.

It is caused by an acquired or genetic defect in ADAMTS-13, the protease that celaves large vWF multimers.

The abnormal (uncleaved) forms of vWF promote platelet aggregation.

The disease is more common in women and most patients are younger than 40.

Front 259

259. How is classic TTP different from idiopathic TTP?

Back 259

Idiopathic TTP and various forms of HUS overlap considerably. In classic TTP, however, CNS involvement is the dominant feature, whereas renal involvement occurs in only about 50% of patients.

In the kidney, eosinophilic granular thrombi are present predominantly in the terminal part of the interlobular arteries, afferent arterioles, and glomerular capillaries.

Other glomerular changes are similar to those described for HUS.

Untreated, the disease was once highly fatal, but exchange transfusions and corticosteroid therapy have reduced mortality to less than 50%.

Front 260

260. What is atherosclerotic ischemic renal disease?

Back 260

Bilateral disease, usually diagnosed via arteriography, now appears to be a fairly common cause of chronic ischemia with renal insufficiency in older individuals, sometimes in the absence of hypertension.

The important of recognizing this condition is that surgical revascularization is beneficial in reversing further decline in renal function.

Front 261

261. What is atheroembolic renal disease?

Back 261

Cholesterol crystals and debris embolize from atheromatous plaques after manipulation of severely disease aortas, usually for repair of aortic aneurysms or during intraaortic cannulation.

They lodge in intrarenal vessels, causing arterial narrowing and focal ischemic injury.

Rarely, renal function becomes compromised.

Front 262

262. What is sickle cell disease nephropathy?

Back 262

Sickle cell disease in both the homo- and heterozygous forms may lead to hematuria and a diminished concentrating ability.

These are thought to be due largely to accelerated sickling in the hypertonic hypoxic milieu of the renal medulla, which increases the viscosity of the blood during its passage thru the vasa recta, leading to plugging of vessels and decreased flow.

Patchy papillary necrosis may occur; this is sometimes associated w/cortical scarring.

Proteinuria is also common in sickle cell disease, occurring in about 30% of patients.

Front 263

263. What is diffuse cortical necrosis?

Back 263

This is an uncommon condition that occurs most freq after an obstretic emergency, septic shock, or extensive surgery.

When bilateral and symmetric, it can be fatal in the absence of supportive therapy, but patchy cortical necrosis may permit survival.

Front 264

264. What is the morphology of diffuse cortical necrosis?

Back 264

The gross alterations of massive ischemic necrosis are sharply limited to the cortex. The histologic appearance is that of acute ischemic infarction. The lesions may be patchy, with areas of coagulative necrosis and apparently better preserved cortex.

Intravascular and intraglomerular thromboses may be prominent but are usually focal, and acute necroses of small arterioles and capillaries may occasionally be present.

Hemorrhages occur into the glomeruli, together with the formation of fibrin plugs in the glomerular capillaries.

Front 265

265. What is the morphology of renal infarcts?

What color is the infarct?

Back 265

The kidneys are favored sites for the development of infarcts.

B/c the arterial supply to the kidney is of the end-organ type, most infarcts of the the "white" anemic type. They may occur as solitary lesions or may be multiple and bilateral.

Within 24 hours, infarcts become sharply demarcated, pale, yellow-white areas that may contain small irregular foci of hemorrhage discoloration. They are usually ringed by a zone of intense hyperemia.

Front 266

266. What is the clinical course in renal infarcts?

Back 266

Many renal infarcts are clinically silent. Sometimes, pain with tenderness localized to the costovertebral angle occurs, and this is associated with showers of red cells in the urine.

Large infarcts of one kidney are likely associated with narrowing of the renal artery or one of its major branches, which in turn may be a cause of hypertension.

Front 267

267. What is recognition of urinary obstruction important?

Back 267

Obstruction increases susceptibility to infection and to stone formation, and unrelieved obstruction almost always leads to permanent renal atrophy, termed hyponephrosis or obstructive uropathy.

Front 268

268. What are the common causes of urinary tract obstruction?

Back 268

1. Congenital anomalies
2. Urinary calculi
3. BPH
4. Tumors
5. Inflammation
6. Sloughed papillae or blood clots
7. Normal pregnancy
8. Uterine prolapse and cytocele
9. Functional disorders (neurogenic and other functional abnormalities)

Front 269

269. What is hydronephrosis?

Back 269

Hydronephrosis is the term used to describe dilation of the renal pelvis and calyces associated w/progressive atrophy of the kidney due to obstruction to the outflow of urine.

Obstruction also triggers and interstitial inflammatory reaction, leading eventually to interstitial fibrosis.

Front 270

270. What is the morphology of urinary tract obstruction?

1/2

Back 270

When the obstruction is sudden and complete, the reduction of GFR usually leads to only mild dilation fo the pelvis and calyces but only somtimes cause atrophy.

When the obstruction is subtotal or intermittent, GFR is not suppressed, and progressive dilation ensues.

Front 271

271. What is the morphology of urinary tract obstruction?

2/2

Back 271

In gross appearance, the kidney may have slight to massive enlargement. The pelvis and calyces may be dilated and there is often interstitial inflammation.

Progressive blunting of the apices of the pyramids occurs, and these eventually become cupped.

In far-advanced cases, the kidney may become transformed into a thin-walled cystic structure having a diameter of up to 15-20 cm with striking parenchyma atrophy, total obliteration of the pyramids, and thinning of the cortex.

Front 272

272. What are the clinical features of urinary tract obstructions?

Back 272

Unilateral obstruction may remain silent for long periods of time, since the unaffected kidney can usually compensate to maintain adequate renal function.

In bilateral partial obstruction, the earliest manifestations are inability to concentrate the urine; this is reflected by polyuria and occasionally acquired distal tubular acidosis, salt wasting, renal calculi, tubulointerstitial nephritis, atrophy, and hypertension.

Complete bilateral obstruction is incompatible with long survival unless the obstruction is relieved. Curiously, after relief of complete urinary tract obstruction, postobstructive diuresis occurs.

Front 273

273. What are the four main types of urolithiasis?

Back 273

1. Most stones (about 70% are calcium containing, composed largely of calcium oxalate or calcium oxalate mixed with calcium phosphate
2. Another 15% are so-called triple stones or struvite stones, composed of magnesium ammonium phosphate
3. 5-10% are uric acid stones
4. 1-2% are made up of cystine

Front 274

274. What is the most important determinant for stone formation?

Back 274

The most important determinant is an increased urinary concentration fo the stones' constituents, such that it exceeds their solubility in urine (supersaturation)

A low urine volume in some metabolically normal patients may also favor supersaturation.

Front 275

275. What are calcium oxalate stones?

Back 275

These stones are associated in about 5% of pts with both hypercalcemia and hypercalciuria, caused by hyperparathyroidism, diffuse bone disease, sarcoidosis, and other hypercalcemic states.

About 55% have hypercalciuria without hypercalcemia.

Hyperoxaluria (in vegetarians) and hyperuricosuria are associated in others.

Front 276

276. What are triple phosphate or struvite stones?

Back 276

Struvite stones are associated with infection by urea-splitting bacteria that convert urea to ammonia.

So-called staghorn calculi are struvite sometimes that are almost always associated with infection.

Front 277

277. What are uric acids stones?

Back 277

Uric acid stones are common in pts with a hyperuricemia, such as gout, and diseases involving rapid cell turnover, such as gout, and diseases involving rapid cell turnover, such as the leukemias.

However, more than half of all pts with urate calculi have neither hyperuricemia nor increased urinary excretion of uric acid.

In this group, it is thought that an unexplained tendency to excrete urine of pH below 5.5 may predispose to uric acid stones, b/c uric acid is insoluble in relatively acidic urine.

In contrast to the radio-opaque calcium stones, uric acid stones are radiolucent.

Front 278

278. What are cystine stones?

Back 278

Cystine stones are caused by genetic defects int eh renal reabsorption of AAs, including cystine, leading to cystinuria. Stones form at a low urinary pH.

Front 279

279. What is another theory for stone formation?

Back 279

It has been postulated that stone formation is enhanced by a deficiency in inhibitors of crystal formation in the urine. These include pyrophosphate, diphosphonate, citrate, glycosaminoglycans, osteopontin, and glycoproteins called nephrocalcin.

Front 280

280. What is the morphology of urolithiasis?

Back 280

Stones are unilateral in about 80% of pts. The favored sites for their formation are within the renal calyces and pelves, and in the bladder. If formed in the renal pelvis, they tend to remain small, having an average diameter of 2-3mm. These may have smooth contours or may take the form of an irregular, jagged mass of spicules.

Often, many stones are found w/in one kidney. On occasion, progressive accretion of salts leads to the development of branching structures known as staghorn stones.

Front 281

281. What are renal papillary adenomas?

Back 281

Small, discrete, *usually yellow* tumors are seen in 7% to 22% of autopsies.

Histologically, most consist of vacuolated epithelial cells forming tubules and complex branching papillary structures with numerous complex fronds. The cells may be histologically indistinguishable from those of low-grade papillary renal cell CA, and they share some of their cytogenetic features (trisomies 7 and 17).

Most are small (0.5 mm in diameter)

Front 282

282. What is a renal fibroma or hamartoma (renomedullary interstitial cell tumor)?

Back 282

On occasion, at autopsy, small foci of gray-white firm tissue, usually less than 1 cm in diameter, are found w/in the pyramids of the kidneys.

Microscopic exam of these nodules discloses fibroblast-like cells and collagenous tissue. Ultrastructurally, the cells have features of renal interstitial cells. The tumors have no malignant propensities.

Front 283

283. What is the most common malignant tumor of the kidney?

Back 283

The renal cell CA, followed by Wilms tumors, and finally urothelial tumors of the calyces and pelves.

Front 284

284. What is an angiomyolipoma?

In which population are these tumors common?

Back 284

This is a benign tumor consisting of vessels, smooth muscle, and fat.

*Angiomylolipomas are present in 25-50% of patients with tuberous sclerosis, a disease characterized by lesions of the cerebral cortex that produce epilepsy and mental retardation as well as a variety of skin abnormalities.

Front 285

285. What is and oncocytoma?

Back 285

This is an epithelial tumor composed of large, eosinophilic cells having small, round, benign-appearing nuclei that have large nucleoli. It is thought to arise from the intercalated cells of collecting ducts.

Ultrastructurally, the eosinophilic cells ahve numerous mitochondria. In gross appearance, the tumors are tan or mahogany brown, relatively homogeneous, and usually well encapsulated. They may achieve a size up to 12 cm in diameter.

This tumor is considered benign.

Front 286

286. What is renal cell CA?

Back 286

Renal cell CA occur most often in older individuals, usually in the6th and 7th decades of life, showing a male preponderance in the ratio of 2 to 3:1.

B/c of their gross yellow color and the resemblance of the tumor cells to clear cells of the adrenal cortex, they were at one time called hypernephromas. These tumors arise from tubular epithelium and are therefore renal adenocarcinomas.

Front 287

287. What is the major risk factor in renal cell CA?

Back 287

Tobacco is the most significant risk factor.

Additional risk factors are obesity, hypertension, unopposed estrogen therapy; and exposure to asbestos, petroleum products, and heavy metals.

Front 288

288. Most renal CAs are sporadic, but autosomal dominant familial cancers account for 4% of cases.

Which ones are these?

Back 288

1. Von Hippel-Lindau (VHL) syndrome
2. Hereditary familial clear cell CA
3. Hereditary papillary CA

Front 289

289. What is Von Hippel-Lindau (VHL) syndrome?

Back 289

Half-to 2/3rds of pts w/VHL, characterized by hemangioblastomas of the cerebellum and retina, develop renal cysts and bilateral, often multiple, renal cell CAs.

Current studies implicate the VHL gene in the development of both familial and sporadic clear cell tumors.

Front 290

290. What is hereditary papillary CA?

Back 290

Hereditary papillary CA is an autosomal dominant disease manifested by multiple bilateral tumors w/papillary histology.

These tumors exhibit a series of cytogenetic abnormalities and mutations in the MET protooncogene.

Front 291

291. What are the four types of renal cell CAs?

Back 291

1. Clear cell CA (most common type - 70-80% of cases)
2. Papillary CA (10-15%)
3. Chromophobe renal CA (5%)
4. Collecting duct (Bellini duct) CA (< 1%)

Front 292

292. What are clear cell CAs?

Back 292

Most common type - 70-80% of cases. On histologic exam, the tumors are made up of cell w/clear or granular cytoplasm and are nonpapillary.

Front 293

293. What is the genetic basis behind clear cell CAs?

Back 293

Whether familial, sporadic, or associated with VHL, there is loss of sequences on the short arm of chromosome 3 that harbors VHL, a tumor-suppressor gene. This occurs by deletion or by unbalanced translocation.

The VHL gene encodes a protein that is part of a ubiquitin ligase complex that targets other proteins for degradation. When VHL is mutated, hypoxia-inducible factor-1 (HIF-1) levels remain high, and this increases cell growth and angiogenesis.

Front 294

294. What is papillary CA?

What is the genetic basis?

Back 294

Papillary CA (10-15%) is characterized by a papillary growth pattern and also occurs in both familial and sporadic forms.

The gene for the familial form is on chromosome 7; it encompasses the locus for MET, a proto-oncogene that exhibits both germ line and somatic mutations.

A second gene called PRCC on chromosome 1 is implicated in sporadic tumors, largely in children.

Front 295

295. What is a chromophobe renal CA?

Back 295

Chromophobe renal CA (5%) is composed of cells w/prominent cell membranes and pale eosinophilic cytoplasm, usually with a halo around the nucleus.

Like the benign oncocytoma, they are thought to grow from intercalated cells of collecting ducts.

On cytogenetic exam, these tumors exhibit multiple chromosome losses and extreme hypdiploidy- they have an excellent prognosis.

Front 296

296. What is a collecting duct (Bellini duct) CA?

Back 296

Collecting duct (Bellini duct) CA (< 1%) arise from collecting duct cells in the medulla.

Histologically, these tumors are characterized by nests of malignant cells enmeshed w/in a prominent fibrotic stoma, typically in a medullary location.

Front 297

297. What is the morphology of renal cell CAs?

Back 297

Clear cell CAs are spherical masses, 3-15 cm in diameter, composed of bright yellow yellow-gray-white tissue that distorts the renal outline.

There are large areas of ischemic opaque, gray-white necrosis, foci of hemorrhagic discoloration, and areas of softening.

*Tumors may bulge into the calyces and pelvis, and invade the renal vein to grow as a solid column of cells w/in this vessel.

Front 298

298. What is the most common type of renal cancer in patients who develop dialysis-associated cystic disease?

Back 298

Papillary carcinomas.

Front 299

299. What is the morphology of the clear cell CA variant?

Back 299

The growth pattern varies from solid to trabecular (cordlike) or tubular. The tumor cells have a rounded or polygonal shape and abundant clear or granular cytoplasm that contain glycogen and lipids.

The tumors have delicate branching vasculature and may exhibit cystic as well as solid areas.

Most tumors are well differentiated, but some show marked nuclear atypia with formation of bizarre nuclei and giant cells.

Front 300

300. What is the morphology of the papillary variant?

Back 300

Papillary CA is composed of cuboidal or low columnar cells arranged in papillary formations.

Interstitial foam cells are common in the papillary cores.

Psammoma bodies may be present.

Front 301

301. What is the morphology of the chromophobe variant?

Back 301

Chromophobe renal CA is made up of pale eosinophilic cells, often w/a perinuclear halo, arranged in solid sheets with a concentration of the largest cells around blood vessels.

Front 302

302. What is the morphology of the collecting duct variant?

Back 302

Collecting duct CA is a rare variant showing irregular channels lined by highly atypical epithelium with a hobnail pattern.

Sarcomatoid changes arise infrequently in all types of renal cell CA and are a decidedly ominous feature of these tumors.

Front 303

303. What are the three classic diagnostic features of renal cell CA?

Back 303

1. Costovertebral pain
2. Palpable mass
3. Hematuria

*These are seen in only 10% of cases. The most reliable of the three is hematuria but it may be microscopic.

Front 304

304. What is the clinical course of renal cell CA?

Back 304

Pts may show hematuria, fever, constitutional symptoms, or a paraneoplastic syndrome (polycythemia, hypercalcemia, hypertension, feminization or masculinization, Cushing syndrome, esoinophilia, leukemoid reaction, and amyloidosis).

Prognosis depends on tumors size and the extend of spread at Dx.

***Renal cell CA has a tendency to metastasize widely before becoming symptomatic*** On average, 45% survive 5 years, and in the absence of metastatic spread at Dx, up to 70% survive 5 years.

Front 305

305. What are urothelial CAs of the renal pelvis?

Back 305

About 5-10% of renal tumors occur in the pelvis, where they manifest relatively early either due to hematuria or obstruction and cause flank pain.

Their histologic type is the same as for urothelial tumors in the bladder, ranging from well differentiated papillary lesions to anaplastic invasive CAs.

They are often multifocal, and in 50% of cases there is a synchronous or metachronous bladder tumors. Evidence suggests they are clonal in origin.

*Pts with analgesic nephropathy have an increased risk of urothelial CAs of the renal pelvis and bladder.

Front 306

306. What are the classes of pharmacologic agents that play a role in cardiac contractility?

Back 306

The cardiac glycosides raise intracellular Ca⁺ concentration via inhibition of the sarcolemmal Na⁺/K⁺-ATPase, while β-agonists and phosphodiesterase inhibitors increase intracellular levels of cAMP.

Front 307

307. What is digoxin?

Back 307

Digoxin is a selective inhibtior of the plasma membrane sodium pump. Cardiac myocytes exposed to digoxin extrude less sodium, leading to a rise in intracellular sodium concentration. In turn, the increase in intracellular sodium alters the equilibrium of the sodium-calcium exchanger: calcium efflux is decreased b/c the gradient for sodium entry is decreased, while calcium influx is increased b/c the gradient for sodium efflux is increased.

The net result is arise in the intracellular calcium concentration.

Front 308

308. What is digitoxin?

Back 308

Digitoxin is structurally identical to digoxin except it is less hydrophilic.

Thus, it is metabolized and excreted primarily by the liver; this makes it a suitable alternative to digoxin for the treatment of patients with HF and chronic kidney disease.

However, digitoxin has a VERY long half life (7 days!).

Front 309

309. Digoxin and digitoxin MOA (3 of them)

Back 309

1) In myocardium, inhibit plasma membrane Na⁺/K⁺-ATPase, leading to increased cytoplasmic calcium concentration, which results in positive inotropy.

2. In autonomic nervous system, inhibit sympathetic outflow and increase parasympathetic (vagal) tone

3. At AV node, prolong effective refractory period and slow conduction velocity.

Front 310

309. Digoxin and digitoxin

Back 310

PURPOSE: Systolic heart failure, supraventricular arrhythmias including Afib, atrial flutter, and paroxysmal atrial tachycardia

ADVERSE: Arryhythmias (esp conduction disturbances w/or w/o AV block, PVCs, and SVT; agitation, fatigue, muscle weakness, blurred vision, yellow-green halo around visual images, anorexia, nausea, vomiting

CONTRA: Vfib and Vtach

Front 311

210. What are the five significant drugs interactions for digoxin and digitoxin?

Back 311

Digoxin has numerous significant drug interactions.

1.Coadministration with beta-blockers increases the risk of developing high grade AV block.
2. Beta-blockers and calcium channel blockers counteract positive inotropic effects of digoxin.
3. Potassium wasting diuretics and hypokalemia predispose to digoxin toxicity.
4. Some antibiotics, such as erythromycin, increase digoxin absorption.
5. Coadministration with verapamil, quinidine, or amiodarone can increase digoxin levels.

Front 312

211. Digoxin and digitoxin therapeutic considerations

Back 312

1. Treat digoxin toxicity by normalizing plasma potassium level or using digoxin antibodies in severe cases.
2. Chronic kidney disease requires reduction in loading dose and maintenance dose of digoxin.
3. Digoxin has not been shown to improve survival; it palliates symptoms and improves functional status
4. Digitoxin undergoes hepatic metabolism and biliary excretion

Front 313

212. Digoxin immune Fab

Back 313

MOA: Antibody fragment that binds to and inhibits digoxin

PURPOSE: Potentially life-threatening digitalis toxicity; acute digoxin toxicity in which ingested amt or serum digoxin level is unknown

ADVERSE: Heart failure, anaphylaxis

CONTRA: Use w/caution in pts allergic to ovine proteins

NOTES: Keep resuscitation equipment available during administration of digoxin immune Fab.

Front 314

213. Dopamine

Back 314

MOA: Increase cAMP levels by activating G protein-coupled adrenergic receptors; acting at cardiac β1 adrenergic receptors, agonists have positive inotropic, chronotropic, and lusitropic effects

PURPOSE: In distributive or cardiogenic shock, use as adjunct to increase CO, BP, and urine flow; Short term treatment of severe, refractory, chronic heart failure

ADVERSE: Bradycardia, asthma attacks, widening of QRS complex, cardiac arrhythmias, hypotension, hypertension, palpitations, tachycardia

CONTRA: Pheochromocytoma, uncorrected tachyarrhythmias, Vfib

NOTES: Coadministration with MOAIs results in decreased metabolism of dopamine which can lead to tachycardia and arrhythmia

Front 315

214. Dopamine doses - what are the effects at low, intermediate, and high doses?

Back 315

1. Low doses cause vasodilation in the periphery by stimulating dopaminergic D1 receptors in renal and mesenteric vascular beds
2. Intermediate doses cause widespread vasodilation via stimulation of D1 receptors, and increased contractility and heart rate via activation of β1 receptors.
3. High doses cause generalized vasoconstriction via stimulation of α1 receptors

Front 316

315. What is dobutamine?

Back 316

Dobutamine is a synthetic sympathomimetic amine that acts as a predominantly β1, modest β2 agonist.

It is the DOC for patients with acute cardiogenic circulatory failure.

Front 317

316. Dobutamine

Back 317

MOA: A racemic mixture of enantiomers that have differential effects on adrenoceptor subtypes; overall effect is predominantly β1 and modest β2.

PURPOSE: Short term treatment of cardiac decomp secondary to depressed contractility (cardiogenic shock)

ADVERSE: Same as dopamine, except cardiac arrhythmias occur less freq

CONTRA: Idiopathic hypertrophic subaortic stenosis

NOTES: Sypathomimetic inotrope of choice for pts with acute cardiogenic circulatory failure; dobutamine induces less SVT and high grade ventricular arrhythmia than dopamine.

Front 318

317. Epinephrine

Back 318

MOA: Nonselective agonist at β1, β2, α1, and α2 receptors

PURPOSE: Bronchospasm, hypersensitivity reaction, anaphylactic shock, cardiac resuscitation, hemostasis, prolong local anesthetic effect, open angle glaucoma, nasal congestion

ADVERSE: Arrhythmias including Vfib, cerebral hemorrhage, severe hypertension; headache, nervousness, tremor, palpitations, tachycardia

CONTRA: Active labor, angle-closure glaucoma, shock, organic brain damage, cardiac arrhythmias, coronary insufficiency, severe hypertension, cerebral atherosclerosis

NOTES: *High doses can cause tachycardia and life-threatening arrhythmias.

Front 319

318. Norepinephrine

Back 319

MOA: Nonselective agonist at β1, α1, and α2 receptors

PURPOSE: BP support in acute hypotensive states (shock), limit GI bleeding via intraperitoneal or nasogastic administration

ADVERSE: Same as epinephrine

CONTRA: Peripheral vascular thrombosis, profound hypoxia, hypercapnia, hypotension from loss of blood volume

NOTES: May cause tachycardias invovling the SA node or ectopic atrial or ventricular sites in pts with contractile dysfunction; Avoid coadministration with MOAI due to risk of severe hypertension.

Front 320

319. Isoproterenol

Back 320

MOA: Nonselective β-agonist at β1 and β2 receptors

PURPOSE: Emergency treatment of arrhythmias (IV), atropine-resistant hemodynamically significant bradycardia (IV); heart block and shock (IV); bronchospasm (inhalation)

ADVERSE: Same as epinephrine

CONTRA: Tachycardia caused by digitalis intoxication; angina pectoris

NOTES: May be useful in treating pts w/β-antagonist overdose and in atropine resistant bradycardia; *Do not administer to pts w/active coronary artery disease!

Front 321

320. What are the names of the four phosphodiesterase inhibitors?

Back 321

1. Theophylline
2. Inamrinone
3. Milrinone
4. Vesnarinone

Front 322

321. What is the MOA of the phosphodiesterase inhibitors?

Back 322

Increase cAMP by inhibiting the PDE enzymes that hydrolyze it.

In cardiac myocytes, PDE inhibitors have postiive inotropic and lusitropic effects.

PDE inhibitors also relax vascular smooth muscle and thereby decrease preload (venodilation ) and afterload (arteriodilation)

Front 323

322.

Theophylline
Inamrinone
Milrinone
Vesnarinone

Back 323

PURPOSE: Short-term treatment of severely failing circulation in pts refractory to conventional therapy

ADVERSE: Ventricular arrhythmias, thrombocytopenia (greater incidence w/inamrinone than w/milrinone); reversible neutropenia and agranulocytosis (vesnarinone)

CONTRA: Asthma; do not use these agents in place of surgical intervention in pts with stenotic valvular disease; acute phase of MI

Front 324

323. PDE inhibitors NOTES

Back 324

1. COadministration with disopyramide may cause severe hypotension
2. Use of inamrinone is limited by 10% occurrence of thrombocytopenia
3. Oral formulation of milrinone is available; milrinone use is associated w/statistically significant increase in mortality in heart failure pts

Front 325

324. Levosimendan

Back 325

MOA: Enhances the sensitivity of troponin C to calcium, which increases the extent of actin-myosin interactions w/o a substantial increase in MVO2.

PURPOSE: Not approved for use in teh US, but it can improve cardiac hemodynamics in severe systolic HF and may reduce short term mortality

ADVERSE: Dose-related hypotensiona nd reflex tachycardia, nausea, headache

CONTRA: Hypersensitivity to levosimendan or racemic simendan.