• Shuffle
    Toggle On
    Toggle Off
  • Alphabetize
    Toggle On
    Toggle Off
  • Front First
    Toggle On
    Toggle Off
  • Both Sides
    Toggle On
    Toggle Off
  • Read
    Toggle On
    Toggle Off

Card Range To Study



Play button


Play button




Click to flip

Use LEFT and RIGHT arrow keys to navigate between flashcards;

Use UP and DOWN arrow keys to flip the card;

H to show hint;

A reads text to speech;

186 Cards in this Set

  • Front
  • Back
1. What is the most common cause of chronic renal failure in humans?
Chronic glomerulonephritis is one of the most common causes of chronic renal failure in humans.
2. What is the difference between primary and secondary glomerular diseases?
Primary glomerular diseases are ones in which the kidney is the only or predominant organ involved. These include: poststreptococcal glomerulonephritis, minimal change disease, IgA nephropathy, etc...

Secondary glomerular diseases include systemic immunologic diseases such as SLE, vascular disorders such as hypertension and polyarteritis nodosa, DM, etc...
3. What are the four main histologic alterations in the various types of glomerulonephritis?
1. Hypercellularity
2. Basement membrane thickening
3. Hyalinization
4. Sclerosis
4. What causes the hypercellularity in glomerulonephritis?

What are the four characteristics of hypercellularity?
Some inflammatory diseases of the glomerulus are characterized by an increase in the number of cells in the glomerular tufts. This is characterized by one or more combos of the following:
1. Cellular proliferation of mesangial or endothelial cells
2. Leukocytic infiltration, consisting of neutrophils, monocytes, and lymphocytes
3. Formation of crescents. These are accumulations of cells composed of proliferating parietal epithelial cells and infiltrating leukocytes.
5. What is the molecule that is mainly responsible for eliciting the crescentic response?
Fibrin, which leaks into the urinary space, often thru ruptured basement membranes, has been long thought to be the molecule that elicits the crescentic response.

In support of this, fibrin can be demonstrated immunohistochemically in the glomerular tufts and urinary spaces of glomeruli that contain crescents.
6. What causes the basement membrane thickening in glomerulonephritis?
Such thickening can be resolved as one of two alterations:

1. Deposition of amorphous electron-dense material, most often immune complexes, on the endothelial or epithelial side of the basement membrane or w/in the GBM itself. Fribrin, amyloid, cryoglobulins, and abnormal fibrillary proteins may also deposit in the GBM.
2. Thickening of the basement membrane proper, as occurs in diabetic glomerulosclerosis.
7. What causes the hyalinization and sclerosis in glomerulonephritis?
Hyalinization denotes the accumulation of material that is homogeneous and eosinophilic by light microscopy. By electron microscopy, the hyalin is extracellular and consists of amorphous substance. This change contributes to obliteration of capillary lumina of the glomerular tuft (a feature of sclerosis).

Hyalinosis is usually a consequence of endothelial or capillary wall injury and typically is the end result of various forms of glomerular damage.
8. What are the two patterns of antibody associated glomerular injury?
1. Injury by antibodies reacting in situ w/in the glomerulus, either with insoluble fixed (intrinsic) glomerular antigens or w/molecules planted w/in the glomerulus

2. Injury resulting from deposition of circulating antigen-antibody complexes in the glomerus
9. What is in situ immune complex deposition?
In this form of injury, antibodies react directly w/intrinsic tissue antigen, or antigens "planted" in the glomerulus from the circulation.

These include Anti-GBM antibody induced nephritis and Heymann nephritis.
10. What is anti-GBM antibody-induced nephritis?
In this type of injury, antibodies are directed against intrinsic fixed antigens that are normal components of the GBM proper.

It results in a diffuse linear pattern of staining of the antibodies by immunofluorescent techniques.
11. What is the GBM antigen responsible for classic anti-GBM antibody induced nephritis and Goodpasture syndrome?
The GBM antigen responsible for classic anti-GBM antibody induced nephritis and Goodpasture syndrome is a component of the noncollagenous domain (NC1) of the α₃-chain of collagen Type IV, which is critical for maintenance of the GBM superstructure.

Most instances of anti-GBM antibody induced nephritis are characterized by severe crescentic glomerular damage and the clinical syndrome of rapidly progressive glomerulonephritis.
12. What is Heymann nephritis?
The Heymann model of rat glomerulonephritis is induced by immunizing animals w/an antigen contained w/in preparations of proximal tubular brush border. The disease results from the reaction of antibody w/an antigen complex located on the basal surface of visceral epithelial cells and cross-reacting w/the brush border antigen.

The rats develop antibodies to this antigen, and a membranous glomerulopathy develops, resembling human membranous glomerulopathy.

On electron microscopy, the glomerulopathy is characterized by the presence of numerous eletron-dense deposits along the subepithelial aspect of the basement membrane. This pattern of immune deposition by immunofluorescence microscopy is granular rather than linear.
13. What are "antibodies against planted antigens" diseases?
Antibodies can react in situ w/antigens that are not normally present in the glomerulus but are "planted" there.

These include exogenous and endogenous antigens. Planted antigens include cationic molecules that bind to glomerular capillary anionic sites; DNA, nucleosomes, and other proteins; bacterial products; and immune complexes themselves.

Antibodies that bind to most of these planted antigens induce a discrete pattern of immunoglobulin deposition detected as granular staining by immunofluorescence microscopy similar to the pattern found in circulating immune complex nephritis.
14. What is circulating immune complex nephritis?
In this type of nephritis, glomerular injury is caused by the trapping of circulating antigen-antibody complexes w/in glomeruli. The antibodies have no immunologic specificity of glomerular constituents, and the complexes localize w/in the glomeruli b/c of their physicochemical properties and the hemodynamic factors peculiar to the glomerulus.
15. What factors affect glomerular localization of antigens, antibody, or complexes?
The molecular charge and size of these reactants are clearly important.

Highly cationic immunogens tend to cross the GBM, and the resultant complexes achieve a subepithleial location.

Highly anionic macromolecules are excluded from the GBM and either are trapped subendothelially or may not be nephrogenic at all.

Neutral molecules tend to accumulate in the mesangium.

*Large circulating complexes are not usually nephritogenic b/c they are cleared by the mononuclear phagocyte system and do not enter the GBM in sufficient quantities.
16. What is the pattern of immune deposition in most of the cases of glomerulonephritis?
In the largest proportion of cases of human glomerulonephritis, the pattern of immune deposition is granular and along the basement membrane or in the mesangium.
17. In sum, what is the summary of immune mechanisms of glomerular injury?
Antigen-antibody deposition in the glomerulus is a major pathway of glomerular injury and that in situ immune reactions, trapping of circulating complexes, interactions between these two events, and local hemodynamic and structural determinants in the glomerulus all contribute to the diverse morphologic and functional alterations in glomerulonephritis.
18. When does activation of alternative complement pathway occur in glomerulonephritis?
Alternative complement pathway activation occurs in the clinicopathologic entity called dense-deposit disease, AKA membranoproliferative glomerulonephritis.
19. What causes the detachment of visceral epithelial cells from the GBM?
It is hypothesized that the detachment of visceral epithelial cells is caused by loss of adhesive interactions w/the basement membrane and that this detachment contributes to protein leakage.
20. What are the nine mediators of glomerular injury?
1. Neutrophils
2. Monocytes, macrophages, lymphocytes, and NK cells
3. Platelets
4. Resident glomerular cells, particularly mesangial cells
5. C5b-C9
6. Coagulation proteins, especially fibrin
7. Hemodynamic regulators
8. Cytokines (IL-1 and TNF)
9. Growth factors (TGF-β, MCP-1, RANTES)
21. What happens when a renal disease, glomerular or otherwise, destroys functioning nephrons and reduces the GFR to about 30-50% of normal?
Progression to ESRD proceeds at a relatively constant rate, independent of the original stimulus or activity of the underlying disease.
22. What are the two major histologic characteristics of such progressive renal damage?
1. Glomerulosclerosis (both segmental and focal)
2. Tubulointerstitial fibrosis
23. What is focal segmental glomerulosclerosis (FSGS)?
Patients w/this secondary change develop proteinuria, even is the primary disease was nonglomerular. The glomerulosclerosis appears to be initiated by the adaptive change that occurs in the relatively unaffected glomeruli of diseased kidneys. Compensatory hypertrophy of the remaining glomeruli serves to maintain renal function, but proteinuria and glomerulosclerosis soon develop, leading eventually to total glomerular sclerosis and uremia. Most of the mediators of chronic inflammation and fibrosis, particularly TGF-β, play a role in the induction of sclerosis.

Treatment w/inhibitors of the renin-angiotensin system can be successful interventions to interrupt these mechanisms of progressive glomerulosclerosis.
24. What else contributes to the progressive injury of focal and segmental glomerulosclerosis?
The inability of mature visceral epithelial cells (podocytes) to proliferate after injury. This can lead to a decrease in glomerular podocyte number after a severe injury resulting in loss of some of these cells, leading structural alterations. These alterations lead to abnormal protein filtration as well as loss of structural support for the glomerular capillary walls.

This latter alteration in turn may lead to segmental loop dilatation b/c of now incompletely opposed intracapillary pressures, w/subsequent formation of a fibrous attachment to Bowman capsule by the bulging capillary segment, and eventual sclerosis of this segment.
25. What is tubulointerstitial fibrosis?
Tubulointerstitial injury, manifested by tubular damage and interstitial inflammation, is a component of many acute and chronic glomerulonephrides.

Tubulointerstitial fibrosis contributes to progression in both immune and nonimmune glomerular diseases, for example, diabetic nephropathy. Indeed, there is often a much better correlation of decline in renal function w/the extent of tubulointerstitial damage than w/the severity of glomerular injury.
26. What factors lead to tubulointerstitial fibrosis?
Many factors, including ischemia distal to sclerotic glomeruli, concomitant immune reactions to shared tubular and glomerular antigens, phosphate or ammonia retention leading to interstitial fibrosis, and the effects of proteinuria on tubular cell structure and function.

Proteinuria, in particular, causes direct injury to an activation of tubular cells. In turn, activated tubular cells elaborate proinflammatory cytokines and growth factors that drive interstitial fibrosis.
27. What is acute glomerulonephritis?
This group of glomerular diseases is characterized anatomically by inflammatory alterations in the glomeruli and clinically by the syndrome of acute nephritis.

The nephritis patient usually presents w/hematuria, red cell casts in the urine, azotemia, oliguria, and mild to moderate hypertension. The patient also commonly has proteinuria and edema.

This syndrome may occur in SLE and microscopic polyarteritis. Typically, however, it is characteristic of acute proliferative glomerulonephritis and is an important component of crescentic glomerulonephritis.
28. What is acute proliferative glomerulonephritis?
AKA post-streptococcal, postinfectious glomerulonephritis.

This cluster of diseases is characterized histologically by diffuse proliferation of glomerular cells, associated w/influx of leukocytes. These lesions are typically caused by immune complexes, and the inciting antigens may be endogenous or exogenous.
29. What is post-streptococcal glomerulonephritis?
This glomerular disease usually appears 1-4 weeks after a streptococcal infection of the pharynx or skin. It occurs most freq in children 6-10 years of age, but adults of any age can be affected.
30. What is the pathogenesis of post-streptococcal glomerulonephritis?
Only certain strains of group A β-hemolytic streptococci are nephritogenic.

Post-streptococcal glomerulonephritis is an immunologically mediated disease. The period between infection and onset of nephritis is compatible w/the time required for the production of antibodies and the formation of immune complexes. The presence of granular immune deposits in the glomeruli demonstrates and immune complex-mediated mechanism.

*Endostreptosin and several cationic antigens related to streptokinase can be present in affected glomeruli.
31. What is the morphology of post-streptococcal glomerulonephritis?
The classic diagnostic picture is one of enlarged, hypercellular glomeruli. The hypercellularity is caused by (1) infiltration by leukocytes, both neutrophils and monocytes; (2) proliferation of endothelial and mesangial cells; and (3) in severe cases by crescent formation.

By immunofluorescence microscopy, there are granular deposits of IgG, IgM, and C3 in the mesangium and along the basement membrane.

*The characteristic electron microscopic findings are discrete, amorphous, electron dense deposits on the epithelial side of the membrane, often having the appearance of "humps".
32. What is the clinical course of post-streptococcal glomerulonephritis?
In the classic case, a young child abruptly develops malaise, fever, nausea, oliguria, and hematuria 1-2 weeks after recovery from a sore throat. The patients has red cell casts in the urine, mild proteinuria, periorbital edema, and mild to moderate hypertension. In adults, the onset is atypical, w/the sudden appearance of hypertension or edema, freq w/elevation of BUN.

More than 95% of children recover. In adults, the epidemic form has a good prognosis, although only 60%% recover after the sporadic form; the remainder develop rapidly progressive disease, chronic renal failure, or delayed, but eventual resolution.
33. What are the lab finding in post-streptococcal glomerulonephritis?
*Important lab findings include elevations of antistreptococcal antibody (ASO) titers and a decline in the serum concentration of C3 and other components of the complement cascade and the presence of cryoglobulins in the serum.
34. What is nonstreptococcal acute glomerulonephritis (postinfectious glomerulonephritis)?
A similar form of glomerulonephritis occurs sporadically in associated w/other bacterial infections, viral disease, and parasitic infections.

In this setting, granular immunofluorescent deposits and subepithelial humps characteristic of immune complex nephritis are present.
35. What is rapidly progressive (crescentic) glomerulonephritis?
Rapidly progressive glomerulonephritis (RPGN) is a syndrome associated w/severe glomerular injury and does not denote a specific etiologic form of glomerulonephritis.

It is characterized clinically by rapid and progressive loss of renal function associated w/severe oliguria and (if untreated) death from renal failure w/in weeks to months.

***Regardless of the cause, the classic histologic picture is characterized by the presence of crescents in most of the glomeruli.
36. What are the three types of RPGN?
Type I RPGN (Anti-GBM antibody)

Type II RPGN (Immune complex)

Type III RPGN (Pauci-immune)
37. What is Type I RPGN (Anti-GBM antibody)?
This is characterized by linear deposits of IgG, and in many cases, C3 in the GBM.

In some patients, the anti GBM antibodies cross-react w/pulmonary alveolar basement membranes to produce the clinical picture of pulmonary hemorrhage associated w/renal failure (Goodpasture syndrome).

Plasmapheresis to remove the pathogenic circulating antibodies is usually part of treatment.
38. What are the environmental and genetic risk factors for Goodpasture syndrome?
Exposure to viruses or hydrocarbon solvents has been implicated in some patients, as have various drugs and cancers. There is a high prevalence of certain HLA subtypes and haplotypes (e.g., HLA-DRB1) in affected patients.
39. What is Type II RPGN (Immune complex)?
The second type of RPGN is the result of immune complex-mediated disease. It can be a complication of any of the immune complex nephritides, indcluding postinfectious glomerulonephritis, SLE, IgA nephropathy, and Henoch-Schonlein purpura.

In all of these cases, immunofluorescence studies reveal the granular pattern of staining characteristic of immune complex deposition.

These patients cannot usually be helped by plasmapheresis, and they require treatment for the underlying disease.
40. What is Type III RPGN (Pauci-immune)?
The third type of RPGN, AKA pauci-immune type, is defined by the lack of anti-GBM antibodies or immune complexes by immunofluorescence and electron microscopy. Most patients w/this type of RPGN have antineutrophil cytoplasmic antibodies (ANCA).

In some cases, this type of RPGN is a component of a systemic vasculitis such as Wegener granulomatosis or microscopic polyarteritis. In many cases, however, pauci-immune crescentic glomerulonephritis is isolated and hence idiopathic. More than 90% of such idiopathic cases have c-ANCA or p-ANCA in the sera. The presence of circulating ANCAs in both idiopathic RPGN and cases of RPGN that occur as a component of systemic vasculitis, and the similar pathologic features in either setting, have led to the idea that these disorders are pathogenetically related.
41. What is the morphology in RPGN?
The common denominator in all types of RPGN is severe glomerular injury.

The kidneys are enlarged and pale, often w/petechial hemorrhages on the cortical surfaces. Depending on the underlying cause, the glomeruli may show focal necrosis, diffuse or focal endothelial proliferation, and mesangial proliferation. The histologic picture, however, is dominated by the formation of distinctive crescents.

Fibrin strands are prominent between the cellular layers in the crescents; indeed, the escape of fibrin into Bowman space is an important contributor to crescent formation.

EM shows distinct ruptures in the GBM. By immunofluorescence microscopy, postinfectious cases exhibit granular immune deposits; Goodpasture syndrome cases show linear fluorescence for Ig and complement, and pauci-immune cases have little or no deposition of immune reactants.
42. What is the clinical course in RPGN?
All forms include hematuria w/urinary RBC casts, moderate proteinuria, and variable hypertension and edema. In Goodpasture syndrome, the course may be dominated by recurrent hemoptysis. Serum analyses for anti-GBm, antinuclear antibodies, and ANCA are helpful in Dx subtyping.

Renal involvement is usually progressive over the course of a few weeks, culminating in severe oliguria. Functional recovery may occur w/intensive plasmapheresis combined w/steroids and cytotoxic agents (e.g., in Goodpasture syndrome).
43. What are the four manifestations of nephrotic syndrome?
1. Massive proteinuria, w/the daily loss of 3.5 gm or more of protein
2. Hypoalbuminemia, w/plasma albumin levels less than 3 gm/dL
3. Generalized edema
4. Hyperlipidemia and lipiduria
44. What is nephrotic syndrome?
Nephrotic syndrome is characterized by excessive permeability of the glomerular capillary wall to plasma proteins. Depending on the lesions, the proteinuria may be highly selective, such as LMW proteins (chiefly albumin). W/more severe injury, relatively nonselective proteinuria leads to loss of HMW proteins in addition to albumin.

Heavy proteinuria leads to hypoalbuminemia, decreased colloid osmotic pressure, and systemic edema. There are also sodium and water retention, hyperlipidemia, lipiduria (oval fat bodies), vulnerability to infection, and thrombotic complications.
45. What is the pathogenesis of nephrotic syndrome?
In children < 17 y/o in the US, the nephrotic syndrome is almost always caused by a lesion primary to the kidney; whereas among adults, it may often be associated w/a systemic disease.

The most frequent systemic causes of nephrotic syndrome are diabetes, amyloidosis, and SLE.

The most important of the primary glomerular lesions are minimal change disease, membranous glomerulopathy, and focal segmental glomerulosclerosis. The first is most common in children, the second is most common in older adults, but focal glomerulosclerosis occurs in all ages.
46. What is membranous glomerulopathy?
Membranous glomerulopathy is the most common cause of the nephrotic syndrome in adults. It is characterized by diffuse thickening of the glomerular capillary wall and the accumulation of electron-dense, Ig containing deposits along the subepithelial side of the basement membrane.
47. What are the five main causes of membranous glomerulopathy?
1. Drugs (penicillamine, captopril, gold, NSAIDs)
2. Underlying malignant tumors, particularly CA of the lung and colon and melanoma
3. SLE; about 15% of glomerulonephritis in SLE is of the membranous type
4. Infections (chronic HBV, HCV, syphilis, schistosomiasis, malaria)
5. Other autoimmune disorders, such as thyroiditis

*In about 85% of patients, however, no associated condition can be uncovered, and the disease is considered idiopathic.
48. What is the pathogenesis of membranous glomerulonephropathy?
Membranous glomerulopathy is a form of chronic immune complex-mediated disease. The lesions bear a striking resemblance to those of experimental Heymann nephritis, which is induced by antibodies to a megalin antigenic complex. Thus, idiopathic membranous glomerulopathy, like Heymann nephritis, is considered an autoimmune disease linked to susceptibility genes and caused by antibodies to a renal autoantigen.
49. How does the glomerular capillary wall become leaky in membranous glomerulopathy?
There is a paucity of neutrophils, monocytes or platelets in glomeruli and the virtually uniform presence of complement, and experimental work suggests a direct action of C5b-C9, the pathway leading to the formation of the MAC.

C5b-C9 causes activation of glomerular epithelial and mesangial cells, inducing them to liberate proteases and oxidants, which cause capillary wall injury and increased protein leakage.
50. What is the morphology of membranous glomerulopathy?
By light microscopy, the glomeruli either appear normal in the early stages of the disease or *exhibit uniform, diffuse thickening of the glomerular capillary wall.* By EM, the thickening is seen to be caused by irregular dense deposits btw the basement membrane and the overlying epithelial cells, the latter having effaced foot processes.

Basement membrane material is laid down between these deposits, appearing as irregular spikes protruding from the GBM. These spikes are best seen by silver stains, which color the basement membrane black.

Immunofluorescence microscopy demonstrates that the granular deposits on the subepithelial side of the basement membrane contain both Igs and various amts of complement.
51. What is the clinical course of membranous glomerulopathy?
This condition usually starts w/the insidious onset of nephrotic syndrome or subnephrotic-range proteinuria. Progression is associated w/increasing sclerosis of the glomeruli, rising BUN, and development of hypertension. Some 40% of cases progress to renal insufficiency over an unpredictable time span of 2-20 years.

Secondary causes of membranous GN should be excluded in any new case.
52. What is minimal change disease (lipoid nephrosis)?
This relatively benign disorder is the most freq cause of nephrotic syndrome in children, but is less common in adults.

It is characterized by diffuse effacement of foot processes of epithelial cells in glomeruli that appear virtually normal by light microscopy. The peak incidence is btw 2-6 years of age.

The disease sometimes follows a respiratory infection or routine prophylactic immunization.

*Its most characteristic feature is its usually dramatic response to corticosteroid therapy.
53. What are six reasons for the immunologic basis of minimal change disease?
1. The clinical association w/respiratory infections and prophylactic immunization
2. The response to corticosteroids and/or other immunosuppressive therapy
3. The association w/other atopic disorders (e.g., eczema, rhinitis)
4. The increased prevalence of certain HLA haplotypes in patients w/minimal change disease associated w/atopy
5. The increased incidence of minimal change disease in patients w/Hodgkin disease, in whom T cell-mediated defected are well recognized
6. Reports of proteinuria inducing factors in the plasma or lymphocyte supernatants of patients w/minimal change disease and focal glomerulosclerosis
54. What is the current hypothesis on the pathogenesis of minimal change disease?
That minimal change disease involves some immune dysfunction, evutally resutling in the elaboration fo a cytokien that damages visceral epithelial cells and causes proteinuria.

The ultrastructural changes point to a primary visceral epithelial cell injury, and this suggests a loss of glomerular polyanions. This leads to defects in the charge barrier, which may contribute to the proteinuria.
55. Mutations in _____ causes a hereditary form of congenital nephrotic syndrome w/minimal change glomerular morphology?

Such mutations and the proteinuria they engender demonstrate that at least some cases of nephrotic syndrome w/minimal change disease morphology can occur in the absence of abnormal responses of the immune system.
57. What is the morphology in minimal change disease?
The glomeruli are normal by light microscopy. By EM, the basement membrane appears normal, and no dense material is deposited.

*The principal lesion is in the visceral epithelial cells, which show a uniform and diffuse effacement of foot processes. It is only when effacement is associated w/normal glomeruli by light microscopy that the Dx of minimal change disease can be made.

The cells of the proximal tubules are often laden w/lipid and protein, reflecting tubular reabsorption of lipoproteins passing thru diseased glomeruli (lipoid nephrosis).
58. What is the clinical course in minimal change disease?
Despite massive proteinuria, renal function remains good, and there is commonly no hypertension or hematuria.

The proteinuria usually is highly selective, most of the protein consisting of albumin. Most children respond to corticosteroid therapy. However, the nephrotic phase may recur, and some pts may become steroid dependent or resistant.

Regardless, the prognosis for adults and children is quite good.
59. What is focal segmental glomerulosclerosis?
This lesion is characterized by sclerosis of some, but not all, glomeruli (thus, it is focal); and in the affected glomeruli, only a portion of the capillary tuft is involved (thus it is segmental).

Focal segmental glomerulosclerosis is freq accompanied clinically by the nephrotic syndrome or heavy proteinuria.
60. What are the five types of focal segmental glomerulosclerosis?
1. Idiopathic
2. A secondary event, reflecting glomerular scarring, consequent to another primary glomerular disease (e.g. IgA nephropathy)
3. Associated w/loss of renal mass as the result of chronic reflex, analgesic abuse, or unilateral renal agenesis
4. Secondary to other known disorders (e.g. heroin abuse, HIV, obesity).
5. The result of inherited mutations of proteins present in the podocytes (podocin, α-actinin 4) or in the slit diaphragm between podocytes (nephrin).
61. What is the most common cause of nephrotic syndrome in adults in the US?
Focal segmental glomerulosclerosis, both primary and secondary, is the most common cause of nephrotic syndrome in adults in the US, especially in Hispanics and Blacks.
62. The clinical signs in FSGS differ from minimal change disease in what five ways?
1. There is a higher incidence of hematuria, reduced GFR, and hypertension
2. Proteinuria is more often nonselective
3. There is poor response to corticosteroid therapy
4. There is progression to chronic glomerulosclerosis, w/at least 50% developing ESRD w/in 10 years
5. Immunofluorescence microscopy may show nonspecific deposition of IgM and C3 in the sclerotic segment
63. What is the morphology of focal segmental glomerulosclerosis?
The lesions tend to initially involve the juxtamedullary glomeruli.

***In the sclerotic segments, there is collapse of basement membranes, increase in matrix, and segmental insudation of plasma proteins along the capillary wall (hyalinosis), which may extend to aggregates w/in glomerular capillaries that occlude the lumen.*** Lipid droplets and foam cells are often present.

By immunofluorescence microscopy, IgM and C3 may be present in the sclerotic areas and/or in the mesangium. In addition to the focal sclerosis, there may be pronounced hyalinosis and thickening of the afferent arterioles.
64. What is collapsing glomerulopathy?
A morphologic variant of FSGS, called collapsing glomerulopathy, is characterized by collapse and scelerosis of the entire glomerular tuft in addition to the usual focal segmental glomerulosclerosis lesions. **A characteristic feature is proliferation and hypertrophy of glomerular visceral epithelial cells.

*This lesion may be seen in idiopathic situations, but it is the most characteristic lesion of HIV-associated nephropathy.*

In both cases, there is associated prominent tubular injury w/formation of microcysts. It has a particularly poor prognosis.
65. What is the hallmark of focal segmental glomerulosclerosis?
The characteristic degeneration and focal disruption of visceral epithelial cells are thought to represent an accentuation of the diffuse epithelial cell change typical of minimal change disease.

It is this epithelial damage that is the hallmark of FSGS.
66. Mutations in what gene is thought to be related to FSGS?
NPHS1; several mutations in this gene have been identified - it encodes nephrin, and they give rise to congenital nephrotic syndrome of the Finnish type.

A distinctive pattern of autosomal recessive FSGS results from mutations in the NPHS2 gene - it encodes podocin.

Also, α-actinin 4 mutations can also underlie cases of autosomal dominant FSGS.
67. What is renal ablation focal segmental glomerulosclerosis?
Renal ablation focal segmental glomerulosclerosis occurs as a complication of glomerular and nonglomerular diseases causing reduction in functioning renal tissue, particularly reflex nephropathy and unilateral agenesis.

These may lead to progressive glomerulosclerosis and renal failure.
68. What is the clinical course of FSGS?
There is little tendency for spontaneous remission in idiopathic FSGS and responses to corticosteroid therapy are variable.

In general, children have a better prognosis than adults do. Progression of renal failure occurs at variable rates. About 20% of patients follow an unusually rapid course, w/intractable massive proteinuria ending in renal failure w/in 2 years.
69. What is HIV-associated nephropathy?
HIV infection can result directly or indirectly in a number of renal complications, including acute renal failure, and/or acute interstitial nephritis induced by drugs, infection, thrombotic microangiopathies, postinfectious glomerulonephritis, and most commonly, *a severe form of the collapsing variant of focal segmental glomerulosclerosis.
70. What are the three main morphologic features of HIV-associated nephropathy?
1. A high frequency of the collapsing variant of focal segmental glomerulosclerosis, with global involvement of the tuft
2. A striking focal cystic dilation of tubule segments, which are filled with proteinaceous material, and inflammation and fibrosis
3. The presence of large numbers of tubuloreticular inclusions in endothelial cells, detected by electron microscopy. Such inclusions, also present in SLE, have been shown to be induced by circulating interferon-α. They are not present in idiopathic focal segmental glomerulosclerosis and therefore may have diagnostic value in a biopsy specimen.
71. What is membranoproliferative glomerulonephritis?
MPGN is characterized histologically by alterations in the basement membrane, proliferation of glomerular cells, and leukocyte infiltration.

B/c the proliferation is predominantly in the mesangium, a frequently used synonym is mesangiocapillary glomerulonephritis. MPGN accounts for 10-20% of cases of nephrotic syndrome in children and young adults. Some patients present only w/hematuria or proteinuria in the non-nephrotic range, and others have a combined nephrotic-nephritic picture.

Like many other glomerunephritides, MPGN either can be associated w/other systemic disorders and known etiologic agents or may be idiopathic.
72. What are the two types of MPGN?
Primary MPGN is divided intwo two major types on teh basis of distinct ultrastructural, immunofluorescent, and pathologic findings: type I and typeII MPGN (dense-deposit disease).
73. What is the morphology of MPGN?
Both types are similar via light microscopy. The glomeruli are large and hypercellular. The glomerui have a "lobular" appearance accentuated by the proliferating mesangial cells and increased mesangial matrix.

The GBM is clearly thickened, often focally, this is most evident in the peripheral capillary loops. The glomerular capillary wall often shows a "double contour" or "tram-track" appearance, especially evident in silver or PAS stains. This is caused by duplication of the basement membrane. W/in the basement membrane there is inclusion or interposition of cellular elements; such interposition gives rise to the appearance of "split" basement membranes.
74. What is the morphology of Type I MPGN?
Most of the cases are this type. It is characterized by the presence of subendothelial electron-dense deposits. Mesangial and occasional subepithelial deposits may also be present.

By immunofluorescence, C3 is deposited in a granular pattern, and IgG and early complement components (C1q and C4) are often also present.
75. What is the morphology of Type II MPGN?
In dense-deposit disease (type II MPGN), a relatively rare entity, the lamina densa of the GBM is transformed into an irregular, ribbon-like, extremely electron-dense structure b/c of the deposition of dense material of unknown composition in the GBM proper, giving rise to the term dense-deposit disease.

C3 is present in irregular granular or linear foci in the basement membranes on either side. C3 is also present in the mesangium in characteristic circular aggregates (mesangial rings). IgG is usually absent, as are the early-acting complement components (C1q and C4).
76. What is the pathogenesis of Type I MPGN?
In most cases of type I MPGN there is evidence of immune complexes in the glomerulus and activation of both classical and alternative complement pathways.

The antigens are believed to be proteins derived from infectious agents such as HCV and HBV viruses.
77. What is the pathogenesis of Type II MPGN?
Most patients w/dense-deposit disease (Type II) have abnormalities that suggest activation of the alternative complement pathway.

These patients have a consistently decreased serum C3 but normal C1 and C4. They also have diminished serum levels of factor B and properdin, parts of the alternative complement pathway.

*More than 70% of patients w/dense-deposit disease have a circulating antibody termed C3 nephritic factor (C3NeF), which is an autoantibody that binds to the alternative pathway C3 convertase. Binding of the antibody stabilizes the convertases, protecting it from degradation and thus favoring persistent C3 degradation and hypocomplementemia.
78. What is the clinical course of primary MPGN?
Although steroids may slow the progression of MPGN, about 50% of patients develop chronic renal failure w/in 10 years. There is a high recurrence rate in transplant recipients, particularly in patients w/type II disease.
79. What is secondary MPGN?
Secondary MPGN (invariably type I) is more common in adults and arises in the following settings:
1. Chronic immune complex disorders, i.e. SLE, HBV, HCV
2. α1-antitrypsin deficiency
3. Malignant diseases (chronic lymphocytic leukemia and lymphoma)
4. Hereditary deficiencies of complement regulatory proteins
80. What is IgA nephropathy (Berger disease)?
This form of glomerulonephritis is characterized by the presence of prominent IgA deposits in the mesangial regions, detected by imunofluorescence microscopy. The disease can be suspected by light microscopy, but Dx is made only by immunocytochemical techniques.

IgA nephropathy is a freq cause of recurrent gross or microscopic hematuria and is probably the most common type of glomerulonephritis worldwide. Mild proteinuria is usually present, and the nephrotic syndrome may occasionally develop.
81. What is the pathogenesis of IgA nephropathy?
In aptients w/IgA nephropathy, serum polymeric IgA is increased, and circulating IgA-containing immune complexes are present in some patients.

*Only IgA1 forms the nephritogenic deposits of IgA nephropathy. The prominent mesangial deposition of IgA suggests entrapment of IgA immune complexes in the mesangium, and the presence of C3 combined w/the absence of C1q and C4 in glomeruli points to activation of the alternative complement pathway.

This is supported by the fact that IgA nephropathy occurs w/increased freq in pts with celiac disease.
82. What is the morphology of IgA nephropathy?
On histologic exam, the glomeruli may be normal or may show mesangioproliferative GN, focal proliferative GN, or rarely, overt crecentic GN. The presence of leukocytes w/in glomerular capillaries is a variable feature.

The characteristic immunofluorescent picture is of mesangial deposition of IgA, often w/C3 and properdin and lesser amts of IgG or IgM. EM confirms the presence of electron-dense deposits in the mesangium.
83. What is the clinical course of IgA nephropathy?
The hematuria typically lasts for several days, then subsides only to recur. Although most patients have an initially benign course, chronic renal failure develops in 50% over a period of 20 years. Recurrence occurs in 20-60% of grafts.

Onset in old age, heavy proteinuria, hypertension, crescents, and vascular sclerosis portend a poorer prognosis.
84. What is hereditary nephritis?
Hereditary nephritis refers to a group of heterogeneous familial renal diseases associated primarily w/glomerular injury. These include Alport syndrome, and thin basement membrane disease, the most common cause of benign familial hematuria.
85. What is Alport syndrome?
Alport syndrome, when fully developed, is manifest by nephritis progressing to chronic renal failure, accompanied by nerve deafness and various eye disorders, including lens dislocation, posterior cataracts, and corneal dystrophy.

In the most common X-linked form, males express the full syndrome, and females are carriers in whom manifestations of disease are typically limited to hematuria.
86. What is the pathogenesis of Alport syndrome?
Defective GBM synthesis b/c of the production of abnormal collagen type IV underlies the renal lesions. In patients w/X-linked disease, the defect is caused by mutations in the gene encoding the α5-chain of collagen type IV (COL4A5), a component of the GBM. This is though to interfere w/the assembly and architecture of collagen type IV and thus the structure and function of the GBM.
87. What is the morphology of Alport syndrome?
On histologic exam, the glomeruli are always involved. The early lesion is detectable only by EM and consists of diffuse glomerular basement membrane thinning. In some kidneys, interstitial cells acquire a foamy appearance owing to accumulation of neutral fats and mucopolysaccharides (foam cells).

*The characteristic features seen w/EM on the GBM are irregular foci of thickening alternating w/attenuation (thinning) with pronounced splitting and lamination of the lamina densa, often w/a distinctive basket-weave appearance.

*There is also absence of α5-chain of collagen type IV in skin biopsies.
88. What is the clinical course of Alport syndrome?
The most common presenting sign is gross or microscopic hematuria, freq accomapnied by erythrocyte casts. Proteinuria may occur, and rarely, the nephrotic syndrome develops. Symptoms appear at ages 5-20 years, and the onset of overt renal failure is between ages 20 and 50 years in men.

The auditory defects may be subtle, requiring sensitive testing.
89. What is thin basement membrane disease (benign familial hematuria)?
This a fairly common entity manifested clinically by familial asymptomatic hematuria, usually uncovered on routine urinalsysis and morphologically by diffuse thinning of the GBM to between 150 and 250 nm (compared to the normal 300-400 nm).

Although mild or moderate proteinuria may also be present, renal function is normal and prognosis is excellent.

In contrast to Alport syndrome, hearing loss, ocular abnormalities, and a family history of renal failure are absent, and skin biopsy specimens show presence of the α5-chain of collagen type IV.
90. What is chronic glomerulonephritis?
Chronic glomerulonephritis is best considered a pool of end-stage glomerular disease fed by a number of streams of specific types of glomerulonephritis.

Nevertheless, in any series of patients w/chronic glomerulonephritis, a variable percentage of cases arise mysteriously w/no antecedent history of any of the well recognized forms of acute glomerulonephritis.
91. What is the morphology of chronic glomerulonephritis?

The kidneys are symmetrically contracted and have diffusely granular, cortical surfaces. On section, the cortex is thinned and there is an increase in peripelvic fat. There eventually ensues hyaline obliteration of glomeruli, transforming them into acellular eosinophilic masses.

B/c hypertension is an accompaniment, arterial and arteriolar sclerosis may be conspicuous. Marked atrophy of associated tubules also occur.
92. What is the morphology of chronic glomerulonephritis?

(Dialysis changes) 2/3
Dialysis changes: kidneys from patients w/ESRD on long term dialysis show arterial intimal thickening, extensive deposition of calcium oxalate crystals in tubules and interstitium, acquired cystic disease, and increased numbers of renal adenomas and adenocarcinomas.
93. What is the morphology of chronic glomerulonephritis?

(Uremic complications) 3/3
Uremic complications: patients dying w/chronic GN also exhibit changes outside the kidney related to the uremic state. Often clinically important, these include uremic pericarditis, uremic gastroenteritis, secondary hyperparathyroidism with nephocalcinosis and renal osteodystrophy, LV hypertrophy due to hypertension, and pulmonary changes of diffuse alveolar damage often ascribed to uremia (uremic pneumonitis).
94. What is the clinical course of chronic GN?
In most patients, chronic GN develops insidiously and slowly progresses to renal insufficiency or death from uremia.

Most patients are hypertensive, and sometimes the dominant clinical manifestations are cerebral or cardiovascular. In all, the disease is relentlessly progressive.
95. What are the renal involvements in SLE?
SLE gives rise to a heterogeneous group of lesions and clinical presentations. The clinical manifestations can include recurrent microscopic or gross hematuria, acute nephritis, the nephrotic syndrome, chronic renal failure, and hypertension.
96. What is Henoch-Schonlein purpura?
This syndrome consists of purpuric skin lesions characteristically involving the extensor surfaces of arms and legs as well as buttocks; abdominal manifestations including pain, vomiting, and intestinal bleed; nonmigratory arthralgia, and renal abnormalities.

Renal involvement occurs in 1/3 of pts and include gross or microscopic hematuria, proteinuria, and nephrotic syndrome.

*IgA is deposited in the glomerular mesangium in a distribution similar to that of IgA nephropathy.
97. What is the morphology of Henoch-Schonlein purpura?
On histologic exam, the renal lesions vary from mild focal mesangial proliferation to diffuse mesangial proliferation to crescentic GN.

Whatever the histologic lesions, the prominent feature by fluorescence is the deposition of IgA, sometimes with IgG and C3 in the mesangial region.

The skin lesions consist of subepidermal hemorrhages and a necrotizing vasculitis in the small vessels of the dermis. IgA is also present in these vessels.
98. What are the renal complications in bacterial endocarditis?
Glomerular lesions in the course of bacterial endocarditis represent a type of immune complex nephritis initiated by compelxes of bacterial antigen and antibody.

Hematuria and proteinuria of various degrees can occur, but an acute nephritic presentation is not uncommon.

The histologic lesions, when present, generally reflect these clinical manifestations. Milder forms have a more focal and segmental necrotizing glomerulonephritis, whereas more severe ones exhibit a diffuse proliferative glomerulonephritis, and the rapidly progressive forms show large numbers of crescents.
99. What is diabetic glomerulosclerosis?
DM is a major cause of renal morbidity. By far the most common lesions involve the glomeruli and are associated clinically w/three glomerular syndromes: non-nephrotic proteinuria, nephrotic syndrome, and chronic renal failure.

Also, DM causes hyalinizing arteriolar sclerosis, papillary necrosis, and a variety of tubular lesions. Thus, diabetic nephropathy is used.
100. What are the three morphologic changes in the glomeruli in diabetic nephropathy?
1. Capillary basement membrane thickening
2. Diffuse mesangial sclerosis
3. Nodular glomerulosclerosis
101. What is the pathogenesis of diabetic nephropathy?
Two processes seem to play a role in the fully developed diabetic glomerular lesions: a metabolic defect, possibly linked to advanced glycosylation end products, that accounts for the thickened GBM and increased mesangial matrix that occur in patients; and hemodynamic effects, associated w/glomerular hypertrophy, which also contributes to the development of glomerulosclerosis.
102. What is the morphology of the capillary basement membrane thickening in diabetic nephropathy?
Widespread thickening of the glomerular capillary basement membrane (GBM) occurs in virtually all diabetics.

This thickening begins as early as 2 years after the onset of type I diabetes and by 5 years amts to about 30% increase. The thickening continues progressively and usually concurrently w/mesangial widening. Simultaneously, there is thickening of the tubular basement membranes.
103. What is the morphology of diffuse mesangial sclerosis in diabetic nephropathy?
This lesion consists of diffuse increase in mesangial matrix. There can be mild proliferation of mesangial cells early in the disease process, but cell proliferation is not a prominent part of this injury.

The mesangial increase is typically associated w/the overall thickening of the GBM. The matrix depositions are PAS positive.
104. What is nodular glomerulosclerosis?
AKA intercapillary glomerulosclerosis or Kimmelsteil-Wilson disease.

The glomerular lesions take on the form of ovoid or spherical, often laminated, nodules of matrix situated in the periphery of the glomerulus. The nodules are PAS-positive.

These nodular lesions are freq accompanied by prominent accumulations of hyaline material in capillary loops ("fibrin caps") or adherent to Bowman's capsules ("capsular drops"). As a consequence of the glomerular and arteriolar lesions, the kidney suffers from ischemia, develops tubular atrophy and interstitial fibrosis, and usually undergoes contraction in size.

*Approx 15-30% of patients w/long term DM develop nodular glomerulosclerosis, and it most instances it is associated w/renal failure.
105. What is the clinical course of diabetic glomerulosclerosis?
Depends on the type of diabetes.

The increased GFR typical of early-onset type 1 DM is associated w/microalbuminuria. Microalbuminuria and increased GFR are important predictors of future overt diabetic nephropathy in these patients.

Systemic hypertension may precede the development of proteinuria and renal insufficiency.

*Most exciting is the fact that good glycemic homeostassi by pancreatic transplantation in patients w/diabetic nephropathy can actually reverse the nephropathy. ACE inhibitors or ARBs can also have a beneficial effect by reversing the increased intraglomerular capillary pressure.
106. What is amyloidosis?
Most types of disseminated amyloidosis may be associated w/deposits of amyloid w/in the glomeruli; most commonly renal amyloid is of light-chain AL or AA type.

The typical Congo red amyloid-positive fibrillary deposits are present w/in the mesangium and capillary walls and rarely are localized to the subepithelial space. Eventually, they obliterate the glomerulus completely.

Pts w/glomerular amyloid may present w/the nephrotic syndrome and later die of uremia. Characteristically, kidney size tends to be either normal or increased.
107. What is fibrillary glomerulonephritis?
Fibrillary GN is a morphologic variant of GN associated w/characteristic fibrillar deposits in the mesangium and glomerular capillary walls that resemble amyloid fibrils in appears but differ from amyloid fibrils when measured ultrastructurally and in that they do not stain w/Congo red.

The fibrils are typically 18-24 nm and hence are larger than the 10-12 nm characteristic of amyloid. There is usually selective deposition of IgG, often of IgG4 subclass, w/complement C3 and Ig kappa and delta light chains also present.

Clinically, pts develop nephrotic syndrome, hematuria, and progressive renal insufficiency.
108. What is immunotactoid GN?
A much rare condition in which the deposits are microtubular in structure and 30-50 nm in width.

Patients often have circulating paraproteins and/or monoclonal Ig deposition in glomeruli.
109. What about Goodpasture syndrome, microscopic polyarteritis, and Wegener granulomatosis?
These diseases are commonly associated with similar forms of GN ranging from focal segmental necrotizing GN to crescentic GN.
110. What is essential mixed cryoglobulinemia?
This is another systemic condition in which deposits of cryoglobulins composed principally of IgG-IgM complexes induce cutaneous vascultitis, synovitis, and a proliferative GN.

Most cases of essential mixed cryoglobulinemia have been associated w/infection w/HCV, and this condition in particular is associated w/GN usually of the MPGN type.
111. What about plasma cell dyscrasias and multiple myelomas?
These are associated w/:
1. Amyloidosis, in which the fibrils are usually composed of monoclonal lambda light chains
2. Deposition of monoclonal Ig or light chains in glomerular basement membranes
3. Distinctive nodular glomerular lesions resulting form the deposition of nonfibrillar light chains

*These patients usually present w/proteinuria or the nephrotic syndrome, hypertension, and progressive azotemia.
112. In which regions of the prostate do cancers arise?

Most hyperplasias arise in the transitional zone, whereas most carcinomas originate in the peripheral zone.
113. What are the three important pathologic processes that affect the prostate gland?
1. Inflammation
2. Benign nodular enlargement
3. Tumors

Of these three, the benign nodular enlargements are by far the most common and occur so often in advanced age that they can almost be considered as normal in the aging process.
114. What are teh different categories of prostatitis?
1. Acute and chronic bacterial prostatitis
2. Chronic abacterial prostatitis
3. Granulomatous prostatitis
115. What is acute bacterial prostatitis?
Acute bacterial prostatitis typically results from bacteria that cause UTIs. Thus, most cases are caused by various strains of E. coli, other gram-negative rods, enterococci, and stapylocci.

Prostatitis sometimes follows some surgical manipulation on the urethra or prostate gland.

Clinically, acute bacterial prostatitis is associated w/fever, chills, and dysuria. On rectal exam, the prostate is tender and boggy.
116. What is chronic bacterial prostatitis?
A common clinical setting is recurrent UTIs caused by the same organism. It may present w/low back pain, dysuria, and perineal and suprapubic discomfort.

B/c most antibiotics penetrate the prostate poorly, bacteria find a safe haven in the parenchyma and constantly see the urinary tract.
117. What is chronic abacterial prostatitis?
Chronic abacterial prostatitis is the most common form of prostatitis seen today.

Clinically, it is indistinguishable from chronic bacterial prostatitis. There is no history, however, of recurrent UTI.

Expressed prostatic secretions contain more than 10 leukocytes per high power field, but bacterial cultures are uniformly negative.
118. What is granulomatous prostatitis?
In the US, the most common cause is related to instiallation w/in the bladder of Bacillus Calmette-Guerin (BCG) for treatment of superficial bladder cancer.

BCG is an attenuated tubercuous strain that gives rise to a histologic picture in the prostate indistinguishable from that seen w/systemic tuberculosis.

Fungal granulomatous prostatitis is typically seen only in immunocompromised hosts.
119. What is the morphology of acute prostatitis?
Acute prostatitis may appear as minute, disseminated abscesses; as large, coalescent focal areas of necrosis; or as a diffuse edema, congestion, and boggy suppuration of the entire gland. When diffuse, they cause an overall soft, spongy enlargement of the gland.

*Biopsy of the prostate in a patient w/acute prostatitis is contraindicated as it may lead to sepsis.
120. What is the morphology of chronic prostatitis?
This Dx should be restricted to those cases of inflammatory reaction int eh prostate characterized by the aggregation of numerous lymphocytes, plasma cells, and macrophages as well as neutrophils w/in the prostatic substance only if accompanied by clinical signs and symptoms of chronic prostatitis.
121. What is nodular hyperplasia (BPH)?
BPH is an extremely common disorder in men over 50. It is characterized by hyperplasia of prostatic stromal and epithelial cells, resulting int he formation fo large, failurly discrete nodules in teh periurethral region of the prostate. When sufficiently large, the nodules compress and narrow the urethral canal to cause partial, or sometimes virtually complete, obstruction of the urethra.
122. What is the pathogenesis of BPH?
Androgens are the cause, baby... DHT, a metabolite of testosterone, is the ultimate mediator of prostatic growth. It binds to nuclear androgen receptors and signals the transcription of growth factors that are mitogenic to the epithelial and stromal cells. While DHT appears to be the major factor, estrogens also appear to play a role, perhaps by rendering cells more susceptible to the action fo DHT.

In addition, clinical symptoms of lower urinary tract obstruction are also due to smooth muscle mediated contraction of the prostate. The tension of prostate smooth muscle is mediated by the α1-adrenoreceptor localized to the prostatic stroma.
123. What is the morphology of BPH?

In the usual case, the prostate weighs between 60-100 gm.

BPH originates almost exclusively in the inner aspect of the prostate gland, in the transition zone.

The first nodules are composed almost entirely of stromal cells; later, predominantly epithelial nodules arise.

In some cases, nodular enlargement may project up into the floor of the urethra as a hemispheric mass directly beneath the mucosa of the urethra, which is termed "median lobe hypertrophy" by clinicians.
124. What is the morphology of BPH?

On cross section, the nodules usually are fairly readily identified. They vary in color and consistency. In nodules w/primarily glandular proliferation, the tissue is yellow-pink w/a soft consistency, and a milky white prostatic fluid oozes out of these areas.

In those primarily due to fibromuscular involvement, each nodule is pale gray, tough, does not exude fluid, and is less clearly demarcated from the surrounding prostatic capsule.
125. What is the morphology of BPH?

Microscopically, the hallmark of BPH is nodularity due to glandular proliferation or dilation and to fibrous or muscular proliferation of the stroma.

The Dx of BPH cannot usually be made via needle biopsy, as the histology of glandular or mixed glandular-stroma nodules of BPH cannot be appreciated on this limited sampling. Also, needle biopsies do not usually sample the transition zone where BPH occurs.
126. What are two other histologic changes associated w/BPH?
1. Foci of squamous metaplasia
2. Small areas of infarction

The former tends to occur in the margins of the foci of infarction as nests of metaplastic reactive squamous cells that can be confused with adenocarcinoma of the prostate or urothelial CA involving the prostate.
127. What is the clinical course of BPH?
Symptoms are related to two secondary effects: (1) compression of the urethra w/difficulty in urination and (2) retention of urine in teh bladder w/subsequent distention and hypertrophy of the bladder, infection fo the urine,a nd development of cystitis and renal infections.

Pts experience frequency, nocturia, difficulty starting and stopping, overflow dribbling, and dysuria. Also, the pts are unable to empty the bladder completely.

However, nodular hyperplasia is not considered to be a premalignant lesion.
128. What is adenocarcinoma of the prostate?

In which populations is it most common?
Adenocarcinoma of the prostate is the most common form of cancer in men and is the second leading cause of cancer death.

It is typically a disease of men over age 50. It is rare among Asians; whereas it common among US white populations. Thus, the initial molecular events that give rise to latent cancers occur at the same rate in Asian and American men, the probability of acquiring additional mutations, presumably environmentally induced, is lower in Asian men.
129. What is the pathogenesis of adenocarcinoma of the prostate?
Androgens also play a role. Neoplastic epithelial cells, similar to their normal counterparts, possess androgen receptors.

Androgen receptor gene amplification may also influence androgen sensitivity of prostatic epithelium. The AR gene is polymorphic, w/individuals having variable lengths of CAG repeats. Studies have shown that prostate cells w/short CAG repeats have an increased sensitivity to androgens. The shortest CAG repeats on average are found in African Americans, Caucasians have an intermediate length, and Asians have the longest.
130. Is there a hereditary form of prostate cancer?
In approx 10% of white American men, the development of prostate CA has been linked to germ line inheritance of prostate cancer susceptibility genes.

In 1/3 of these familial cases, a susceptibility gene has been mapped to chromosome 1q24-25.

Men with relatives w/prostate CA are at greater risk and those with a strong family history of prostate CA also tend to develop the disease at an earlier age.
131. What genetic events take place in early events in prostate carcinogenesis?

Late events?
Putative cancer suppressor genes that are lost early in prostate carcinogenesis have been localized to chromosomes 8p, 10q, 13q, and 16q.

p53 mutations are late events in prostate carcinogenesis.

Other tumor suppressor genes that are though to play a role in prostate CA are PTEN and KAI1.

Prostate CAs also show a relatively freq loss of E-cadherin and CD44.
132. What is one of the most common genetic alterations in prostate CA?
Hyeprmethylation of glutathione S-transferase (GSTP1) gene promoter.

More than 90% of prostate CAs show hypermethylation of the gene, which turns off its expression. The GSTP1 gene is an important part of the pathway that prevents damage from a wide range of carcinogens.
133. What is the morphology of prostate adenocarcinomas?
Prostate CA refers to the common or acinar variant of prostate CA.

In approx 70% of cases, the CA arises in the peripheral zone of the gland, classically in a posterior location, often rendering it palpable on rectal exam.

Characteristically, on cross section, the neoplastic tissue is gritty and firm, but when embedded w/in the prostatic substance, it may be extremely difficult to visualize and be more readily apparent on palpation.
134. Metastatic spread of prostate CA goes to where...?
Local extension most commonly involves the seminal vesicles and the base of the urinary bladder.

Hematogenous spread occurs chiefly to the bones, particular to the axial skeleton. The bony metastases are typically osteoblastic. The bones that are most commonly involved are lumbar spine, proximal femur, pelvis, thoracic spine, and ribs.
135. What are the histologic characteristics of prostate CA?
Histologically, most lesions are adenocarcinomas that produce well-defined, readily demonstrable gland patterns. The neoplastic glands are typically smaller than benign glands and are lined by single layer of cuboidal or low columnar epithelium.

In contrast to benign glands, prostate CA glands are more crowded, characteristically lacking branching and papillary infolding.

*Benign glands contain basal cells that are absent in cancer.
136. What are high-grade prostatic intraepithelial neoplasias (PIN)s?
In approx 80% of cases, prostatic tissue removed for CA also harbors presumptive precursor lesions, referred to as high-grade PINs. These lesions consist of benign glands w/intra-acinar proliferation of cells that demonstrate nuclear anaplasia.

High-grade PIN consists of more widely separated, larger branching glands w/papillary infolding, in contrast to invasive CA, which is typically characterized by small, crowded glands w/straight luminal borders. PIN glands are surrounded by a patchy layer of basal cells an an intact basement membrane?
137. What are four lines of evidence that suggest high-grade PINs lead to prostate CA?
1. Both high-grade PIN and CA typically predominate in the peripheral zone.
2. Prostates containing CA have a higher freq and greater extent of high-grade PIN
3. High-grade PIN is also often seen in proximity to CA
4. Studies have found that many of the molecular changes that are seen in invasive CAs are also present in PIN
138. What is the grading and staging system of prostate CA?
The Gleason system stratifies prostate CAs into five patterns on the basis of glandular patterns.

Pattern 1 represents the most well differentiated tumors; by contrast, Pattern 5 tumors show no glandular differentiation and the tumor cells infiltrate the stroma.

Most tumors contain more than one pattern; the pathologist assigns a dominant pattern and then the second most prevalent pattern. The primary and secondary patterns are added to obtain a combined Gleason score. Tumors w/only one pattern are treated as if their primary and secondary patterns are the same, hence, the number is doubled.

Thus, 2-4 represent well differentiated; 5-6 intermediate-grade CA; 7 moderate to poorly differentiated CA; and 8-10 high grade CA.
139. What is the staging of prostatic CA?
Stage T1 refers to CA found incidentally either on TURP done for BPH (T1a and T1b depending on the extent and grade) or on needle biopsy typically performed for elevated PSA levels (stage T1c).

Stage T2 is organ confined CA

Stage T3a and T3b tumors show extraprostatic extension, w/and w/o seminal vesicle invasion, respectively.

Stage T4 reflects direct invasion of contiguous organs.

Spread of tumors to the lymph nodes is designated N1.
140. What are the symptoms of prostate CA?
Patients w/clinically advanced prostate CA may present w/urinary symptoms. Some pts come to attention b/c of back pain caused by vertebral metastases.

***The finding of osteoblastic metastases in bone is virtually diagnostic of prostate CA in men. The outlook for these patients is universally fatal.
141. How is prostate CA diagnosed and confirmed?
DREs may detect some early prostatic CA b/c of their posterior location, although the test suffers from both low sensitivity and specificity.

A transrectal biopsy is required to confirm the Dx. B/c microscopic metastases are usually missed by radiologic studies, most centers use pelvic lymphadenectomy as a staging procedure.
142. How is prostate CA treated?
The treatmetn and prognosis depends on the stage of the disease. Lacalized (T1 or T2) disease is treated primarily w/surgery or radiotherapy w/a 15 year survivial rate of 90%.

Hormonal treatment can also be used (orchiectomy via synthetic analogues of LH) to treat advanced disease or combined w/radiotherapy for local disease.
143. What is PSA?
Prostate-specific antigen (PSA) is used in the Dx and management of prostate CA. PSA is a product of prostatic epithelium and is normally secreted in the semen.

Serum levels of PSA are elevated to a lesser extent in BPH than prostate CA, although there is a considerable overlap with 4 ng/mL being the cutoff point btwn normal and abnormal.
144. What five refinements in the estimation and interpretation of PSA values have been proposed?
1. PSA is organ-specific, yet not cancer-specific (other events can elevate PSA levels, i.e. infarcts, prostatitis, BPH, etc...)
2. PSA density factors out the contribution of benign prostatic tissue to serum PSA levels. This results in PSA levels produced per gram of prostate tissue.
3. Age specific PSA upper reference ranges are based on correspondingly higher PSA levels in older men.
4. PSA velocity (Rate of change of PSA) reflects the finding that men w/prostate CA demonstrate an increased rate of rise in PSA.
5. Percentage of free PSA measures the fraction of serum PSA bound to antichymotrypsin and a minor free fraction. Percentage of free PSA is lower in men w/prostate CA than in men w/BPH.
145. What is ductal adenocarcinoma of the prostate?
Ductal adenocarcinomas arising in peripheral ducts may present in a fashion similar to that of ordinary prostate CA, whereas those arising in the larger periurethral ducts present w/signs and symptoms similar to urothelial CA (hematuria and urinary obstructive symptoms).

Ductal adenocarcinomas are associated w/a relatively poor prognosis, although early detection and treatment may be curative w/surgery or radiation.
146. Prostate CAs that reveal abundant mucinous secretions are termed...?
Colloid carcinoma of the prostate.
147. What is the most aggressive variant of prostate CA?
Small cell CA. In some cases, the small cell CA represents de-differentiation of recurrent acinar adenocarcinoma; in other cases, men present w/de novo small cell CA of the prostate.

Almost all such cases are rapidly fatal.
148. What is the most common tumors to secondarily involve the prostate?
The most common tumor to secondarily involve the prostate is urothelial cancer.

Two distinct patterns of involvement exist. Large, invasive urothelial CAs can directly invade from the bladder into the prostate. Alternatively, carcinoma in situ of the bladder can extend into the prostatic urethra and down into the prostatic ducts and acini.
149. What is the mechanism/time course/treatment for hyperacute rejection?
MOA: Preformed recipient antibodies react w/donor antigen and activate clomplement

Time course: Minutes to hours

How suppressed: Matching of donor and recipient blood types
150. What is the mechanism/time course/treatment for acute rejection?
MOA: Cellular- donor antigen activates recipient T cells; Humoral- recipient generates antibody response to donor antigen

Time course: weeks to months

How suppressed: Immunosuppression
151. What is the mechanism/time course/treatment for chronic rejection?
MOA: Unknown but thought to be caused by chronic inflammation resulting from R-cell responses to donor antigen

Time course: Months to years

How suppressed: Cannot be suppressed.
152. What are glucocorticoids?

How do they act?
Glucocorticoids have broad anti-inflammatory effects. They are steroid hormones that exert their physiologic actions by binding to the cytosolic glucocorticoid receptor. The glucocorticoid-glucocorticoid receptor complex translocates to the nucleus and bind to glucocorticoid response elements in the promoter region of specific genes, either up-regulating or down-regulating gene expression.
153. What are the important metabolic effects of glucocorticoids?
They down-regulate expression of inflammatory mediators, including key cytokines such as TNF-alpha, IL-1, and IL-4.
154. What are the drawbacks on long-term glucocorticoid use?
Diabetes, reduced resistance to infection, osteoporosis, cataracts, increased appetite leading to weight gain, hypertension and its sequelae, as well as the masking of inflammation must be closely monitored in pts receiving glucocorticoids.

*Abrupt cessation of glucocorticoid therapy can result in acute adrenal insufficiency b/c the hypothalamus and pituitary gland require a number of weeks to months to re-establish adequate ACTH production.
155. What are the names of the four glucocorticoids?
1. Prednisone
2. Prednisolone
3. Methylprednisolone
4. Dexamethasone
156. What are mycophenolic acid and mycophenolate mofetil?
Mycophenolic acid (MPA) is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), the rate limiting enzyme in the formation of guanosine.

B/c MPA has low oral bioavailability, it is usually administered in its prodrug form, mycophenolate mofetil (MFF), which has much higher oral bioavailability.
157. How does MPA and MMF work?
These drugs act primarily on lymphocytes. Inhibition of IMPDH by MPA reduces intracellular guanosine levels and elevates intracellular adenosine levels, with many downstream effects on lymphocyte activation and activity.

*Decreased guanosine levels lead to decreased expression of adhesion molecules involved in inflammation; also, it leads to a reduction in inducible NO synthase (iNOS), which leads to decreased NO production by neutrophils.
158. Mycophenolic acid and mycophenolate mofetil
MOA: Inhibitor of inosine monophosphate dehydrogenase (IMPDH), the rate limiting step in the formation of guanosine

PURPOSE: Solid organ transplantation, lupus nephritis, RA, pemphigus

ADVERSE: hypertension, peripheral edema, GI hemorrhage, leukopenia, myelosuppression, neutropenia, increased risk of infection, lymphoma, GI disturbance, headache

CONTRA: hypersensitivity to MPA or MMF, or to polysorbate 80 (IV formulation)

NOTES: Avoid concurrent administration of oral iron b/c it markedly reduces the bioavailability of MMF.
159. What is azathioprine (AZA)?
AZA was the first drug to be used for suppression of the immune system after transplantation. It is a prodrug of the purine analogue 6-MP, which is slowly released as AZA reacts nonenzymatically w/sulfhydryl compounds such as glutathione.

Although AZA does prolong organ graft survival, this drug is less efficacious than mycophenolate mofetil in improving the long-term survival of kidney allografts.

The slow release of 6-MP from AZA favors immunosuppression, while 6-MP itself is more useful as an antineoplastic drug.
160. What is methotrexate (MTX)?
MTX is a folate analogue used to treat malignancies and a wide variety of immune-mediated diseases, including RA and psoriasis. In addition, MTX is used for prevention of G vs. H disease.

The MOA by which MTX exerts its anti-inflammatory effect is uncertain, but does not appear to involve depletion of folate pools b/c the combo of MTX and folate is as effective as MTX alone in the treatment of RA.
161. How does MTX work as an anti-inflammatory and immunosuppressant?
MTX may act as an anti-inflammatory agent by increasing adenosine levels. Adenosine is a potent endogenous anti-inflammatory mediator that inhibits neutrophil adhesion, phagocytosis, and superoxide generation.

MTX has also been shown to cause apoptosis of activated CD4 and CD8 T cells, but not of resting cells.
162. What is leflunomide?
Leflunomide is an inhibitor of pyrimidine synthesis, specifically blocking the synthesis of UMP by inhibiting dihydroorotate dehydrogenase (DHOD). DHOD is a key enzyme in the synthesis of UMP, which is essential for the synthesis of all pyrimidines.

Lefunomide is approved for RA, but the drug has also shown significant efficacy in the treatment of other immune diseases.
163. Leflunomide
MOA: Inhibitor of pyrimidine synthesis by blocking DHOD.


ADVERSE: Hypertension, hepatotoxicity, interstitial lung disease, alopecia, diarrhea, rash

CONTRA: Pregnancy

NOTES: Leflunomide undergoes significant enterohepatic circulation, resulting in a prolonged pharmacologic effect. ***Cholestyramine may be administered to wash out leflunomide.
164. What is cyclophosphamide?
Cyclophosphamide is a highly toxic drug that alkylates DNA. B/c Cy has a major effect on B-cell proliferation but can enhance T-cell responses, the use of Cy in immune diseases is limited to disorders of humoral immunity, particularly SLE.

Adverse effects of Cy are severe and widespread, including leukopenia, cardiotoxicity, alopecia, and an increased risk of CA b/c of mutagenicity. The risk fo bladder CA is especially notable b/c Cy produces acrolein, which is concentrated in the urine.

Acrolein can be detoxed via administration of mesna.
165. What is cylcosporine (CsA)?
CsA is a specific inhibitor of T cell mediated immunity. CsA inhibits the production of IL-2 by activated T cells. CsA acts by binding to cyclophilin, and the CsA-cyclophilin complex binds to calcineurin in the NFAT pathway.

By inhibiting calcineurin-mediated NFAT dephosphorylation, CsA prevents translocation of NFAT to the nucleus and thereby suppresses IL-2 production.
166. Cyclosporine (CsA)
MOA: Binds to cyclophilin and the resulting complex inhibits the phosphatase activity of calcineurin, a cell-signaling protein that mediates T-cell activation.

PURPOSE: Keratoconjuctivitis sicca (topical cyclosporine)

ADVERSE: Nephrotoxicity, hypertension, neutrotoxicity, hepatotoxicity, infection, gingival hyperplasia, hyperlipidemia, hirsutism, GI disturbance

CONTRA: Active ocular infection

NOTES: Danazol and other androgens can increase serum CsA levels. Rifampin and St. John's wort reduce serum CsA levels.
167. What is tacrolimus?
AKA FK506, Tacrolimus is a more potent immunosupppresant drug than CsA; thought its structure differs from CsA, it acts by a similar MOA.

Tacrolimus is a macrocyclic triene that binds to FK-binding proteins, and the tacrolimus-FKBP complex inhibits calcineurin. Tacrolimus also inhibits IL-3, IL-4, IFN-y, and TNF-a production.
168. Tacrolimus
MOA: Binds to FK-binding protein and the tacrolimus-FKBP complex inhibits calcineurin.

PURPOSE: Organ transplantation, atopic dermatitis (topical)

ADVERSE: Nephrotoxicity, hypertension, prolonged QT interval, hyperglycemia, lymphoma infection, alopecia, GI disturbance , anemia, leukocytosis, thrombocytopenia, headache, insomnia, paresthesia, tremor, skin irritation.

CONTRA: Hypersensitivity to hydrogenated castor oil (IV formulation)

NOTES: Topical tacrolimus is used widely to treat atopic dermatitis and other eczematous dermatitis. St. Johns wort markedly reduces serum tacrolimus levels.
169. What is sirolimus?
Sirolimus, AKA rapamycin, is a macrocyclic triene that is used to prevent and treat organ rejection.

It also binds to FKBP, but the sirolimus-FKBP complex does not inhibit calcineurin; instead, it blocks the IL-2 receptor signaling required for T-cell proliferation.

Sirolimus-FKBP binds to and inhibits mTOR, a regulator of protein translation, and thus it arrests cell division in the G1 phase.
170. Sirolimus
MOA: Sirolimus binds to FKBP, and the resulting sirolimus-FKBP complex inhibits mTOR, a regulator of protein translation

PURPOSE: Organ transplantation, coronary artery disease (cardiac stents)

ADVERSE: Hypertension, peripheral edema, thromboembolic disorder, hyperlipidemia, hepatotoxcitiy, anemia, thrombocytopenia, arthralgia, asthenia, headache.

CONTRA: Hypersensitivity

NOTES: Sirolimus-eluting stents are also used in the treatment of coronary artery disease. Coadministration w/voriconazole markedly increases serum sirolimus level.
171. Etanercept
MOA: Etanercept is a soluble TNF receptor dimer that binds to both TNF-α and TNF-β.

PURPOSE: RA, juvenile RA, psoriasis, psoriatic arthritis, ankylosing spondylitis

ADVERSE: Myelosuppression, heart failure, optic neuritis, reactivation of tuberculosis, increased risk of infection, demyelinating disease of CNS, injection site reaction, URI, abdominal pain, vomiting.

CONTRA: Sepsis and heart failure

NOTES: *All patients should undergo screening for TB before therapy. Any patient developing an infection while taking a TNF inhibitor should undergo eval and aggressive antibiotic treatment.
172. Infliximab and adalimumab
MOA: Infliximab is a partially humanized mouse antibody against human TNF-α; adalimumab is a fully humanized IgG1 antibody against TNF-α.

PURPOSE: RA, Crohn's disease (infliximab), UC (infliximab), ankylosing spondylitis (infliximab), psoriatic arthritis (adalimumab)

ADVERSE: Same as etanercept

CONTRA: Sepsis and heart failure

NOTES: Certolizumab pegol, a pegylated TNF-α antibody, is currently is late stage clinical trials.
173. What is anakinra?
Anakinra is a recombinant form of IL-1ra, and is approved for use in RA. It has modest effects on pain and swelling but significantly reduces bony erosions, possibly b/c it decreases osteoclast production and blocks IL-1 induced metalloproteinase release fro synovial cells.
174. Anakinra
MOA: Recombinant IL-1 receptor antagonist


ADVERSE: Neutropenia, increased risk of infection

CONTRA: Hypersensitivity to anakinra or E. coli derived proteins

NOTES: Reduces bony erosions possibly by decreasing metalloproteinase release from synovial cells.
175. What is anti-thymocyte globulin (ATG)?
ATG is a preparation of antibodies induced by injecting rabbits w/human thymobytes. The rabbit antibodies are polyclonal and probably target many epitopes on human T cells.

B/c ATG targets essentially all T cells, ATG treatment results in broad immunosuppression that can predispose to infection.
176. Anti-thymocyte globulin (ATG)
MOA: Polyclonal antibodies against human T-cell epitopes

PURPOSE: Organ transplantation

ADVERSE: Cytokine release syndrome (fever, shivering, myalgia, headache), hypertension, anemia, leukopenia, thrombocytopenia, increased risk of infection.

CONTRA: Acute viral illness, history of allergy or anaphylaxis to rabbit proteins

NOTES: ATG treatment can result in a broad immunosuppression that can lead to infection.
177. What is OKT3?
OKT3 is a mouse monoclonal antibody against human CD3, one of the cell-surface signaling molecules important for activation of T-cell receptor.

Treatment with OKT3 depletes the available pool of T cells via antibody-mediated activation of complement and clearance of immune complexes.
178. OKT3
MOA: Mouse monoclonal antibody against human CD3, a signaling molecule important for T cell receptor mediated cell activation

PURPOSE: Organ transplantation

ADVERSE: Cytokine release syndrome (fever, shivering, myalgia, headache), hypertension, anemia, leukopenia, thrombocytopenia, increased risk of infection.

CONTRA: Anti-mouse antibody titers greater than 1:1000; heart failure, seizures, pregnancy or breastfeeding, uncontrolled hypertension.
179. What is rituximab (anti-CD20 mAb)
Rituximab is a partially humanized anti-CD20 antibody. CD20 is expressed on the surface of all mature B cells, and administration of rituximab causes profound depletion of circulating B cells.

Originally approved for the treatment of CD20+ non-Hodgkin's lymphoma, rituximab has also been approved for use in RA refractory to TNF-a inhibitors.
180. Daclizumab and basiliximab
MOA: Antibodies to CD25, the high-affinity IL-2 receptor

PURPOSE: Organ transplantation

ADVERSE: Cytokine release syndrome (fever, shivering, myalgia, headache), hypertension, anemia, leukopenia, thrombocytopenia, increased risk of infection.

CONTRA: Hypersensitivity
181. Alemtuzumab
MOA: Antibody to Campath-1 (CD52), an antigen expressed on most mature lymphocytes and some lymphocyte precursors

PURPOSE: B-cell chronic lymphocytic leukemia

ADVERSE: Cytokine release syndrome (fever, shivering, myalgia, headache), hypertension, anemia, leukopenia, thrombocytopenia, increased risk of infection.

CONTRA: Active systemic infection, underlying immunodeficiency.
182. Alefacept
MOA: LFA-3Fc fusion protein that interrupts CD2/LFA-3 signaling by binding to T-cell CD2, leading to inhibition of T-cell activation.

PURPOSE: Psoriasis

ADVERSE: Cytokine release syndrome (fever, shivering, myalgia, headache), hypertension, anemia, leukopenia, thrombocytopenia, increased risk of infection.

CONTRA: HIV infection, low CD4 T-cell count

NOTES: Pts taking alefacept may have an increased risk of serious infection and malignancy, primarily skin CA.
183. Abatacept
MOA: CTLA-4 analogues fused to an IgG1 constant region; by forming a complex w/cell-surface B7 molecules, the drug prevents delivery of a costimulatory signal and the T cell develops anergy or undergoes apoptosis.

PURPOSE: RA refractory to MTX or TNF-a inhibitors

ADVERSE: Exacerbation of COPD, increased susceptibility to infection, nausea, headache, UTI

CONTRA: Hypersensitivty

NOTES: Abatacept should not be administered concurrently w/TNF-a inhibitors or anakinra due to increased risk of infection.
184. What is belatacept?
Belatacept is a close structural congener of abatacept that has increased affinity for B7-1 and B7-2.

In a large clinical trial, belatacept was as effective as cyclosporine at inhibiting acute rejection in renal transplant recipients.
185. Efalizumab
MOA: Monoclonal antibody against LFA-1 that inhibits the LFA-1/ICAM-1 interaction and thereby limits T-cell adhesion, activation, and migration to sites of inflammation.

PURPOSE: Chronic plaque psoriasis

ADVERSE: Increased risk of serious infection, immune-mediated thrombocytopenia, immune-mediated hemolytic anemia, inluenza-like symptoms, acne, lymphocytosis, elevated ALKPHOS, antibody formation to efalizumab

CONTRA: Hypersensitivity

NOTES: Symptoms of psoriasis return promptly after discontinuation
186. Natalizumab
MOA: Monoclonal antibody against α4 integrin that inhibits immune cell interaction w/cells expressing VCAM-1 and MAdCAM-1

PURPOSE: Multiple sclerosis

ADVERSE: Cholelithiasis, progressive multifocal leukoencephalopathy, depression, pneumonia, rash, arthralgia, headache, fatigue, UTI, lower respiratory tract infection

CONTRA: History of progressive multifocal leukoencephalopathy (PML) or existing PML

NOTES: PML is a rare demyelinating disorder caused by infection w/JC virus.
187. Eculizumab
Eculizumab is a humanized monoclonal antibody against C5, a complement protein that mediates late steps in complement activation and triggers assembly of the MAC.

In clinical trials, eculizumab is used to treat paroxysmal nocturnal hemoglobinuria.