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2H. Pathology > Renal > Flashcards

Flashcards in Renal Deck (146):
1

The study of kidney diseases is facilitated by dividing them into those that affect the four basic
morphologic components: 

  1. glomeruli
  2. tubules,
  3. interstitium,
  4. and blood vessels

2

most glomerular diseases are _________________

immunologically
mediated 

3

whereas tubular and interstitial disorders are frequently caused by ______________

toxic or
infectious agents.

4

Disease primarily in the blood vessels, for
example, inevitably affects all the structures that depend on this blood supply.

Severe
glomerular damage impairs the flow through the peritubular vascular system and also delivers
potentially toxic products to tubules; conversely, tubular destruction, by increasing
intraglomerular pressure, may induce glomerular injury. Thus, whatever the origin, there is a
tendency for all forms of chronic kidney disease ultimately to destroy all four components of the
kidney,
culminating in chronic renal failure and what has been called____________

 end-stage kidneys

5

The
functional reserve of the kidney is large, and much damage may occur before there is evident
functional impairment. For these reasons the early signs and symptoms are particularly
important clinically.

:)

6

____________ is a biochemical abnormality that refers to an elevation of the blood urea nitrogen
(BUN) and creatinine levels, and is related largely to a decreased glomerular filtration rate
(GFR). Azotemia is a consequence of many renal disorders, but it also arises from extrarenal
disorders.

Azotemia

7

____________- is encountered when there is hypoperfusion of the kidneys (e.g.,
in hemorrhage, shock, volume depletion, and congestive heart failure) that impairs renal function in the absence of parenchymal damage.

Prerenal azotemia

8

_____________- is seen whenever urine
flow is obstructed beyond the level of the kidney. Relief of the obstruction is followed by
correction of the azotemia.

Postrenal azotemia

9

When azotemia becomes associated with a constellation of clinical signs and symptoms and
biochemical abnormalities, it is termed___________ This is characterized not only by failure of
renal excretory function
but also by a host of metabolic and endocrine alterations resulting from
renal damage
.

These patients frequently manifest secondary involvement of the
gastrointestinal system (e.g., uremic gastroenteritis), peripheral nerves (e.g., peripheral
neuropathy), and heart (e.g., uremic fibrinous pericarditis).

 uremia.

10

___________________ is due to glomerular disease and is dominated by the acute onset of
usually grossly visible hematuria
(red blood cells in urine), mild to moderate proteinuria,
and hypertension; it is the classic presentation of acute poststreptococcal
glomerulonephritis.

Nephritic syndrome

11

_________________ is characterized as a nephritic syndrome with
rapid decline (hours to days) in GFR.

Rapidly progressive glomerulonephritis

12

The _____________also due to glomerular disease, is characterized by heavy
proteinuria
(more than 3.5 gm/day), hypoalbuminemia, severe edema, hyperlipidemia,
and lipiduria
(lipid in the urine).

nephrotic syndrome, 

13

______________, or a combination of these two, is usually a
manifestation of subtle or mild glomerular abnormalities.

Asymptomatic hematuria or proteinuria

14

_______________ is dominated by oliguria or anuria (reduced or no urine flow), and
recent onset of azotemia
. It can result from glomerular, interstitial, or vascular injury or
acute tubular injury.

Acute renal failure

15

_____________, characterized by prolonged symptoms and signs of uremia, is the
end result of all chronic renal parenchymal diseases.

Chronic renal failure

16

_______________are dominated by polyuria (excessive urine formation), nocturia,
and electrolyte disorders (e.g., metabolic acidosis). They are the result of diseases that
either directly affect tubular structure
(e.g., medullary cystic disease) or cause defects in
specific tubular functions.

 

The latter can be inherited (e.g., familial nephrogenic
diabetes, cystinuria, renal tubular acidosis) or acquired (e.g., lead nephropathy).

Renal tubular defects 

17

____________ is characterized by bacteriuria and pyuria (bacteria and
leukocytes in the urine). The infection may be symptomatic or asymptomatic, and it may
affect the kidney (pyelonephritis) or the bladder (cystitis).

Urinary tract infection

18

_________- is manifested by severe spasms of pain (renal colic) and
hematuria, often with recurrent stone formation.

Nephrolithiasis (renal stones)

19

Urinary tract obstruction and renal tumors have varied clinical manifestations based on
the specific anatomic location and nature of the lesion.

Urinary tract obstruction 

20

renal failure broadly progresses through a series of four stages that merge into one another.
1. In ____________ the GFR is about 50% of normal. Serum BUN and
creatinine values are normal
, and the patients are asymptomatic. However, they are
more susceptible to developing azotemia with an additional renal insult.
2. In ______________ the GFR is 20% to 50% of normal. Azotemia appears, usually associated with anemia and hypertension. Polyuria and nocturia can occur as a result
of decreased concentrating ability. Sudden stress (e.g., with nephrotoxins) may
precipitate uremia.
3. In ________ the GFR is less than 20% to 25% of normal. The kidneys cannot
regulate volume and solute composition
, and patients develop edema, metabolic
acidosis, and hyperkalemia
. Overt uremia may ensue, with neurologic, gastrointestinal,
and cardiovascular complications.

4. In end-stage renal disease the GFR is less than 5% of normal; this is the terminal stage
of uremia.
Recent clinical classifications of chronic kidney disease, adopted in part to
better stratify patients in clinical trials, adhere to this schema of progressive injury but
divide patients into five classes based on levels of GFR.

diminished renal reserve

 renal insufficiency 

chronic renal failure 

end-stage renal disease 

21

Principal Systemic Manifestations of Chronic Kidney Disease and Uremia

 

FLUID AND ELECTROLYTES
______________

Dehydration
Edema
Hyperkalemia
Metabolic
acidosis

22

Principal Systemic Manifestations of Chronic Kidney Disease and Uremia

 

CALCIUM PHOSPHATE AND BONE
_________________________________________

Hyperphosphatemia
Hypocalcemia
Secondary
hyperparathyroidism
Renal osteodystrophy

23

Principal Systemic Manifestations of Chronic Kidney Disease and Uremia

 

HEMATOLOGIC
__________

Anemia
Bleeding
diathesis (unusual susceptibility to bleeding (hemorrhage) mostly due to hypocoagulability, in turn caused by acoagulopathy (a defect in the system of coagulation)

24

Principal Systemic Manifestations of Chronic Kidney Disease and Uremia

CARDIOPULMONARY
_____________

Hypertension
Congestive heart
failure
Cardiomyopathy
Pulmonary edema
Uremic pericarditis

25

Principal Systemic Manifestations of Chronic Kidney Disease and Uremia

 

GASTROINTESTINAL
Nausea and vomiting
Bleeding
Esophagitis, gastritis,
colitis

Nausea and vomiting
Bleeding
Esophagitis, gastritis,
colitis

26

Clinical Manifestations of Renal Diseases

Myopathy
Peripheral
neuropathy
Encephalopathy

27

Clinical Manifestations of Renal Diseases

 

DERMATOLOGIC
Sallow color
Pruritus
Dermatitis

Sallow color
Pruritus
Dermatitis

28

_______________ is one of the most common causes of chronic kidney disease in humans.
Glomeruli may be injured by a variety of factors and in the course of several systemic diseases

chronic
glomerulonephritis

29

Systemic immunological diseases such as systemic lupus erythematosus (SLE), vascular
disorders
such as hypertension, metabolic diseases such as diabetes mellitus, and some
hereditary conditions such as Fabry disease often affect the __________. These are termed
secondary glomerular diseases .

glomerulus.

30

only or predominant organ involved. The latter constitute the various types of____________ or, because some do not have a cellular inflammatory component,
glomerulopathy
. However, both the clinical manifestations and glomerular histologic changes in
primary and secondary forms can be similar.

 primary
glomerulonephritis

31

PRIMARY GLOMERULOPATHIES
 

Acute proliferative glomerulonephritis
Post-infectious
Other
Rapidly progressive (crescentic)
glomerulonephritis
Membranous glomerulopathy
Minimal-change disease
Focal segmental glomerulosclerosis
Membranoproliferative glomerulonephritis
IgA nephropathy
Chronic glomerulonephritis

32

SYSTEMIC DISEASES WITH GLOMERULAR INVOLVEMENT
______________

Systemic lupus erythematosus
Diabetes mellitus
Amyloidosis
Goodpasture syndrome
Microscopic
polyarteritis/polyangiitis
Wegener granulomatosis
Henoch-Schönlein purpura
Bacterial endocarditis

33

HEREDITARY DISORDERS GLOMERULUS
 

Alport syndrome
Thin basement membrane
disease
Fabry disease

34

The clinical manifestations of glomerular disease are clustered into the five major glomerular syndromes summarized in Table 20-3 .

Both the primary glomerulopathies and the systemic
disease
s affecting the glomerulus can result in these syndromes. Because glomerular diseases
are often associated with systemic disorders, mainly diabetes mellitus, SLE, vasculitis, and
amyloidosis,
in any patient with manifestations of glomerular disease it is essential to consider
these systemic conditions.

Nephritic syndrome

Rapidly progressive glomerulonephritis

Nephrotic syndrome

Chronic Renal Failure

Isolated urinary abnormalities

 

35

____________ Hematuria,

azotemia,

variable proteinuria,

oliguria,

edema, and

hypertension
 

Nephritic syndrome

36

_____________
Acute nephritis, proteinuria, and acute renal failure
 

Rapidly progressive
glomerulonephritis

37

______________>3.5 gm/day proteinuria, hypoalbuminemia, hyperlipidemia,
lipiduria
 

Nephrotic syndrome 

38

______________➙ uremia progressing for months to years
 

Chronic renal failure Azotemia 

39

________________ Glomerular hematuria and/or subnephrotic proteinuria

Isolated urinary abnormalities

40

Many clinical manifestations of glomerular disease result from perturbations of specific
components of the glomerular tuft,
so we present key anatomic structures that are subject to
alteration in disease. The ________consists of an anastomosing network of capillaries lined
by fenestrated endothelium invested by two layers of epithelium ( Fig. 20-1 ). 

 glomerulus 

41

The glomerulus consists of an anastomosing network of capillaries lined
by fenestrated endothelium invested by two layers of epithelium ( Fig. 20-1 ).

The__________- is incorporated into and becomes an intrinsic part of the capillary wall, separated
from endothelial cells by a basement membrane. The __________, situated on the
Bowman capsule, lines the urinary space, the cavity in which plasma filtrate first collects.

 visceral epithelium

 parietal epithelium

42

The glomerular capillary wall is the filtering membrane and consists of the following
structures:

 

 

endothelial cells

glomerular basement membrane (GBM)

visceral epithelial cells (podocytes)

mesangial cells

43

A _______________ with a thick electron-dense central layer, the
lamina densa, and thinner electron-lucent peripheral layers, the lamina rara interna and
lamina rara externa. The GBM consists of collagen (mostly type IV), laminin, polyanionic
proteoglycans (mostly heparan sulfate), fibronectin, entactin, and several other
glycoproteins.

Type IV collagen forms a network suprastructure to which other
glycoproteins attach. The building block (monomer) of this network is a triple-helical
molecule made up of three α chains, composed of one or more of six types of α chains (
α1 to α6 or COL4A1 to COL4A6), the most common consisting of α1, α2, α1. [3,] [5]
Each molecule consists of a 7S domain at the N terminus, a triple-helical domain in the
middle, and a globular noncollagenous domain (NC1) at the C terminus. The NC1
domain is important for helix formation and for assembly of collagen monomers into the
basement membrane suprastructure. Glycoproteins (laminin, entactin) and proteoglycans (heparan sulfate, perlecan) attach to the collagenous suprastructure.
These biochemical determinants are critical to understanding glomerular diseases. For
example, as we shall see, the antigens in the NC1 domain are the targets of antibodies
in anti-GBM nephritis; genetic defects in the α-chains underlie some forms of hereditary
nephritis; and the proteoglycan content of the GBM may contribute to its permeability
characteristics.

glomerular basement membrane (GBM)

44

The_____________ are structurally complex cells that possess
interdigitating processes embedded in and adherent to the lamina rara externa of the
basement membrane. Adjacent foot processes (pedicels) are separated by 20- to 30-
nm-wide filtration slits, which are bridged by a thin diaphragm (see Fig. 20-2 ).

 visceral epithelial cells (podocytes)

45

The entire glomerular tuft is supported by ____________lying between the capillaries.
Basement membrane–like mesangial matrix forms a meshwork through which the
mesangial cells are centered (see Fig. 20-1 ). These cells, of mesenchymal origin, are
contractile, phagocytic, and capable of proliferation, of laying down both matrix and
collagen, and of secreting several biologically active mediators. Biologically, they are
most akin to vascular smooth muscle cells and pericytes. They are, as we shall see,
important players in many forms of human glomerulonephritis.

mesangial cells 

46

The major characteristics of normal glomerular filtration are an _________________-, because of the highly fenestrated nature of the endothelium, and
impermeability to proteins, such as molecules of the size of albumin (∼3.6-nm radius; 70
kilodaltons [kD] molecular weight) or larger.

extraordinarily high permeability
to water and small solutes

47

The latter property of the glomerular filtration
barrier allows discrimination among various protein molecules, depending on their ____________and ________________. This size- and
charge-dependent barrier function is accounted for by the complex structure of the capillary
wall
, the collagenous porous and charged structure of the GBM, and the many anionic moieties
present within the wall, including the acidic proteoglycans of the GBM and the
sialoglycoproteins of epithelial and endothelial cell coats (also called glycocalyx).

size (the
larger, the less permeable) 

charge (the more cationic, the more permeable)

48

The chargedependent
restriction is important in the __________________
because albumin is an anionic molecule of a pI 4.5.

virtually complete exclusion of albumin from the filtrate,

49

The_______________, also known as a
podocyte, is important for the maintenance of glomerular barrier function; its slit diaphragm
presents a size-selective distal diffusion barrier
to the filtration of proteins, and it is the cell type
that is largely responsible for synthesis of GBM components.

 visceral epithelial cell

50

Proteins located in the slit
diaphragm control glomerular permeability. Three of the most important slit diaphragm proteins
are depicted in Figure 20-3 .___________ is a transmembrane protein with a large extracellular
portion made up of immunoglobulin (Ig)-like domains. This molecules extend toward each
other from neighboring foot processes and dimerize across the slit diaphragm. Within the
cytoplasm of the foot processes, _________ forms molecular connections with podocin, CD2-
associated protein, and ultimately the actin cytoskeleton. The number of identified slit
diaphragm proteins continues to grow rapidly, and more comprehensive descriptions of their
complex localization and interactions have been published. [6,] [7] The importance of these
proteins in maintaining glomerular permeability is demonstrated by the observation that
mutations in the genes encoding them give rise to nephrotic syndrome (discussed later). This
has resulted in renewed appreciation of the importance of the slit diaphragm in glomerular
barrier function and its contribution to protein leakage in disease states. [

  1.  Nephrin
  2. podocin
  3. actin cytoskeleton

51

HISTOLOGIC ALTERATIONS
Various types of glomerulopathies are characterized by one or more of four basic tissue
reactions.

Hypercellularity.

Basement Membrane Thickening.

Hyalinosis and Sclerosis.

52

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
combinations of the following:
 

 

Hypercellularity

• Cellular proliferation of mesangial or endothelial cells.
• Leukocytic infiltration consisting of neutrophils, monocytes, and, in some diseases,
lymphocytes.

Formation of crescents. These are accumulations of cells composed of proliferating
parietal epithelial cells and infiltrating leukocytes.
The epithelial cell proliferation that
characterizes crescent formation occurs following an immune/inflammatory injury (see
later).

Fibrin, which leaks into the urinary space, often through 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. Mice that are
deficient in fibrinogen are protected to a degree from crescent formation, and mice that
are deficient in molecules important in fibrinolysis (e.g., plasminogen activators) exhibit
enhanced crescent formation in models of anti-GBM antibody–mediated crescentic
glomerulonephritis. [9] Other molecules that have been implicated in crescent formation
and recruitment of leukocytes into crescents include procoagulants such as tissue factor
and cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and interferon-γ.

53

In hypercellularity what type of cells proliferate?

Cellular proliferation of mesangial or endothelial cells.

54

 These are accumulations of cells composed of proliferating
parietal epithelial cells
and infiltrating leukocytes. The epithelial cell proliferation that
characterizes crescent formation occurs following an immune/inflammatory injury (see
later).

Formation of crescents.

55

_________, which leaks into the urinary space, often through 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.

Fibrin

 

Note : Mice that are
deficient in fibrinogen are protected to a degree from crescent formation, and mice that
are deficient in molecules important in fibrinolysis (e.g., plasminogen activators) exhibit
enhanced crescent formation in models of anti-GBM antibody–mediated crescentic
glomerulonephritis.
[9] 

56

Other molecules that have been implicated in _____
and recruitment of leukocytes into crescents include __________

crescent formation 

procoagulants such as tissue factor

and cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and interferon-γ.

57

_____________
By light microscopy, this change appears as thickening of the capillary walls, best seen in
sections stained with periodic acid–Schiff (PAS).

Basement Membrane Thickening.

58

 By electron microscopy such thickening takes
one of two forms:
____________________________

Deposition of amorphous electron-dense material, most often immune complexes, on
the endothelial or epithelial side of the basement membrane or within the GBM itself.
Fibrin, amyloid, cryoglobulins, and abnormal fibrillary proteins may also deposit in the
GBM.
• Thickening of the basement membrane due to increased synthesis of its protein
components, as occurs in diabetic glomerulosclerosis.

59

___________, as applied to the glomerulus, denotes the accumulation of material that is
homogeneous and eosinophilic by light microscopy

Hyalinosis

60

By electron microscopy the ____________- is
extracellular and amorphous. It is made up of plasma proteins that have insudated from the
circulation into glomerular structures. When extensive, this change contributes to obliteration of
the capillary lumens of the glomerular tuft

hyalin

61

____________- is usually a consequence of endothelial or
capillary wall injury
and typically the end result of various forms of glomerular damage. It is a
common feature of focal segmental glomerulosclerosis.

Hyalinosis

62

Hyalinosis is usually a consequence of endothelial or
capillary wall injury
and typically the end result of various forms of glomerular damage. It is a
common feature of _____________________

focal segmental glomerulosclerosis.

63

_____________- is characterized by accumulations of extracellular collagenous matrix, either confined
to mesangial areas
as is often the case in diabetic glomerulosclerosis, or involving the capillary
loops, or both. The sclerosing process may also result in obliteration of some or all of the
capillary lumens
in affected glomeruli, which in turn can result in formation of fibrous adhesions
between the sclerotic portions of glomeruli and the nearby parietal epithelium and Bowman
capsules.

Sclerosis

64

Because many of the primary glomerulopathies are of unknown cause, they are often classified
by their histology, as can be seen in Table 20-2 . The histologic changes can be further
subdivided by their distribution into :

diffuse

global

focal

segmental

65

 _____________, involving all glomeruli;

diffuse 

66

__________, involving the entire
glomerulus; 

 global

67

__________, involving only a proportion of the glomeruli; 

focal

68

___________, affecting a part of
each glomerulus; and by either capillary loop or mesangial, affecting predominantly capillary or
mesangial regions. These terms are sometimes appended to the histologic classifications.

segmental

 

Note: < or > 50 %

69

Immune Mechanisms of Glomerular Injury
 

  1. ANTIBODY-MEDIATED INJURY IN SITU IMMUNE COMPLEX DEPOSITION
  2. CIRCULATING IMMUNE COMPLEX DEPOSITION
  3. CYTOTOXIC ANTIBODIES
  4. CELL-MEDIATED IMMUNE INJURY
  5. ACTIVATION OF ALTERNATIVE COMPLEMENT PATHWAY

70

WHAT ARE THE ANTIBODY-MEDIATED INJURY
IN SITU IMMUNE COMPLEX DEPOSITION? 
 

  1. Fixed intrinsic tissue antigens
  • NC1 domain of collagen type IV antigen (anti-GBM

nephritis)

  • Heymann antigen (membranous glomerulopathy)
  • Mesangial antigens
  • Others

2. Planted antigens

  • Exogenous (infectious agents, drugs)
  • Endogenous (DNA, nuclear proteins, immunoglobulins, immune

complexes, IgA)


 

71

CIRCULATING IMMUNE COMPLEX DEPOSITION

 

  1. Endogenous antigens (e.g., DNA, tumor

antigens)

2.    Exogenous antigens (e.g., infectious products)

72

Two forms of antibody-associated injury have been established: 

(1) injury by antibodies
reacting in situ within the glomerulus, either binding to insoluble fixed (intrinsic) glomerular
antigens or to molecules planted within the glomerulus, and (2) injury resulting from deposition
of circulating antigen-antibody complexes in the glomerulus. In addition, there is experimental
evidence that cytotoxic antibodies directed against glomerular cell components may cause
glomerular injury. These pathways are not mutually exclusive, and in humans, all may contribute
to injury.

73

_________-
In these forms of injury, antibodies react directly with intrinsic tissue antigen, or antigens
“planted” in the glomerulus from the circulation. The best established experimental models for
anti–glomerular antibody–mediated glomerular injury, for which there are counterparts in human
disease, are anti–glomerular basement membrane (antiGBM) antibody–induced
glomerulonephritis and Heymann nephritis.

Immune Complex Deposition Involving Intrinsic and in Situ Renal Antigens

74

The study of kidney diseases is facilitated by dividing them into those that affect the four basic
morphologic components: 

  1. glomeruli
  2. tubules,
  3. interstitium,
  4. and blood vessels

75

most glomerular diseases are _________________

immunologically
mediated 

76

whereas tubular and interstitial disorders are frequently caused by ______________

toxic or
infectious agents.

77

Disease primarily in the blood vessels, for
example, inevitably affects all the structures that depend on this blood supply.

Severe
glomerular damage impairs the flow through the peritubular vascular system and also delivers
potentially toxic products to tubules; conversely, tubular destruction, by increasing
intraglomerular pressure, may induce glomerular injury. Thus, whatever the origin, there is a
tendency for all forms of chronic kidney disease ultimately to destroy all four components of the
kidney,
culminating in chronic renal failure and what has been called____________

 end-stage kidneys

78

The
functional reserve of the kidney is large, and much damage may occur before there is evident
functional impairment. For these reasons the early signs and symptoms are particularly
important clinically.

:)

79

____________ is a biochemical abnormality that refers to an elevation of the blood urea nitrogen
(BUN) and creatinine levels, and is related largely to a decreased glomerular filtration rate
(GFR). Azotemia is a consequence of many renal disorders, but it also arises from extrarenal
disorders.

Azotemia

80

____________- is encountered when there is hypoperfusion of the kidneys (e.g.,
in hemorrhage, shock, volume depletion, and congestive heart failure) that impairs renal function in the absence of parenchymal damage.

Prerenal azotemia

81

_____________- is seen whenever urine
flow is obstructed beyond the level of the kidney. Relief of the obstruction is followed by
correction of the azotemia.

Postrenal azotemia

82

When azotemia becomes associated with a constellation of clinical signs and symptoms and
biochemical abnormalities, it is termed___________ This is characterized not only by failure of
renal excretory function
but also by a host of metabolic and endocrine alterations resulting from
renal damage
.

These patients frequently manifest secondary involvement of the
gastrointestinal system (e.g., uremic gastroenteritis), peripheral nerves (e.g., peripheral
neuropathy), and heart (e.g., uremic fibrinous pericarditis).

 uremia.

83

___________________ is due to glomerular disease and is dominated by the acute onset of
usually grossly visible hematuria
(red blood cells in urine), mild to moderate proteinuria,
and hypertension; it is the classic presentation of acute poststreptococcal
glomerulonephritis.

Nephritic syndrome

84

_________________ is characterized as a nephritic syndrome with
rapid decline (hours to days) in GFR.

Rapidly progressive glomerulonephritis

85

The _____________also due to glomerular disease, is characterized by heavy
proteinuria
(more than 3.5 gm/day), hypoalbuminemia, severe edema, hyperlipidemia,
and lipiduria
(lipid in the urine).

nephrotic syndrome, 

86

______________, or a combination of these two, is usually a
manifestation of subtle or mild glomerular abnormalities.

Asymptomatic hematuria or proteinuria

87

_______________ is dominated by oliguria or anuria (reduced or no urine flow), and
recent onset of azotemia
. It can result from glomerular, interstitial, or vascular injury or
acute tubular injury.

Acute renal failure

88

_____________, characterized by prolonged symptoms and signs of uremia, is the
end result of all chronic renal parenchymal diseases.

Chronic renal failure

89

_______________are dominated by polyuria (excessive urine formation), nocturia,
and electrolyte disorders (e.g., metabolic acidosis). They are the result of diseases that
either directly affect tubular structure
(e.g., medullary cystic disease) or cause defects in
specific tubular functions.

 

The latter can be inherited (e.g., familial nephrogenic
diabetes, cystinuria, renal tubular acidosis) or acquired (e.g., lead nephropathy).

Renal tubular defects 

90

____________ is characterized by bacteriuria and pyuria (bacteria and
leukocytes in the urine). The infection may be symptomatic or asymptomatic, and it may
affect the kidney (pyelonephritis) or the bladder (cystitis).

Urinary tract infection

91

_________- is manifested by severe spasms of pain (renal colic) and
hematuria, often with recurrent stone formation.

Nephrolithiasis (renal stones)

92

Urinary tract obstruction and renal tumors have varied clinical manifestations based on
the specific anatomic location and nature of the lesion.

Urinary tract obstruction 

93

renal failure broadly progresses through a series of four stages that merge into one another.
1. In ____________ the GFR is about 50% of normal. Serum BUN and
creatinine values are normal
, and the patients are asymptomatic. However, they are
more susceptible to developing azotemia with an additional renal insult.
2. In ______________ the GFR is 20% to 50% of normal. Azotemia appears, usually associated with anemia and hypertension. Polyuria and nocturia can occur as a result
of decreased concentrating ability. Sudden stress (e.g., with nephrotoxins) may
precipitate uremia.
3. In ________ the GFR is less than 20% to 25% of normal. The kidneys cannot
regulate volume and solute composition
, and patients develop edema, metabolic
acidosis, and hyperkalemia
. Overt uremia may ensue, with neurologic, gastrointestinal,
and cardiovascular complications.

4. In end-stage renal disease the GFR is less than 5% of normal; this is the terminal stage
of uremia.
Recent clinical classifications of chronic kidney disease, adopted in part to
better stratify patients in clinical trials, adhere to this schema of progressive injury but
divide patients into five classes based on levels of GFR.

diminished renal reserve

 renal insufficiency 

chronic renal failure 

end-stage renal disease 

94

Principal Systemic Manifestations of Chronic Kidney Disease and Uremia

 

FLUID AND ELECTROLYTES
______________

Dehydration
Edema
Hyperkalemia
Metabolic
acidosis

95

Principal Systemic Manifestations of Chronic Kidney Disease and Uremia

 

CALCIUM PHOSPHATE AND BONE
_________________________________________

Hyperphosphatemia
Hypocalcemia
Secondary
hyperparathyroidism
Renal osteodystrophy

96

Principal Systemic Manifestations of Chronic Kidney Disease and Uremia

 

HEMATOLOGIC
__________

Anemia
Bleeding
diathesis (unusual susceptibility to bleeding (hemorrhage) mostly due to hypocoagulability, in turn caused by acoagulopathy (a defect in the system of coagulation)

97

Principal Systemic Manifestations of Chronic Kidney Disease and Uremia

CARDIOPULMONARY
_____________

Hypertension
Congestive heart
failure
Cardiomyopathy
Pulmonary edema
Uremic pericarditis

98

Principal Systemic Manifestations of Chronic Kidney Disease and Uremia

 

GASTROINTESTINAL
Nausea and vomiting
Bleeding
Esophagitis, gastritis,
colitis

Nausea and vomiting
Bleeding
Esophagitis, gastritis,
colitis

99

Clinical Manifestations of Renal Diseases

Myopathy
Peripheral
neuropathy
Encephalopathy

100

Clinical Manifestations of Renal Diseases

 

DERMATOLOGIC
Sallow color
Pruritus
Dermatitis

Sallow color
Pruritus
Dermatitis

101

_______________ is one of the most common causes of chronic kidney disease in humans.
Glomeruli may be injured by a variety of factors and in the course of several systemic diseases

chronic
glomerulonephritis

102

Systemic immunological diseases such as systemic lupus erythematosus (SLE), vascular
disorders
such as hypertension, metabolic diseases such as diabetes mellitus, and some
hereditary conditions such as Fabry disease often affect the __________. These are termed
secondary glomerular diseases .

glomerulus.

103

only or predominant organ involved. The latter constitute the various types of____________ or, because some do not have a cellular inflammatory component,
glomerulopathy
. However, both the clinical manifestations and glomerular histologic changes in
primary and secondary forms can be similar.

 primary
glomerulonephritis

104

PRIMARY GLOMERULOPATHIES
 

Acute proliferative glomerulonephritis
Post-infectious
Other
Rapidly progressive (crescentic)
glomerulonephritis
Membranous glomerulopathy
Minimal-change disease
Focal segmental glomerulosclerosis
Membranoproliferative glomerulonephritis
IgA nephropathy
Chronic glomerulonephritis

105

SYSTEMIC DISEASES WITH GLOMERULAR INVOLVEMENT
______________

Systemic lupus erythematosus
Diabetes mellitus
Amyloidosis
Goodpasture syndrome
Microscopic
polyarteritis/polyangiitis
Wegener granulomatosis
Henoch-Schönlein purpura
Bacterial endocarditis

106

HEREDITARY DISORDERS GLOMERULUS
 

Alport syndrome
Thin basement membrane
disease
Fabry disease

107

The clinical manifestations of glomerular disease are clustered into the five major glomerular syndromes summarized in Table 20-3 .

Both the primary glomerulopathies and the systemic
disease
s affecting the glomerulus can result in these syndromes. Because glomerular diseases
are often associated with systemic disorders, mainly diabetes mellitus, SLE, vasculitis, and
amyloidosis,
in any patient with manifestations of glomerular disease it is essential to consider
these systemic conditions.

Nephritic syndrome

Rapidly progressive glomerulonephritis

Nephrotic syndrome

Chronic Renal Failure

Isolated urinary abnormalities

 

108

____________ Hematuria,

azotemia,

variable proteinuria,

oliguria,

edema, and

hypertension
 

Nephritic syndrome

109

_____________
Acute nephritis, proteinuria, and acute renal failure
 

Rapidly progressive
glomerulonephritis

110

______________>3.5 gm/day proteinuria, hypoalbuminemia, hyperlipidemia,
lipiduria
 

Nephrotic syndrome 

111

______________➙ uremia progressing for months to years
 

Chronic renal failure Azotemia 

112

________________ Glomerular hematuria and/or subnephrotic proteinuria

Isolated urinary abnormalities

113

Many clinical manifestations of glomerular disease result from perturbations of specific
components of the glomerular tuft,
so we present key anatomic structures that are subject to
alteration in disease. The ________consists of an anastomosing network of capillaries lined
by fenestrated endothelium invested by two layers of epithelium ( Fig. 20-1 ). 

 glomerulus 

114

The glomerulus consists of an anastomosing network of capillaries lined
by fenestrated endothelium invested by two layers of epithelium ( Fig. 20-1 ).

The__________- is incorporated into and becomes an intrinsic part of the capillary wall, separated
from endothelial cells by a basement membrane. The __________, situated on the
Bowman capsule, lines the urinary space, the cavity in which plasma filtrate first collects.

 visceral epithelium

 parietal epithelium

115

The glomerular capillary wall is the filtering membrane and consists of the following
structures:

 

 

endothelial cells

glomerular basement membrane (GBM)

visceral epithelial cells (podocytes)

mesangial cells

116

A _______________ with a thick electron-dense central layer, the
lamina densa, and thinner electron-lucent peripheral layers, the lamina rara interna and
lamina rara externa. The GBM consists of collagen (mostly type IV), laminin, polyanionic
proteoglycans (mostly heparan sulfate), fibronectin, entactin, and several other
glycoproteins.

Type IV collagen forms a network suprastructure to which other
glycoproteins attach. The building block (monomer) of this network is a triple-helical
molecule made up of three α chains, composed of one or more of six types of α chains (
α1 to α6 or COL4A1 to COL4A6), the most common consisting of α1, α2, α1. [3,] [5]
Each molecule consists of a 7S domain at the N terminus, a triple-helical domain in the
middle, and a globular noncollagenous domain (NC1) at the C terminus. The NC1
domain is important for helix formation and for assembly of collagen monomers into the
basement membrane suprastructure. Glycoproteins (laminin, entactin) and proteoglycans (heparan sulfate, perlecan) attach to the collagenous suprastructure.
These biochemical determinants are critical to understanding glomerular diseases. For
example, as we shall see, the antigens in the NC1 domain are the targets of antibodies
in anti-GBM nephritis; genetic defects in the α-chains underlie some forms of hereditary
nephritis; and the proteoglycan content of the GBM may contribute to its permeability
characteristics.

glomerular basement membrane (GBM)

117

The_____________ are structurally complex cells that possess
interdigitating processes embedded in and adherent to the lamina rara externa of the
basement membrane. Adjacent foot processes (pedicels) are separated by 20- to 30-
nm-wide filtration slits, which are bridged by a thin diaphragm (see Fig. 20-2 ).

 visceral epithelial cells (podocytes)

118

The entire glomerular tuft is supported by ____________lying between the capillaries.
Basement membrane–like mesangial matrix forms a meshwork through which the
mesangial cells are centered (see Fig. 20-1 ). These cells, of mesenchymal origin, are
contractile, phagocytic, and capable of proliferation, of laying down both matrix and
collagen, and of secreting several biologically active mediators. Biologically, they are
most akin to vascular smooth muscle cells and pericytes. They are, as we shall see,
important players in many forms of human glomerulonephritis.

mesangial cells 

119

The major characteristics of normal glomerular filtration are an _________________-, because of the highly fenestrated nature of the endothelium, and
impermeability to proteins, such as molecules of the size of albumin (∼3.6-nm radius; 70
kilodaltons [kD] molecular weight) or larger.

extraordinarily high permeability
to water and small solutes

120

The latter property of the glomerular filtration
barrier allows discrimination among various protein molecules, depending on their ____________and ________________. This size- and
charge-dependent barrier function is accounted for by the complex structure of the capillary
wall
, the collagenous porous and charged structure of the GBM, and the many anionic moieties
present within the wall, including the acidic proteoglycans of the GBM and the
sialoglycoproteins of epithelial and endothelial cell coats (also called glycocalyx).

size (the
larger, the less permeable) 

charge (the more cationic, the more permeable)

121

The chargedependent
restriction is important in the __________________
because albumin is an anionic molecule of a pI 4.5.

virtually complete exclusion of albumin from the filtrate,

122

The_______________, also known as a
podocyte, is important for the maintenance of glomerular barrier function; its slit diaphragm
presents a size-selective distal diffusion barrier
to the filtration of proteins, and it is the cell type
that is largely responsible for synthesis of GBM components.

 visceral epithelial cell

123

Proteins located in the slit
diaphragm control glomerular permeability. Three of the most important slit diaphragm proteins
are depicted in Figure 20-3 .___________ is a transmembrane protein with a large extracellular
portion made up of immunoglobulin (Ig)-like domains. This molecules extend toward each
other from neighboring foot processes and dimerize across the slit diaphragm. Within the
cytoplasm of the foot processes, _________ forms molecular connections with podocin, CD2-
associated protein, and ultimately the actin cytoskeleton. The number of identified slit
diaphragm proteins continues to grow rapidly, and more comprehensive descriptions of their
complex localization and interactions have been published. [6,] [7] The importance of these
proteins in maintaining glomerular permeability is demonstrated by the observation that
mutations in the genes encoding them give rise to nephrotic syndrome (discussed later). This
has resulted in renewed appreciation of the importance of the slit diaphragm in glomerular
barrier function and its contribution to protein leakage in disease states. [

  1.  Nephrin
  2. podocin
  3. actin cytoskeleton

124

HISTOLOGIC ALTERATIONS
Various types of glomerulopathies are characterized by one or more of four basic tissue
reactions.

Hypercellularity.

Basement Membrane Thickening.

Hyalinosis and Sclerosis.

125

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
combinations of the following:
 

 

Hypercellularity

• Cellular proliferation of mesangial or endothelial cells.
• Leukocytic infiltration consisting of neutrophils, monocytes, and, in some diseases,
lymphocytes.

Formation of crescents. These are accumulations of cells composed of proliferating
parietal epithelial cells and infiltrating leukocytes.
The epithelial cell proliferation that
characterizes crescent formation occurs following an immune/inflammatory injury (see
later).

Fibrin, which leaks into the urinary space, often through 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. Mice that are
deficient in fibrinogen are protected to a degree from crescent formation, and mice that
are deficient in molecules important in fibrinolysis (e.g., plasminogen activators) exhibit
enhanced crescent formation in models of anti-GBM antibody–mediated crescentic
glomerulonephritis. [9] Other molecules that have been implicated in crescent formation
and recruitment of leukocytes into crescents include procoagulants such as tissue factor
and cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and interferon-γ.

126

In hypercellularity what type of cells proliferate?

Cellular proliferation of mesangial or endothelial cells.

127

 These are accumulations of cells composed of proliferating
parietal epithelial cells
and infiltrating leukocytes. The epithelial cell proliferation that
characterizes crescent formation occurs following an immune/inflammatory injury (see
later).

Formation of crescents.

128

_________, which leaks into the urinary space, often through 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.

Fibrin

 

Note : Mice that are
deficient in fibrinogen are protected to a degree from crescent formation, and mice that
are deficient in molecules important in fibrinolysis (e.g., plasminogen activators) exhibit
enhanced crescent formation in models of anti-GBM antibody–mediated crescentic
glomerulonephritis.
[9] 

129

Other molecules that have been implicated in _____
and recruitment of leukocytes into crescents include __________

crescent formation 

procoagulants such as tissue factor

and cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and interferon-γ.

130

_____________
By light microscopy, this change appears as thickening of the capillary walls, best seen in
sections stained with periodic acid–Schiff (PAS).

Basement Membrane Thickening.

131

 By electron microscopy such thickening takes
one of two forms:
____________________________

Deposition of amorphous electron-dense material, most often immune complexes, on
the endothelial or epithelial side of the basement membrane or within the GBM itself.
Fibrin, amyloid, cryoglobulins, and abnormal fibrillary proteins may also deposit in the
GBM.
• Thickening of the basement membrane due to increased synthesis of its protein
components, as occurs in diabetic glomerulosclerosis.

132

___________, as applied to the glomerulus, denotes the accumulation of material that is
homogeneous and eosinophilic by light microscopy

Hyalinosis

133

By electron microscopy the ____________- is
extracellular and amorphous. It is made up of plasma proteins that have insudated from the
circulation into glomerular structures. When extensive, this change contributes to obliteration of
the capillary lumens of the glomerular tuft

hyalin

134

____________- is usually a consequence of endothelial or
capillary wall injury
and typically the end result of various forms of glomerular damage. It is a
common feature of focal segmental glomerulosclerosis.

Hyalinosis

135

Hyalinosis is usually a consequence of endothelial or
capillary wall injury
and typically the end result of various forms of glomerular damage. It is a
common feature of _____________________

focal segmental glomerulosclerosis.

136

_____________- is characterized by accumulations of extracellular collagenous matrix, either confined
to mesangial areas
as is often the case in diabetic glomerulosclerosis, or involving the capillary
loops, or both. The sclerosing process may also result in obliteration of some or all of the
capillary lumens
in affected glomeruli, which in turn can result in formation of fibrous adhesions
between the sclerotic portions of glomeruli and the nearby parietal epithelium and Bowman
capsules.

Sclerosis

137

Because many of the primary glomerulopathies are of unknown cause, they are often classified
by their histology, as can be seen in Table 20-2 . The histologic changes can be further
subdivided by their distribution into :

diffuse

global

focal

segmental

138

 _____________, involving all glomeruli;

diffuse 

139

__________, involving the entire
glomerulus; 

 global

140

__________, involving only a proportion of the glomeruli; 

focal

141

___________, affecting a part of
each glomerulus; and by either capillary loop or mesangial, affecting predominantly capillary or
mesangial regions. These terms are sometimes appended to the histologic classifications.

segmental

 

Note: 50 %

142

Immune Mechanisms of Glomerular Injury
 

  1. ANTIBODY-MEDIATED INJURY IN SITU IMMUNE COMPLEX DEPOSITION
  2. CIRCULATING IMMUNE COMPLEX DEPOSITION
  3. CYTOTOXIC ANTIBODIES
  4. CELL-MEDIATED IMMUNE INJURY
  5. ACTIVATION OF ALTERNATIVE COMPLEMENT PATHWAY

143

WHAT ARE THE ANTIBODY-MEDIATED INJURY
IN SITU IMMUNE COMPLEX DEPOSITION? 
 

  1. Fixed intrinsic tissue antigens
  • NC1 domain of collagen type IV antigen (anti-GBM

nephritis)

  • Heymann antigen (membranous glomerulopathy)
  • Mesangial antigens
  • Others

2. Planted antigens

  • Exogenous (infectious agents, drugs)
  • Endogenous (DNA, nuclear proteins, immunoglobulins, immune

complexes, IgA)


 

144

CIRCULATING IMMUNE COMPLEX DEPOSITION

 

  1. Endogenous antigens (e.g., DNA, tumor

antigens)

2.    Exogenous antigens (e.g., infectious products)

145

Two forms of antibody-associated injury have been established: 

(1) injury by antibodies
reacting in situ within the glomerulus, either binding to insoluble fixed (intrinsic) glomerular
antigens or to molecules planted within the glomerulus, and (2) injury resulting from deposition
of circulating antigen-antibody complexes in the glomerulus. In addition, there is experimental
evidence that cytotoxic antibodies directed against glomerular cell components may cause
glomerular injury. These pathways are not mutually exclusive, and in humans, all may contribute
to injury.

146

_________-
In these forms of injury, antibodies react directly with intrinsic tissue antigen, or antigens
“planted” in the glomerulus from the circulation. The best established experimental models for
anti–glomerular antibody–mediated glomerular injury, for which there are counterparts in human
disease, are anti–glomerular basement membrane (antiGBM) antibody–induced
glomerulonephritis and Heymann nephritis.

Immune Complex Deposition Involving Intrinsic and in Situ Renal Antigens

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