Kidney & Urinary tract

CLINICAL MANIFESTATIONS OF RENAL DISEASES

1-Azotemia
refers to an elevation of blood urea nitrogen(BUN) and creatinine levels It is largely related to a decreased glomerular filtration rate (GFR).

 2-uremia when azotemia progresses to clinical manifestations and systemic biochemical abnormalities. Uremia is characterized by: 1- failure of renal excretory function. 2- metabolic and endocrine alterations.
3

 3- 2ry gastrointestinal manifestations

(e.g., uremic gastroenteritis).

4- 2ry neuromuscular manifestations

(e.g., peripheral neuropathy).

5- 2ry cardiovascular manifestations

(e.g., uremic fibrinous pericarditis).

The major renal syndromes

1-Acute nephritic syndrome:

it is a glomerular syndrome characterized by:

1- acute onset . 2- gross hematuria. 3- mild to moderate proteinuria (< 3.5 gm of protein/day in adults) 4- azotemia. 5- edema. 6- hypertension.
5

2-Nephrotic syndrome
it is a glomerular syndrome characterized by: 1- heavy proteinuria (excretion of >3.5 gm of protein/day in adults) 2- hypoalbuminemia 3- severe edema 4- hyperlipidemia 5- lipiduria (lipid in the urine).
6

3-Asymptomatic hematuria or proteinuria

is usually a manifestation of mild glomerular abnormalities.

4-Rapidly progressive glomerulonephritis

It results in loss of renal function in a few days or weeks It is manifested by : 1-microscopic hematuria. 2-dysmorphic red blood cells and red blood cell casts in the urine sediment. 3-mild-moderate proteinuria.
8

5-Acute renal failure

is dominated by oliguria or anuria (no urine flow). recent onset of azotemia. It can result from : 1-glomerular injury (such as crescentic glomerulonephritis). 2-interstitial injury. 3-vascular injury (such as thrombotic microangiopathy). 4-acute tubular necrosis.
9

6- Chronic renal failure

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

10

7- Urinary tract infection

It is characterized by bacteriuria and pyuria (bacteria and leukocytes in the urine). The infection may be symptomatic or asymptomatic. Types : 1- pyelonephritis (affection of the kidney ). 2- cystitis (affection of the bladder).
11

8-Nephrolithiasis
Renal stones. It is manifested by: 1-renal colic. 2-hematuria. 3-recurrent stone formation.

12

GLOMERULAR DISEASES
chronic glomerulonephritis is one of the most common causes of chronic kidney disease in humans. the glomerulus consists of an anastomosing network of capillaries invested by two layers of epithelium. The visceral epithelium (podocytes) is an intrinsic part of the capillary wall. the parietal epithelium lines Bowman space (urinary space), the cavity in which plasma ultrafiltrate first collects.
13

 The glomerular capillary wall is the filtration unit and consists of : 1-A thin layer of fenestrated endothelial cells, each fenestra 70 to 100 nm in diameter. 2-A glomerular basement membrane (GBM).

14

 The capillary basement membrane consists of : 1- a thick electron-dense central layer (lamina densa) 2- thinner and electron-lucent peripheral layers ( lamina rara interna and lamina rara externa ).

15

 The GBM consists of collagen (mostly type IV), laminin, polyanionic proteoglycans, fibronectin, and several other glycoproteins.

16

 3-The visceral epithelial cells (podocytes), structurally complex cells that possess interdigitating processes embedded in and adherent to the lamina rara externa of the basement membrane.

17

 Adjacent foot processes are separated by 20- to 30-nm-wide filtration slits which are bridged by a thin slit diaphragm composed in large part of nephrin.

18

4-Supportive cells (mesangial cells) lying between the capillaries. Basement membrane-like mesangial matrix forms a meshwork through which the mesangial cells are scattered.

19

20

Normal glomerulus by LM. The glomerular capillary loops are thin and delicate. Endothelial and mesangial cells are normal in number. The surrounding tubules are normal.

21

EM-GLOMERULUS
CL-capillary lumen, End-endothelium, US-urinary space, B-basement membrane, Ep-epithelial cell, Mes-mesangial cell, Fp-foot process.

Fp
22

The major characteristics of glomerular filtration

1- an extraordinarily high permeability to water and small solutes 2- an almost complete impermeability to molecules of the size and molecular charge of albumin (size: 3.6 nm radius; 70,000 kD).

23

 The selective permeability discriminates among protein molecules depending on: 1- their size (the larger the less permeable), 2- their charge (the more cationic the more permeable). 3-their configuration. Nephrin and its associated proteins, including podocin, have a crucial role in maintaining the selective permeability of the glomerular filtration barrier.
24

Pathogenesis of Glomerular Diseases

Antibody-associated (1) injury resulting from deposition of soluble circulating Ag-Ab complexes in the glomerulus. (2) injury by Abs reacting in situ within the glomerulus. )3) Abs directed against glomerular cell components.
25

1-Nephritis Caused by Circulating Immune Complexes

The antigen is not of glomerular origin. 1- endogenous as in the GN associated with SLE. 2- exogenous as in the GN that follows certain bacterial (streptococcal), viral (hepatitis B), parasitic (Plasmodium falciparum malaria), and spirochetal (Treponema pallidum) infections.
26

 antigen-antibody complexes are formed in situ or in the circulation and are then trapped in the glomeruli activation of complement and the recruitment of leukocytes injury. the glomerular lesions usually consist of leukocytic infiltration (exudation) into glomeruli and variable proliferation of endothelial, mesangial, and parietal epithelial cells.
27

 Electron microscopy reveals the immune complexes as electron-dense deposits or clumps that lie at one of three sites: 1-in the mesangium. 2-between the endothelial cells and the GBM (subendothelial deposits). 3-between the outer surface of the GBM and the podocytes (subepithelial deposits).
28

 Deposits may be located at more than one site. The presence of Igs and complement in these deposits can be demonstrated by immunofluorescence microscopy. The pattern of immune complex deposition is helpful in distinguishing various types of GN.
29

IF-Granula deposition of immune complexes . characteristic of circulating and in situ immune complex deposition

30

immunofluorescence linear deposition of immune complexes

31

2-Nephritis Caused by In Situ Immune Complexes

antibodies in this form of injury react directly with fixed or planted antigens in the glomerulus.

32

Planted antigens include: 1- DNA. 2- bacterial products 3-large aggregated proteins (e.g., aggregated IgG), which deposit in the mesangium because of their size 4- immune complexes themselves because they continue to have reactive sites for further interactions with free antibody, free antigen, or complement.
33

3-Anti-Glomerular Basement Membrane (GBM) Antibody Glomerulonephritis

Classic anti-GBM antibody GN (less than 1% of human GN cases). Abs are directed against fixed antigens in the GBM. Deposition of these antibodies creates a linear pattern of staining when the bound antibodies are visualized with IF microscopy.

34

IF- linear deposition of immune complexes , characteristic of classic anti-GBM antibody GN

35

 The basement membrane antigen responsible for classic anti-GBM antibody GN is a component of the noncollagenous domain of the 3 chain of collagen type IV. The anti-GBM antibodies cross-react with basement membranes of lung alveoli resulting in simultaneous lung and kidney lesions (Goodpasture syndrome).

36

The Nephrotic Syndrome

The nephrotic syndrome refers to a clinical complex that includes the following: (1) massive proteinuria with daily protein loss in the urine of 3.5 gm or more in adults. (2) hypoalbuminemia with plasma albumin levels less than 3 gm/dL. (3) generalized edema (4) hyperlipidemia and lipiduria. (5) little or no azotemia, hematuria, or hypertension.
37

Causes of Nephrotic Syndrome A-primary glomerular diseases

Cause

Prevalence )%( Prevalence (%) Children Adults

5 65 10 10 10 30 10 35 10 15

Primary Glomerular Disease Membranous GN Minimal-change disease Focal segmental glomerulosclerosis Membranoproliferative GN IgA nephropathy
38

B-Systemic Diseases with Renal

Manifestations: Diabetes mellitus: Amyloidosis Systemic lupus erythematosus drugs (gold, penicillamine, "street heroin") Infections (malaria, syphilis, hepatitis B, HIV) Malignancy (carcinoma, melanoma) Miscellaneous (e.g bee-sting allergy)
39

Minimal-Change Disease (Lipoid Nephrosis(

This relatively benign disorder. The most frequent cause of the nephrotic syndrome in children (ages 1-7 years). It is characterized by glomeruli that have a normal appearance by LM but show diffuse effacement of podocytes by the EM.
40

Pathogenesis
The pathogenesis of proteinuria is still not clear. Based on some experimental studies, the proteinuria has been attributed to a T-cell derived factor that causes podocyte damage and effacement of foot processes. neither the nature of such a putative factor nor a causal role of T cells is established in the human disease.
41

Morphology
LM the glomeruli in minimal change disease appear normal. The cells of the proximal convoluted tubules are often heavily laden with protein droplets and lipids but this is secondary to tubular reabsorption of the lipoproteins passing through the diseased glomeruli (lipoid nephrosis).
42

 EM
the GBM appears normal. The only obvious glomerular abnormality is the uniform and diffuse effacement of the foot processes of the podocytes . The cytoplasm of the podocytes thus appears flattened over the external aspect of the GBM obliterating the network of arcades between the podocytes and the GBM. There are also epithelial cell vacuolization microvillus formation and occasional focal detachments.
43

 When the changes in the podocytes reverse (e.g., in response to corticosteroids) the proteinuria remits.

44

45

Minimal change disease. A Under the light microscope the PAS-stained glomerulus appears normal, with a delicate basement membrane B Schematic diagram illustrating diffuse effacement of foot processes of podocytes with no immune deposits.

MCD-EM the capillary loop in the lower half contains two electron dense RBC's. Fenestrated endothelium is present and the BM is normal. The overlying epithelial cell foot processes are fused (arrows).

46

Clinical Course
insidious development of the nephrotic syndrome in an otherwise healthy child. There is no hypertension. renal function is preserved in most individuals. selective proteinuria (the protein loss is usually confined to albumin ) The prognosis is good.
47

 More than 90% of cases respond to a short course of corticosteroid therapy. proteinuria recurs in more than 2/3 of the initial responders some of whom become steroid dependent. < 5% develop chronic renal failure after 25 years and it is likely that most persons in this subgroup had nephrotic syndrome caused by FSGS not detected by biopsy. Adults with minimal change disease also respond to steroid therapy but the response is slower and relapses are more common.
48

Focal and Segmental Glomerulosclerosis

characterized histologically by sclerosis affecting some but not all glomeruli (focal involvement) and involving only segments of each affected glomerulus. This histologic picture is often associated with the nephrotic syndrome.
49

 It can occur : (1)in association with other known conditions as AIDS or heroin abuse (HIV or heroin nephropathy). (2) as a secondary event in other forms of GN (e.g IgA nephropathy).

50

 (3) as a maladaptation after nephron loss. (4) in inherited or congenital forms resulting from mutations affecting cytoskeletal or related proteins expressed in podocytes (e.g., nephrin). (5) as a primary disease( 20% to 30% of all cases of the nephrotic syndrome) .
51

MCD
hematuria -

FSGS
+

hypertension
proteinuria

selective

+
nonselective

response to corticosteroid 52 therapy

good

poor

 At least 50% of individuals with FSGS develop end-stage renal failure within 10 years of diagnosis. Adults do worse than children.

53

Pathogenesis
unknown . injury to the podocytes is thought to represent the

initiating event of primary FSGS.

permeability-increasing factors produced by lymphocytes. The deposition of hyaline masses in the glomeruli represents the entrapment of plasma proteins and lipids in foci of injury where sclerosis develops. IgM and complement proteins commonly seen in the lesion are also believed to result from nonspecific entrapment in damaged glomeruli.
54

 The recurrence of proteinuria after renal allografts transplantation sometimes within 24 hours of transplantation supports the idea that a circulating mediator is the cause of the damage to podocytes .

55

Morphology
The disease is "focal" and initially affects only the juxtamedullary glomeruli. With progression eventually all levels of the cortex are affected. LM-FSGS is characterized by lesions occurring in some tufts within a glomerulus and sparing of the others ( "segmental").

56

 The affected glomeruli exhibit increased mesangial matrix, obliterated capillary lumens, and deposition of hyaline masses (hyalinosis) and lipid droplets. progression of the disease leads to global sclerosis of the glomeruli (global sclerosis) with pronounced tubular atrophy and interstitial fibrosis.
57

focal and segmental glomerulosclerosis (PAS stain). a mass of scarred, obliterated capillary lumens with accumulations of matrix material

58

FSGS blue collagen deposition (MT stain).

59

 IF microscopy nonspecific trapping of Igs usually IgM, and complement in the areas of hyalinosis. EM the podocytes exhibit effacement of foot processes as in MCD.

60

FSGS effacemant of foot processes

Collapsing glomerulopathy
It is a morphologic variant of FSGS. It carries a particularly poor prognosis. It is characterized by collapse of the entire glomerular tuft and podocyte hyperplasia. It may be : 1-idiopathic . 2-associated with HIV infection. 3-drug-induced toxicities.
62

Clinical Course
Poor responses to corticosteroid therapy. about 50% of individuals suffer renal failure after 10 years.

63

Membranous Glomerulonephritis ( MGN)

It is slowly progressive disease. most common between 30 -50 years of age. It is characterized morphologically by

the presence of subepithelial Igcontaining deposits along the GBM.

64

 Membranous glomerulonephritis : 1-Idiopathic (85% of cases). 2-2ry.

65

 secondary to other disorders including: (1) infections (HBV, syphilis,schistosomiasis, malaria). (2) malignant tumors (carcinoma of the lung and colon and melanoma). (3) autoimmune diseases as SLE . (4) exposure to inorganic salts (gold, mercury). (5) drugs (penicillamine, captopril,NSAID).

66

Pathogenesis
Membranous GN is a form of chronic immune complex nephritis. circulating complexes of 1- exogenous (e.g., hepatitis B virus) . 2- endogenous (DNA in SLE) antigen .

67

Morphology
LM the basic change appears to be diffuse thickening of the GBM .

68

LM- membranous glomerulonephritis in which the capillary loops are thickened and prominent, but the cellularity is not increased

69

Membranous nephropathy. A ,Diffuse thickening of the glomerular basement membrane . B ,Schematic diagram illustrating subepithelial deposits, effacement of foot processes, and the presence of "spikes" of basement membrane material between the immune deposits .

70

A silver stain of the glomerulus highlights the proteinaceous basement membranes in black. There are characteristic "spikes" seen with membranous glomerulonephritis seen here in which the black basement membrane material appears as projections around the capillary loops.

71

 IF diffuse granular deposits of immunoglobulins and complement along the GBM . mainly IgG and complement.

72

MGN IF-deposits of mainly IgG and complement collect in the basement membrane and appear in a diffuse granular pattern

73

 EM subepithelial deposits thickening of the GBM and are separated from each other by small, spikelike protrusions of GBM matrix that form in reaction to the deposits ("spike and dome" pattern). As the disease progresses, these spikes close over the deposits, incorporating them into the GBM.
74

EM-the darker electron dense immune deposits are seen scattered within the thickened basement membrane .

75

 the podocytes show effacement of foot processes. the incorporated deposits may be catabolized and eventually disappear leaving cavities within the GBM. Continued deposition of basement membrane matrix leads to progressively thicker basement membranes. With further progression the glomeruli can become sclerosed.
76

Clinical Course
insidious development of the nephrotic syndrome, usually without antecedent illness. some individuals with membranous nephropathy may have lesser degrees of proteinuria rather than the full-blown nephrotic syndrome. the proteinuria is nonselective. no response to corticosteroid therapy.
77

 Membranous nephropathy follows a variable and often indolent course. Overall proteinuria persists in over 60% of cases. ~ 40% suffer progressive disease terminating in renal failure after 2 to 20 years. 10%-30% have a more benign course with partial or complete remission of proteinuria.

78

Membranoproliferative Glomerulonephritis
MPGN is characterizedby alterations in the GBM and mesangium and by proliferation of glomerular cells. It accounts for 5% to 10% of cases of idiopathic nephrotic syndrome in children and adults. Some individuals present only with hematuria or proteinuria in the nonnephrotic range. others have a combined nephroticnephritic picture.
79

Pathogenesis
Types of MPGN: 1-type I is (about 80% of cases). 2-type II.

80

Type I MPGN
circulating immune complexes similar to chronic serum sickness but the inciting antigen is not known. It occurs in association with: 1- hepatitis B and C antigenemia. 2- SLE. 3- infected A-V shunts. 4- extra-renal infections with persistent or episodic antigenemia.
81

Type II MPGN (dense-deposit

disease)
The fundamental abnormality

appears to be excessive complement activation which may

be caused by several mechanisms not involving antibodies.

82

 Some patients have an autoantibody against C3 convertase called C3 nephritic factor, which is believed to stabilize the enzyme and lead to uncontrolled cleavage of C3 and activation of the alternative complement pathway. Mutations in the gene encoding the complement regulatory protein Factor H have been described in some patients. These mutations may lead to a deficiency of plasma Factor H or defective function of the protein, again resulting in excessive complement activation

83

 Functional impairment of Factor H may also be caused by autoantibodies or abnormalities in the C3 protein that prevent its interaction with Factor H. Hypocomplementemia is more marked in type II due to: 1- excessive consumption of C3 2- reduced synthesis of C3 by the liver. It is still not clear how the complement abnormality induces the glomerular changes.
84

Morphology
LM
both types of MPGN are similar. The glomeruli are large with an accentuated lobular appearance and show proliferation of mesangial and endothelial cells as well as infiltrating leukocytes The GBM is thickened and the glomerular capillary wall often shows a double contour or "tram track," appearance especially evident in silver or PAS stains.
85

 The tram track appearance is caused by "splitting" of the GBM due to the inclusion within it of processes of mesangial and inflammatory cells extending into the peripheral capillary loops (MPGN II).

86

Membranoproliferative GN, showing mesangial cell proliferation, basement membrane thickening, leukocyte infiltration, and accentuation of lobular architecture.

87

Schematic representation of patterns in the two types of membranoproliferative GN. In type I there are subendothelial deposits; type II is characterized by intramembranous dense deposits (dense-deposit disease). In both, mesangial interposition gives the appearance of split basement membranes when viewed by light microscopy.

88

membranoproliferative glomerulonephritis (MPGN(

89

This silver stain demonstrates a double contour of the basement membranes("tram-tracking" )that is characteristic of (MPGN)(arrows).

90

 IF C3 is deposited in an irregular granular pattern. IgG and early complement components (C1q and C4) are often also present (immune complex pathogenesis).

91

IF Granular deposition of immune complexes characteristic of circulating and in situ immune complex deposition

92

 Type I MPGN is characterized by discrete subendothelial electron-dense deposits .

splitting" of the GBM (tram track) occurs when the mesangial cell (which has a macrophage-like function) goes after subendothelial immune deposits.

93

EM-MPGN type I a mesangial cell at the lower left that is interposing its cytoplasm at the arrow into the basement membrane leading to splitting" of the GBM (tram track).

94

 In type II lesions the lamina densa and the subendothelial space of the GBM are transformed into an irregular, ribbon-like, extremely electron-dense structure, resulting from the deposition of material of unknown composition, giving rise to the term densedeposit disease. C3 is present in irregular chunky and segmental linear foci in the basement membranes and in the mesangium in characteristic circular aggregates (mesangial rings). IgG ,C1q and C4 are usually absent.
95

EM-dense deposits in the basement membrane of MPGN type II. There are dark electron dense deposits within the basement membrane that often coalesce to form a ribbon-like mass of deposits ) arrows)

96

Clinical Course
Nephrotic syndrome (in 50% of cases). MPGN may begin as acute nephritis or mild proteinuria. The prognosis of MPGN is generally poor. No remission. 40% progressed to end-stage renal failure. 30% had variable degrees of renal insufficiency. the remaining 30% had persistent nephrotic syndrome without renal failure.
97

 Dense-deposit disease has a worse prognosis. It tends to recur in renal transplant recipients.

98

The Nephritic Syndrome

characterized by:
(1) hematuria with dysmorphic red cells and red blood cell casts in the urine. (2) some degree of oliguria and azotemia. (3) hypertension. Although there may also be some proteinuria and even edema, these are usually not as severe as in the nephrotic syndrome.
99

Pathogenesis
proliferation of the cells within the glomeruli accompanied by a leukocytic infiltrate injures the capillary walls permitting escape of red cells into the urine GFR oliguria, reciprocal fluid retention, and azotemia. Hypertension is probably a result of both the fluid retention and some augmented renin release from the ischemic kidneys.
100

Acute Postinfectious (Poststreptococcal) Glomerulonephritis is typically caused by glomerular deposition of immune complexes resulting in diffuse proliferation and swelling of resident glomerular cells and frequent infiltration of leukocytes, especially neutrophils. The inciting antigen may be exogenous or endogenous.
101

 Exogenous antigens: 1-poststreptococcal GN. 2-Infections by organisms as pneumococci and staphylococci 3-infections by several common viral diseases such as mumps, measles, chickenpox, and hepatitis B and C. Endogenous antigens as occur in SLE
102

Poststreptococcal GN
It develops in a child 1-4 wks after the individual recovers from a group A streptococcal infection. Only certain "nephritogenic" strains of -hemolytic streptococci are capable of evoking glomerular disease. In most cases the initial infection is localized to the pharynx or skin.
103

Pathogenesis
Ag-Ab complex deposition. Typical features of immune complex disease, such as hypocomplementemia and granular deposits of IgG and complement on the GBM are seen. The relevant antigens are probably streptococcal proteins but their identity is not established.
104

 It is also not clear if immune complexes are formed in the circulation or in situ. Studies indicate that C3 may be deposited on the GBM before IgG ( the primary injury might be by complement activation).

105

Morphology
LM
The most characteristic change in postinfectious GN is a fairly uniformly increased cellularity of the glomerular tufts that affects nearly all glomeruli( "diffuse" ). The increased cellularity is caused both by proliferation and swelling of endothelial and mesangial cells and by a neutrophilic and monocytic infiltrate. Sometimes there is necrosis of the capillary walls. "crescents" within the urinary space in response to the severe inflammatory injury.

106

Post-streptococcal glomerulonephritis. This glomerulus is hypercellular and capillary loops are poorly defined.

107

Post-streptococcal glomerulonephritis is due to increased numbers of epithelial, endothelial, and mesangial cells as well as neutrophils in and around the capillary loops (arrows)

108

 IF
reveals scattered granular deposits of IgG and complement within the capillary walls and some mesangial areas. These deposits are usually cleared over a period of about 2 wks.

109

APGN immune deposits are distributed in the capillary loops in a granular, bumpy pattern because of the focal nature of the deposition process .

110

 EM
shows deposited immune complexes arrayed as subendothelial, intramembranous, or, most often, subepithelial "humps" nestled against the GBM. Mesangial deposits are also occasionally present.
111

EM -immune deposits of PSGN are predominantly subepithelial, a large subepithelial "hump" at the right of the BM (arrows). The capillary lumen is filled with a PMN whose nuclear lobes (arrows)and cytoplasmic granules are visibl(arrows).

112

EM-Typical electron-dense subepithelial "hump(arrow) and intramembranous deposits.

BM, basement membrane; CL, capillary lumen; E, endothelial cell; Ep, visceral epithelial cells (podocytes )

113

Clinical Course
abrupt onset . malaise, a slight fever, nausea, and the nephritic syndrome. oliguria, azotemia, and hypertension are only mild to moderate. gross hematuria. Some proteinuria is a constant feature of the disease and it may occasionally be severe enough to produce the nephrotic syndrome. Serum complement levels are low during the active phase of the disease. serum anti-streptolysin O antibody titers.
114

 Recovery occurs in most children in epidemic cases. Some children develop rapidly progressive GN due to severe injury with crescents or chronic renal disease due to secondary scarring. The prognosis in sporadic cases is less clear. In adults 15% to 50% of individuals develop end-stage renal disease over the ensuing few years or 1 to 2 decades. in children the prevalence of chronicity after sporadic cases of acute postinfectious GN is much lower.

115

IgA Nephropathy (Berger Disease)

is one of the most common causes of

recurrent microscopic or gross hematuria

It usually affects children and young adults. begins as an episode of gross hematuria that occurs within 1 or 2 days of a nonspecific upper respiratory tract infection.
116

 the hematuria lasts several days and then subsides only to recur every few months. It is often associated with loin pain. The pathogenic hallmark is the

deposition of IgA in the mesangium.

117

 Some have considered IgA

nephropathy to be a localized variant of Henoch-Schnlein purpura, also characterized by IgA deposition in the mesangium.

118

 Henoch-Schnlein purpura is a

systemic syndrome involving the skin (purpuric rash), gastrointestinal tract (abdominal pain), joints (arthritis), and kidneys .

119

Pathogenesis
1- It is associated with an abnormality in IgA production and clearance. IgA is increased in 50% of patients with IgA nephropathy due to increased production in the marrow. circulating IgA-containing immune complexes are present in some individuals. A genetic influence is suggested by the occurrence of this condition in families and in HLA-identical siblings, and by the increased frequency of certain HLA and complement phenotypes in some populations
120

 2-abnormality in glycosylation of the IgA immunoglobulin plasma clearance of IgA deposition in the mesangium. 3-the absence of C1q and C4 in glomeruli points to activation of the alternative complement pathway.

121

 4-increased IgA synthesis in response to respiratory or gastrointestinal exposure to environmental agents (e.g., viruses, bacteria, food proteins) may lead to deposition of IgA and IgA-Ag complexes in the mesangium, where they activate the alternative complement pathway and initiate glomerular injury.
122

 5-IgA nephropathy occurs with increased frequency in individuals with celiac disease and in liver disease where there is defective hepatobiliary clearance of IgA complexes (secondary

IgA nephropathy).

123

Morphology
1-focal proliferative GN
The glomeruli may be normal or may show mesangial widening and segmental inflammation confined to some glomeruli .

2-diffuse mesangial proliferation (mesangioproliferative) 3-overt crescentic GN.

124

The IgA is deposited mainly in mesangium, which then

increases mesangial cellularity (arrow)

125

mesangial matrix enlargement is conspicuous and predominates over a

relatively mild mesangial cell proliferation.

126

Mesangial proliferation can be much more intense, global

and diffuse

127

 IF mesangial deposition of IgA often with C3 and properdin and smaller amounts of IgG or IgM . Early components of the classical complement pathway are usually absent.

128

IF demonstrates positivity with antibody to IgA.

the pattern is that of mesangial staining.

129

 EM Electron-dense deposits in the mesangium. The deposits may extend to the subendothelial area of adjacent capillary walls in a minority of cases usually those with focal proliferation.

130

small electrondense mesangial deposits are found even in

glomeruli with a normal appearance by LM.

131

Mesangial involvement is variable, but often characterized by a submembranous concentration of the electrondense deposits.(x 4600)

132

Hereditary Nephritis
Hereditary nephritis refers to a group of hereditary glomerular diseases caused by mutations in GBM proteins. Alport syndrome, in which nephritis is accompanied by nerve deafness and various eye disorders, including lens dislocation, posterior cataracts, and corneal dystrophy.
133

Pathogenesis
The GBM is largely composed of type IV collagen, which is made up of heterotrimers of 3, 4, and 5 type IV collagen. This form of type IV collagen is crucial for normal function of the lens, cochlea, and glomerulus. Mutation of any one of the chains results in defective heterotrimer assembly and thus the disease manifestations of Alport syndrome.
134

Morphology
Histologically, glomeruli in hereditary nephritis appear unremarkable until late in the course when secondary sclerosis may occur. Interstitial cells take on a foamy appearance as a result of accumulation of neutral fats and mucopolysaccharides (foam cells) as a reaction to marked proteinuria.
135

 With progression, there is increasing glomerulosclerosis, vascular sclerosis, tubular atrophy, and interstitial fibrosis.

136

LM-The renal tubular cells appear foamy (arrows)because of the accumulation of neutral fats and mucopolysaccharides. The glomeruli show irregular thickening and splitting of basement membranes.

137

 EM the BM of glomeruli appears thin and attenuated early in the course. Late in the course, the GBM develops irregular foci of thickening or attenuation with pronounced splitting and lamination of the lamina densa, yielding a "basket-weave" appearance.
138

thin and attenuated BM in Alport syndrome

139

The diagrams below illustrate normal BM(LT) vs the thickened and 'falling apart' of Alport GBM(RT)

BM

140

Clinical Course
X-linked as a result of mutation of the gene encoding 5 type IV collagen. Males > females and are more likely to develop renal failure. Rarely, inheritance is autosomal recessive or dominant, linked to defects in the genes that encode 3 or 4 type IV collagen.
141

 presentation at age 5-20 yrs with gross or microscopic hematuria and proteinuria. overt renal failure occurs between 2050 yrs of age.

142

 Female carriers of X-linked Alport syndrome or carriers of either gender of the autosomal forms usually present with persistent hematuria which is most often asymptomatic and follows a benign course. a heterozygous defect in the 3 or 4 chains is associated with persistent often familial hematuria and a benign course (benign familial hematuria, or thin basement membrane lesion).
143

Rapidly Progressive (Crescentic) Glomerulonephritis

RPGN is a clinical syndrome and not a specific etiologic form of GN. Clinically, it is characterized by rapid and progressive loss of renal function with features of the nephritic syndrome. With severe oliguria and if untreated death from renal failure within weeks to months.
144

 The histologic picture is characterized

by the presence of crescents

(crescentic GN). These are produced in part by proliferation of the parietal epithelial cells of Bowman's capsule in response to injury and in part by infiltration of monocytes and macrophages.
145

Pathogenesis
Primary kidney or systemic disease. In most cases the glomerular injury is immunologically mediated. CrGN is divided into 3 groups on the basis of immunologic findings.

146

 Type I (Anti-GBM Antibody): Goodpasture syndrome (12%) characterized by linear deposits of IgG and, C3 on the GBM. The anti-GBM antibodies also bind to pulmonary alveolar capillary basement membranes to produce the clinical picture of pulmonary hemorrhages associated with renal failure (Goodpasture).
147

 Anti-GBM antibodies are present in the serum and are helpful in diagnosis. Plasmapheresis which removes pathogenic antibodies from the circulation is beneficial.

Type II (Immune Complex) (44%): Idiopathic Postinfectious/infection related Systemic lupus erythematosus(SLE) Henoch-Schnlein purpura/IgA nephropathy Type III (Pauci-Immune) ANCA Associated (44% ): Idiopathic Wegener granulomatosis Microscopic angiitis

Morphology
LM Glomeruli show segmental necrosis and GBM breaks with resulting proliferation of the parietal epithelial cells in response to the exudation of plasma proteins (fibrinogen) into Bowman's space. These distinctive lesions of proliferation are called crescents due to their shape as they fill Bowman's space.
150

 The crescents eventually obliterate Bowman's space and compress the glomeruli. Fibrin strands are prominent between the cellular layers in the crescents. Crescents may undergo scarring(fibrous crescents).

151

Crescentic GN (PAS stain). the collapsed glomerular tufts and the crescent-shaped mass of proliferating cells and leukocytes internal to Bowman's capsule.

152

IF micrograph of a glomerulus CGN demonstrates

positivity with antibody to fibrinogen

 IF strong linear staining of deposited IgG and C3 along the GBM Type I (Anti-GBM Antibody).

154

 EM
deposits are not visualized because the endogenous collagen IV antigen to which the antibody is reacting is diffusely distributed, and so the large lattices of antigens and antibodies that occur in deposited immune complexes are not formed. distinct ruptures in the GBM may be seen.

155

Immune Complex-Mediated (Type II) Crescentic Glomerulonephritis immune complex-mediated disorders. it can be a complication of any of the immune complex nephritides including : 1-poststreptococcal GN 2-SLE 3-IgA nephropathy 4-Henoch-Schnlein purpura 5-idiopathic
156

Morphology
LM
There is severe injury with segmental necrosis and GBM breaks with resultant crescent formation. in contrast to type I CrGN (anti-GBM antibody disease), segments of glomeruli without necrosis show evidence of the underlying immune complex GN (e.g., diffuse proliferation and leukocyte exudation in postinfectious GN or SLE, and mesangial proliferation in IgA nephropathy or HenochSchnlein purpura(.
157

 IF
reveal the characteristic granular ("lumpy bumpy") pattern of staining of the GBM and/or mesangium for immunoglobulin and/or complement.

158

Pauci-Immune (Type III) Crescentic Glomerulonephritis

It is defined by the lack of anti-GBM antibodies or significant immune complex deposition detectable by IF and EM. Most of these individuals have antineutrophil cytoplasmic antibodies in the serum (ANCA). Type III CrGN is a component of a systemic vasculitis such as microscopic polyangiitis or Wegener granulomatosis. When pauci-immune CrGN is limited to the kidney it is called idiopathic.
159

Morphology
Glomeruli show segmental necrosis and GBM breaks with resulting crescent formation. Uninvolved segments of glomeruli appear normal without proliferation or prominent inflammatory cell influx. IF& EM for immunoglobulin and complement are negative and there are no deposits detectable by electron microscopy.
160

Clinical Course
The onset of RPGN is by nephritic syndrome except that the oliguria and azotemia are more pronounced. Proteinuria sometimes approaching nephrotic range may occur. Some of these persons become anuric and require long-term dialysis or transplantation.
161

 The prognosis can be roughly related to the number of crescents. When No. of crescents in less than 80% of the glomeruli have a better prognosis than those with higher percentages of crescents.

162

Chronic Glomerulonephritis
It is an important cause of end-stage renal disease presenting as chronic renal failure. Among all individuals who require chronic hemodialysis or renal transplantation, 30% to 50% have the diagnosis of chronic GN. It probably represents the end stage of a variety of entities: 1-CrGNs. 2-FSGS. 3-MGN. 4-IgA nephropathy. 5-MPGN. 6-Idiopathic( 20% of cases).
163

 Although chronic GN may develop at any age, it is usually first noted in young and middle-aged adults.

164

Morphology
Classically, the kidneys are symmetrically contracted and their surfaces are red-brown and diffusely granular. LM scarring of the glomeruli sometimes to in the point of complete sclerosis (obliteration of the glomeruli).
165

 There is also marked interstitial fibrosis, associated with atrophy and dropout of many of the tubules in the cortex, and diminution and loss of portions of the peritubular capillary network. The small and medium-sized arteries are frequently thick walled, with narrowed lumina, secondary to hypertension. Lymphocytic and plasma cells are present in the fibrotic interstitial tissue. The markedly damaged kidneys are designated end-stage kidneys.
166

Chronic GN. A MT stain shows complete replacement of virtually all glomeruli by blue-staining collagen.

167

DISEASES AFFECTING TUBULES AND INTERSTITIUM

168

Tubulointerstitial Nephritis
Causes : 1- bacterial infection. 2- drugs. 3- metabolic disorders such as hypokalemia. 4- physical injury such as irradiation. 5- viral infections. 6- immune reactions.
169

 TIN isdivided into : 1-acute 2-chronic

170

Acute Pyelonephritis
Acute pyelonephritis, a common suppurative inflammation of the kidney and the renal pelvis. It is caused by bacterial infection. It is an important manifestation of urinary tract infection (UTI) : 1- lower UT (cystitis, prostatitis, urethritis). 2- upper UT(pyelonephritis). 3- both.
171

Pathogenesis
The principal causative organisms are : 1- Escherichia coli is the most common . 2- Proteus.

3- Klebsiella. 3- Enterobacter. 4- Pseudomonas.

5- Staphylococci and Streptococcus faecalis (uncommon).
172

Routes of infection
1-hematogenous. 2-ascending infection (commonest). acute pyelonephritis may result from seeding of the kidneys by bacteria in the course of septicemia or infective endocarditis. Ascending infection from the lower urinary tract is the most important and common route by which the bacteria reach the kidney.

173

 bladder urine is sterile and remains so as a result of: 1- the antimicrobial properties of the bladder mucosa. 2- the flushing action associated with periodic voiding of urine.

174

 The first step is adhesion of bacteria to mucosal surfaces colonization of the distal urethra bladder by expansive growth of the colonies and by moving against the flow of urine.

175

Predisposing factors
1-urethral instrumentation, including catheterization and cystoscopy 2-female sex because of the close proximity of the urethra to the rectum 3-trauma to the urethra

176

 4-outflow obstruction or bladder dysfunction Obstruction at the level of the urinary bladder results in incomplete emptying and increased residual volume of urine stasis bacteria introduced into the bladder multiplication without being flushed out or destroyed by the bladder wall the bacteria ascend along the ureters to infect the renal pelvis and parenchyma.
177

 UTI is particularly frequent among individuals with: - benign prostatic hyperplasia - uterine prolapse. - neurogenic bladder dysfunction

178

 5-Pregnancy. 4% to 6% of pregnant women develop bacteriuria sometime during pregnancy and 20% -40% of these eventually develop UTI. 6-UTI is increased in diabetes because of the increased susceptibility to infection. 7-vesicoureteral reflux An incompetent vesicoureteral orifice allows the reflux of bladder urine into the ureters &allows bacteria to ascend the ureter into the pelvis. .
179

The normal ureteral insertion into the bladder is a competent one-way valve that prevents retrograde flow of urine, especially during micturition when the intravesical pressure rises.

180

 VUR is present in 20% to 40% of young children with UTI. 1- congenital defect that results in incompetence of the ureterovesical valve. 2-acquired in spinal cord injury and with neurogenic bladder dysfunction secondary to diabetes.
181

Acute pyelonephritis. The cortical surface is studded with focal pale abscesses

182

Drug-Induced Interstitial Nephritis

Two forms of TIN caused by drugs are : 1-Acute Drug-Induced Interstitial Nephritis 2-Analgesic Nephropathy

183

Acute TIN
1-most frequently occurs with synthetic penicillins (methicillin, ampicillin) 2- other synthetic antibiotics (rifampin), diuretics (thiazides) 3- nonsteroidal anti-inflammatory agents 4-other drugs (phenindione, cimetidine).
184

Pathogenesis
Many features of the disease suggest an immune mechanism. Clinical evidence of hypersensitivity is not dose related. Serum IgE levels are increased in some persons suggesting type I hypersensitivity. The mononuclear or granulomatous infiltrate, together with positive skin tests to drugs, suggests a T cell-mediated (type IV) hypersensitivity reaction.
185

 the drugs act as haptens that covalently bind to some cytoplasmic or extracellular component of tubular cells and become immunogenic. The resultant tubulointerstitial injury is then caused by IgE- and cell-mediated immune reactions to tubular cells or their basement membranes.
186

Morphology
the interstitium shows pronounced edema and infiltration by mononuclear cells, lymphocytes and macrophages . Eosinophils and neutrophils may be present, often in large numbers. With some drugs (e.g., methicillin, thiazides, rifampin), interstitial non-necrotizing granulomas with giant cells may be seen. The glomeruli are normal except in some cases caused by nonsteroidal antiinflammatory agents.
187

Clinical course
The disease begins about 15 days (range 240 days) after exposure to the drug. It is characterized by fever, eosinophilia & rash in about 25% of persons, and renal

abnormalities.
Renal findings include hematuria, minimal or no proteinuria, and leukocyturia (sometimes including eosinophils).

188

 A rising serum creatinine or acute renal failure with oliguria develops in about 50% of cases, particularly in older patients. It is important to recognize drug-induced renal failure, because withdrawal of the offending drug is followed by recovery although it may take several months for renal function to return to normal.

189

Analgesic Nephropathy
Consumption large quantities of analgesics may cause chronic interstitial nephritis often

associated with renal papillary necrosis.

Although at times ingestion of single types of analgesics has been incriminated, most people who develop this nephropathy consume mixtures containing some combination of phenacetin, aspirin, acetaminophen, caffeine, and codeine for long periods.
190

 Aspirin and acetaminophen While they can cause renal disease in apparently healthy individuals preexisting renal disease seems to be a necessary precursor to analgesicinduced renal failure.

191

Pathogenesis
The pathogenesis of the renal lesions is not entirely clear. Papillary necrosis is the initial event, and the interstitial nephritis in the overlying renal parenchyma is a secondary phenomenon. Acetaminophen, a phenacetin metabolite, injures cells by both covalent binding and oxidative damage.
192

 The ability of aspirin to inhibit prostaglandin synthesis suggests that this drug may induce its potentiating effect by inhibiting the vasodilatory effects of prostaglandin and predisposing the papilla to ischemia. The papillary damage may be caused by a combination of direct toxic effects of phenacetin metabolites as well as ischemic injury to both tubular cells and vessels.
193

Morphology
The papillae show coagulative necrosis Foci of dystrophic calcification may occur in the necrotic areas. The cortex drained by the necrotic papillae shows tubular atrophy, interstitial scarring, and inflammation. The small vessels in the papillae and urinary tract submucosa exhibit characteristic PASpositive basement membrane thickening.
194

Clinical Course
Chronic renal failure, hypertension, and anemia. The anemia results in part from damage to red cells by phenacetin metabolites. A complication of analgesic abuse is the increased incidence of transitionalcell carcinoma of the renal pelvis or bladder in persons who survive the renal failure.
195

Acute Tubular Necrosis (ATN)

ATN is a clinicopathologic entity characterized morphologically by damaged tubular epithelial cells and clinically by acute suppression of renal function. It is the most common cause of acute renal

failure.
In acute renal failure, urine flow falls within 24 hours to less than 400 mL/day (oliguria).

196

 Other causes of acute renal failure include : (1) severe glomerular diseases manifesting as RPGN. (2) diffuse renal vascular diseases such as microscopic polyangiitis and thrombotic microangiopathies. (3) acute papillary necrosis associated with acute pyelonephritis. (4) acute drug-induced interstitial nephritis. (5) diffuse cortical necrosis.
197

198

ATN is a reversible renal lesion. predisposing clinical settings:

ischemic ATN is associated with shock

1- severe trauma. 2- acute pancreatitis. 3- septicemia. 4- mismatched blood transfusions and other hemolytic crises, as well as myoglobinuria.
199

 nephrotoxic ATN poisons including heavy metals (e.g., mercury) organic solvents (e.g., carbon tetrachloride) drugs such as gentamicin and other antibiotics, and radiographic contrast agents.

Pathogenesis
(1) tubular injury (2) persistent and severe disturbances in blood flow resulting in diminished oxygen and substrate delivery to tubular cells. Tubular epithelial cells are particularly sensitive to anoxia and are also vulnerable to toxins. Ischemia causes numerous structural alterations in epithelial cells

 Loss of cell polarity reversible early event. Redistribution of membrane proteins (e.g., Na+, [Kgr ]+ATPase) from the basolateral to the luminal surface of tubular cells Decreased sodium reabsorption by proximal tubules and hence increased sodium delivery to distal tubules. Vasoconstriction. Redistribution or alteration of integrins that anchor tubular cells to their underlying basement membranes results in shedding of tubular cells into the urine.

 damage to the tubules and the resultant tubular debris can block urine outflow and eventually increase intratubular pressure decreasing GFR. fluid from the damaged tubules could leak into the interstitium resulting in increased interstitial pressure and collapse of the tubules. Ischemic tubular cells also express chemokines, cytokines, and adhesion molecules such as Pselectin that recruit and immobilize leukocytes that can participate in tissue injury.

Benign Nephrosclerosis
the term used for the renal changes in benign hypertension It is always associated with hyaline arteriolosclerosis. Some degree of mild benign nephrosclerosis is present at autopsy in many persons older than 60 years of age. The frequency and severity of the lesions are increased at any age when hypertension or diabetes mellitus are present.
204

Pathogenesis
many renal diseases cause hypertension which in turn is associated with benign nephrosclerosis. this renal lesion is often seen superimposed on other primary kidney diseases. Similar changes in arteries and arterioles are seen in individuals with chronic thrombotic microangiopathies.

205

Morphology
the kidneys are symmetrically atrophic, each weighing 110 to 130 gm, with a surface of diffuse, fine granularity that resembles grain leather. the basic anatomic change is hyaline thickening of the walls of the small arteries and arterioles known as hyaline arteriolosclerosis. This appears as a homogeneous, pink hyaline thickening at the expense of the vessel lumina with loss of underlying cellular detail .
206

 The narrowing of the lumen results in markedly decreased blood flow through the affected vessels and thus produces ischemia in the organ served All structures of the kidney show ischemic atrophy.

207

Benign nephrosclerosis. arterioles with hyaline deposition, marked thickening of the walls and a narrowed lumen.

208

 In advanced cases of benign nephrosclerosis the glomerular tufts may become globally sclerosed. Diffuse tubular atrophy and interstitial fibrosis are present.

209

 The larger blood vessels (interlobar and arcuate arteries) show reduplication of internal elastic lamina along with fibrous thickening of the media and the subintima (fibroelastic hyperplasia).

210

Clinical Course
rarely causes severe damage to the kidney except in susceptible populations, such as African Americans. all persons with this lesion usually show some functional impairment, such as loss of concentrating ability or a variably diminished GFR. A mild degree of proteinuria.
211

Malignant Hypertension and Malignant Nephrosclerosis

It accounts for only 5% of persons with elevated blood pressure. It may arise de novo or it may appear suddenly in a person who had mild hypertension. In less developed countries it occurs more commonly.

212

Pathogenesis
vascular damage to the kidneys. most commonly results from long-standing benign hypertension with eventual injury to the arteriolar walls. The result is increased permeability of the small vessels to fibrinogen and other plasma proteins, endothelial injury, and platelet deposition. fibrinoid necrosis of arterioles and small arteries and intravascular thrombosis.

213

 Mitogenic factors from platelets (e.g., PDGF) and plasma cause intimal smooth hyperplasia of vessels, resulting in the hyperplastic arteriolosclerosis typical of malignant hypertension and of morphologically similar thrombotic microangiopathies

214

 The kidneys become markedly ischemic. Renin-angiotensin system is stimulated. angiotensin II causes intrarenal vasoconstriction renal ischemia renin secretion. Aldosterone levels are also elevated salt retention Bp.
215

 The consequences of the markedly elevated blood pressure on the blood vessels throughout the body are known as malignant arteriolosclerosis, and the renal disorder is referred to as

malignant nephrosclerosis.

216

Morphology
The kidney is normal-slightly shrunken, depending on the duration and severity of the hypertensive disease. Small pinpoint petechial hemorrhages may appear on the cortical surface from rupture of arterioles or glomerular capillaries giving the kidney a peculiar, flea-bitten appearance.
217

 fibrinoid necrosis of the arterioles . In the interlobular arteries and larger arterioles, proliferation of intimal cells produces an onion-skin appearance . This lesion, called hyperplastic arteriolosclerosis, causes marked narrowing of arterioles and small arteries to the point of total obliteration. Necrosis may also involve glomeruli with microthrombi within the glomeruli as well as necrotic arterioles.

218

Malignant hypertension.
Fibrinoid necrosis of afferent arteriole (PAS stain).

219

Malignant hypertension Hyperplastic arteriolosclerosis (onion-skin lesion).

220

Clinical Course
malignant hypertension is characterized by : 1-diastolic pressures > 120 mm Hg, 2-papilledema 3-encephalopathy 4-cardiovascular abnormalities 5-renal failure
221

 Early symptoms are related to increased intracranial pressure and include headache, nausea, vomiting, and visual impairment, particularly the development of scotomas, or spots before the eyes. At the onset of rapidly mounting blood pressure there is marked proteinuria and microscopic or macroscopic hematuria but no significant alteration in renal function. The syndrome is a true medical emergency that requires prompt and aggressive antihypertensive therapy before irreversible renal lesions develop.

222

 About 50% of patients survive at least 5 years. 90% of deaths are caused by uremia. 10% by cerebral hemorrhage or cardiac failure.

CYSTIC DISEASES OF THE KIDNEY

224

 1-Simple Cysts 2-Autosomal Dominant (Adult) Polycystic Kidney Disease 3-Autosomal Recessive (Childhood) Polycystic Kidney Disease 4-Medullary Cystic Disease
225

1-Simple Cysts
Multiple or single cystic spaces that vary widely in diameter ( 1-5 cm in diameter ) filled with clear fluid. The cysts are usually confined to the cortex. Massive cysts as large as 10 cm in diameter are rare. Simple cysts are a common post-mortem finding that has no clinical significance. The main importance of cysts lies in their differentiation from kidney tumors when they are discovered either incidentally or because of hemorrhage and pain.

226

Simple renal Cysts

 Dialysis-associated acquired cysts occur in the kidneys of patients with end-stage renal disease who have undergone prolonged dialysis. They are present in both cortex and medulla and may bleed causing hematuria. renal adenomas or even adenocarcinomas arise in the walls of these cysts.

228

Cystic change associated with chronic renal dialysis. These kidneys are about normal in size but have a few scattered cysts, none of which is over 2 cm in size. This is

2-Autosomal Dominant (Adult) Polycystic Kidney Disease

Characterized by multiple expanding cysts of both kidneys that ultimately destroy the intervening parenchyma. It is seen in approximately 1: 500-1000 persons Accounts for 10% of cases of chronic renal failure. It can be caused by inheritance of one of at least 2 autosomal dominant genes of very high penetrance.
230

 1-In 85-90% of families, PKD1, the defective gene is on the short arm of chromosome 16. This gene encodes a large and complex cell membrane-associated protein called polycystin-1.

 2-The PKD2 gene (10-15% of cases) on chromosome 4 and encodes polycystin 2. Polycystin 2 is thought to function as a calcium-permeable membrane channel. polycystins 1 and 2 are believed to act together by forming heterodimers. mutation in either gene gives rise to essentially the same phenotype although patients with PKD2 mutations have a slower rate of disease progression as compared with patients with PKD1 mutations.
232

233

Clinical presentation
asymptomatic until the 4th decade by which time the kidneys are quite large although small cysts start to develop in adolescence. The most common presenting complaint is flank pain or a heavy dragging sensation. Acute distention of a cyst either by intracystic hemorrhage or by obstruction may cause excruciating pain. palpation of an abdominal mass. Intermittent gross hematuria commonly occurs. hemorrhage.
234

Complications
1-hypertension (75% ). 2-urinary infection. 3-Saccular aneurysms of the circle of Willis are present in 10% to 30% of patients (subarachnoid hemorrhage ). 4-end-stage renal failure occurs at about age 50 .
235

3-Autosomal Recessive (Childhood) Polycystic Kidney Disease

autosomal recessive inheritance. It occurs in approximately 1:20,000 live births. Perinatal, neonatal, infantile, and juvenile subcategories have been defined, depending on time of presentation and the presence of associated hepatic lesions.
236

 Mutations in a gene PKHD1 coding for a putative membrane receptor protein called fibrocystin, localized to chromosome 6p. Fibrocystin may be involved in the function of cilia in tubular epithelial cells .

Normal term infant kidneys

Cysts are fairly small but uniformly distributed throughout the parenchyma so that the disease is usually symmetrical in appearance with both kidneys markedly enlarged.

239

4-Medullary Cystic Disease

There are 2 major types of medullary cystic disease: 1-medullary sponge kidney a relatively common and usually innocuous condition. 2-nephronophthisis-medullary cystic

disease complex
is almost always associated with renal dysfunction.
240

Nephronophthisis-medullary cystic disease

usually begins in childhood. 4 variants of this disease complex are recognized on the basis of the time of onset: 1-infantile. 2-juvenile. 3-adolescent. 4-adult.
241

 The juvenile form is the most common. Approximately 15-20% of individuals with juvenile nephronophthisis have extra-renal manifestations: 1- retinal abnormalities, including retinitis pigmentosa. 2- oculomotor apraxia. 3- mental retardation. 4- cerebellar malformations. 5- liver fibrosis.
242

 The initial manifestations are usually polyuria and polydipsia a consequence of diminished tubular function. Progression to end-stage renal disease ensues over a 5-10-year period. The disease is difficult to diagnose, since there are no serologic markers and the cysts may be too small to be seen with radiologic imaging. cysts may not be apparent on renal biopsy if the cortico-medullary junction is not well sampled. A positive family history and unexplained chronic renal failure in young patients should lead to suspicion of medullary cystic disease.
243

URINARY OUTFLOW OBSTRUCTION

Renal Stones Urolithiasis Calculus formation at any level in the urinary collecting system. Most often the calculi arise in the kidney. They occur frequently (1%)of all autopsies. Symptomatic urolithiasis is more common in men than in women. Familial tendency toward stone formation
244

Pathogenesis
Renal stones are composed of: 1-calcium oxalate or calcium oxalate mixed with calcium phosphate(80%) . 2-10% are composed of magnesium ammonium phosphate. 3-6%-9% are either uric acid or cystine stones.
245

 In all cases there is an organic matrix of mucoprotein that makes up about 2.5% of the stone by weight.

Causes
1-increased urine concentration of the

stone's constituents so that it exceeds their solubility in urine (supersaturation). 50% of patients who develop calcium stones have hypercalciuria that is not
associated with hypercalcemia.

247

 Hypercalciuria: A. absorptive hypercalciuria. B. renal hypercalciuria due to primary renal defect of calcium reabsorption.

 In 5% to 10% of persons there is hypercalcemia and consequent hypercalciuria.

249

 2-The presence of a nidus In 20% of this subgroup there is excessive excretion of uric acid in the urine which favors calcium stone formation. Urates provide a nidus for calcium deposition. Desquamated epithelial cells

 3-urine pH High urine pH favors crystallization of calcium phosphate and stone formation. Magnesium ammonium phosphate (struvite) stones almost always occur with a persistently alkaline urine due to UTIs.

 Uric acid stones formed in acidic urine (under pH 5.5). Cystine stones are more likely to form when the urine is relatively acidic.

 4-infections The urea-splitting bacteria such as Proteus vulgaris and the staphylococci predispose the person to urolithiasis.

253

 5-lack of substances that normally inhibit mineral precipitation. Inhibitors of crystal formation in urine include Tamm-Horsfall protein, osteopontin, pyrophosphate, mucopolysaccharides, diphosphonates, and a glycoprotein called nephrocalcin No deficiency of any of these substances has been consistently demonstrated in individuals with urolithiasis.
254

 Stones are unilateral in about 80% of patients. Common sites of formation are renal pelves and calyces and the bladder. They tend to be small (average diameter 2-3 mm) and may be smooth or jagged. Progressive precipitation of salts leads to the development of branching structures known as staghorn calculi. These massive stones are usually composed of magnesium ammonium phosphate.
255

Hydronephrosis
Refers to dilation of the renal pelvis and calyces, with accompanying atrophy of the parenchyma. The obstruction may be sudden or insidious and it may occur at any level of the urinary tract from the urethra to the renal pelvis.

256

The most common causes are as follows:

1-Congenital:
Atresia of the urethra Valve formations in either ureter or urethra Aberrant renal artery compressing the ureter Renal ptosis with torsion or kinking of the ureter

 2-Acquired: Foreign bodies: Calculi, necrotic apillae Tumors: Benign prostatic hyperplasia, carcinoma of the prostate, bladder tumors (papilloma and carcinoma), contiguous malignant disease (retroperitoneal lymphoma, carcinoma of the cervix or uterus Inflammation: Prostatitis, ureteritis, urethritis, retroperitoneal fibrosis Neurogenic: Spinal cord damage with paralysis of the bladder Normal pregnancy: Mild and reversible

Hydronephrosis of the kidney, with marked dilation of the pelvis and calyces and thinning of renal parenchyma.

259