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Kidney & Urinary tract
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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).
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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.
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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).
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The major renal syndromes
1-Acute nephritic syndrome: itis a glomerular syndrome characterized by:
1- acute onset .
2- gross hematuria.
3- mild to moderate proteinuria (< 3.5 gm ofprotein/day in adults)
4- azotemia. 5- edema.
6- hypertension.
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2-Nephrotic syndrome
itis 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).
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3-Asymptomatic hematuriaor
proteinuria
is usually a manifestation of mild
glomerular abnormalities.
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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.
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5-Acute renal failure
is dominated by oliguria or anuria (no urineflow).
recent onset of azotemia.
It can result from : 1-glomerular injury (such as crescentic
glomerulonephritis).
2-interstitial injury.
3-vascular injury (such as thromboticmicroangiopathy).
4-acute tubular necrosis.
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6- Chronic renal failure
It is characterized by prolonged
symptoms and signs of uremia.
It is the end result of all chronic renal
diseases .
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7- Urinary tract infection
It is characterized by bacteriuria andpyuria (bacteria and leukocytes in theurine).
The infection may be symptomatic orasymptomatic.
Types :
1- pyelonephritis (affection of thekidney ).
2- cystitis(affection of the bladder).
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8-Nephrolithiasis
Renal stones.
It is manifested by:
1-renal colic. 2-hematuria.
3-recurrent stone formation.
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GLOMERULAR DISEASES
chronic glomerulonephritis is one of themost common causes of chronic kidneydisease in humans.
the glomerulus consists of an anastomosing
network of capillaries invested by two layersof epithelium.
The visceral epithelium (podocytes) is anintrinsic part of the capillary wall.
the parietal epithelium lines Bowman space(urinary space), the cavity in which plasmaultrafiltrate first collects.
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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).
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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 ).
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The GBM consists of collagen (mostly
type IV), laminin, polyanionic
proteoglycans, fibronectin, and several
other glycoproteins.
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3-The visceral epithelial cells
(podocytes), structurally complex cells
that possess interdigitating processes
embedded in and adherent to thelamina rara externa of the basement
membrane.
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Adjacent foot processesare separated
by 20- to 30-nm-wide filtration slits
which are bridged by a thin slit
diaphragm composed in large part ofnephrin.
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4-Supportive cells (mesangial cells)
lying between the capillaries.
Basement membrane-like mesangial
matrix forms a meshwork through
which the mesangial cells are
scattered.
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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.
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EM-GLOMERULUSCL-capillary lumen, End-endothelium, US-urinary space, B-basement
membrane, Ep-epithelial cell, Mes-mesangial cell, Fp-foot process.
Fp
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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).
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The selective permeability discriminatesamong protein molecules depending on:
1- theirsize (the larger the less permeable),
2- theircharge (the more cationic the morepermeable).
3-theirconfiguration.
Nephrin and its associated proteins, including
podocin, have a crucial role in maintaining theselective permeability of the glomerular filtrationbarrier.
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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.
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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
falciparummalaria), and spirochetal
(Treponema pallidum)infections.
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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 epithelialcells.
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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 andthe podocytes (subepithelial deposits).
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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.
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IF-Granula deposition of immune complexes .
characteristic of circulating and in situ immune complex
deposition
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immunofluorescence linear deposition of
immune complexes
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2-Nephritis Caused by In Situ
Immune Complexes
antibodies in this form of injury react
directly with fixed or planted antigens
in the glomerulus.
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Planted antigens include:
1- DNA.
2- bacterial products
3-large aggregated proteins (e.g., aggregatedIgG), which deposit in the mesangiumbecause of their size
4- immune complexes themselves because
they continue to have reactive sites forfurther interactions with free antibody, freeantigen, or complement.
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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 theGBM.
Deposition of these antibodies creates alinearpatternof staining when the boundantibodies are visualized with IF microscopy.
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IF- linear deposition of immune complexes ,
characteristic of classic anti-GBM antibody GN
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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).
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The Nephrotic Syndrome
The nephrotic syndrome refers to a clinicalcomplex that includes the following:
(1) massive proteinuria with daily protein loss inthe urine of 3.5 gm or more in adults.
(2) hypoalbuminemia with plasma albumin levelsless than 3 gm/dL.
(3) generalized edema
(4) hyperlipidemia and lipiduria. (5) little or no azotemia, hematuria, or
hypertension.
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Causes of Nephrotic Syndrome
A-primary glomerular diseases
Prevalence(%)
Adults
Prevalence )%(
Children
Cause
Primary Glomerular
Disease
305Membranous GN
1065Minimal-change disease
3510Focal segmentalglomerulosclerosis
1010Membranoproliferative GN
1510IgA nephropathy
B-Systemic Diseases with Renal
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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)
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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 podocytesby the EM.
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Pathogenesis
The pathogenesis of proteinuria is still not
clear.
Based on some experimental studies, the
proteinuria has been attributed to a T-cellderived 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.
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Morphology
LM
the glomeruli in minimal change diseaseappear normal.
The cells of the proximal convolutedtubules are often heavily laden with proteindroplets and lipids but this is secondary to
tubular reabsorption of the lipoproteinspassing through the diseased glomeruli(lipoid nephrosis).
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EM the GBM appears normal.
The only obvious glomerular abnormality is the uniformand 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 thenetwork of arcades between the podocytes and theGBM.
There are also epithelial cell vacuolization microvillusformation and occasional focal detachments.
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When the changes in the podocytes
reverse (e.g., in response to
corticosteroids) the proteinuria remits.
Minimal change
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g
disease.
A
Under the light
microscope thePAS-stained
glomerulus
appears normal,
with a delicatebasement
membrane
B
Schematic diagram
illustrating diffuseeffacement of foot
processes of
podocytes with no
immune deposits.
MCD EM
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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).
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Clinical Course
insidious development of the nephroticsyndrome in an otherwise healthychild.
There is no hypertension. renal function is preserved in most
individuals.
selective proteinuria (the protein loss isusually confined to albumin )
The prognosisis good.
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More than 90% of cases respond to a shortcourse of corticosteroid therapy.
proteinuria recurs in more than 2/3 of theinitial responders some of whom become
steroid dependent. < 5% develop chronic renal failure after 25
years and it is likely that most persons in thissubgroup had nephrotic syndrome causedby FSGS not detected by biopsy.
Adults with minimal change disease alsorespond to steroid therapy but the responseis slower and relapses are more common.
F l d S t l
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Focal and Segmental
Glomerulosclerosis
characterized histologically by
sclerosis affecting some but not all
glomeruli (focal involvement) and
involving only segments of eachaffected glomerulus.
This histologic picture is often
associated with the nephroticsyndrome.
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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).
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(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% ofall cases of the nephrotic syndrome) .
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FSGSMCD
+-hematuria
+-hypertension
nonselectiveselectiveproteinuria
poorgoodresponse to
corticosteroid
therapy
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At least 50% of individuals with FSGS
develop end-stage renal failure within
10 years of diagnosis.
Adults do worse than children.
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Pathogenesis
unknown .
injury to the podocytes is thought to represent theinitiating event of primary FSGS.
permeability-increasing factors produced by
lymphocytes. The deposition of hyaline masses in the glomeruli
represents the entrapment of plasma proteins andlipids in foci of injury where sclerosis develops.
IgM and complement proteins commonly seen in thelesion are also believed to result from nonspecificentrapment in damaged glomeruli.
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The recurrence of proteinuria after
renal allografts transplantation
sometimes within 24 hours of
transplantation supports the idea that acirculating mediator is the cause of the
damage to podocytes .
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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").
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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 tubularatrophy and interstitial fibrosis.
f l d t l l l l i (PAS t i )
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focal and segmental glomerulosclerosis (PAS stain).
a mass of scarred, obliterated capillary lumens with accumulations of
matrix material
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FSGS
blue collagen deposition (MT stain).
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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.
FSGS
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FSGS
effacemant of foot processes
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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.
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Clinical Course
Poor responses to corticosteroid
therapy.
about 50% of individuals suffer renal
failure after 10 years.
Membranous Glomerulonephritis ( MGN)
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Membranous Glomerulonephritis ( MGN)
It is slowly progressive disease.
most common between 30 -50 years of
age.
It is characterized morphologically by
the presence ofsubepithelial Ig-
containingdeposits along the GBM.
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Membranous glomerulonephritis :
1-Idiopathic (85% of cases).
2-2ry.
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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).
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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 .
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Morphology
LM
the basic change appears to be diffuse
thickening of the GBM .
LM- membranous glomerulonephritis in which the
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LM membranous glomerulonephritis in which the
capillary loops are thickened and prominent, but the
cellularity is not increased
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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 membranematerial between the immune deposits .
A silver stain of the glomerulus highlights the proteinaceous basement
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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.
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IF
diffuse granular deposits of
immunoglobulins and complement along
the GBM .
mainly IgG and complement.
MGN
IF d it f i l I G d l t ll t i th b t
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IF-deposits of mainly IgG and complement collect in the basement
membrane and appear in a diffuse granular pattern
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EM
subepithelial deposits thickening ofthe GBM and are separated from each
other by small, spikelike protrusions ofGBM matrix that form in reaction to thedeposits ("spike and dome" pattern).
As the disease progresses, these spikesclose over the deposits, incorporatingthem into the GBM.
EM-the darker electron dense immune deposits
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are seen scattered within the thickened
basement membrane .
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the podocytes showeffacement of footprocesses.
the incorporated deposits may be catabolizedand eventually disappear leaving cavities within
the GBM.
Continued deposition of basement membranematrix leads to progressively thicker basementmembranes.
With further progression the glomeruli canbecome sclerosed.
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Clinical Course
insidious development of the nephroticsyndrome, usually without antecedentillness.
some individuals with membranousnephropathy may have lesser degreesof proteinuria rather than the full-blownnephrotic syndrome.
the proteinuria is nonselective.
no response to corticosteroid therapy.
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Membranous nephropathy follows a variableand 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.
Membranoproliferative
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Membranoproliferative
Glomerulonephritis
MPGN is characterizedby alterations inthe GBM and mesangium and byproliferation of glomerular cells.
It accounts for 5% to 10% of cases ofidiopathic nephrotic syndrome inchildren and adults.
Some individuals present only withhematuria or proteinuria in the non-nephrotic range.
others have a combined nephrotic-nephritic picture.
P th i
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Pathogenesis
Types of MPGN:
1-type I is (about 80% of cases).
2-type II.
T I MPGN
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Type I MPGN circulating immune complexes similar
to chronic serum sickness but theinciting 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 persistentor episodic antigenemia.
Type II MPGN (dense-deposit
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Type II MPGN (dense deposit
disease)
The fundamental abnormality
appears to beexcessive
complement activationwhich may
be caused by several mechanisms
not involving antibodies.
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Some patients have an autoantibody against C3convertase called C3 nephritic factor, which isbelieved to stabilize the enzyme and lead touncontrolled cleavage of C3 and activation of thealternative complement pathway.
Mutations in the gene encoding the complementregulatory protein Factor Hhave been described insome patients.
These mutations may lead to a deficiency of plasma
Factor H or defective function of the protein, againresulting in excessive complement activation
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Functional impairment of Factor H may alsobe caused by autoantibodies orabnormalities in the C3 protein that preventits interaction with Factor H.
Hypocomplementemia is more marked intype II due to:
1- excessive consumption of C3
2- reduced synthesis of C3 by the liver.
It is still not clear how the complementabnormality induces the glomerular changes.
M h l
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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 asinfiltrating 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.
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The tram track appearance is caused by"splitting" of the GBM due to the
inclusion within it of processes of
mesangial and inflammatory cellsextending into the peripheral capillary
loops (MPGN II).
Membranoproliferative GN, showing mesangial cell proliferation,
basement membrane thickening leukocyte infiltration and accentuation
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basement membrane thickening, leukocyte infiltration, and accentuation
of lobular architecture.
Schematic representation of patterns in the two types of membranoproliferative GN.
In type I there are subendothelial deposits;
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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.
membranoproliferative
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p
glomerulonephritis (MPGN(
This silver stain demonstrates a double contour of the basement
( ) f
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membranes("tram-tracking" )that is characteristic of
(MPGN)(arrows).
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IF
C3 is deposited in an irregular granular
pattern.
IgG and early complement components
(C1q and C4) are often also present
(immune complex pathogenesis).
IF Granular deposition of immune complexes
h t i ti f i l ti d i it i
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characteristic of circulating and in situ immune
complex deposition
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Type I MPGNis characterized by discretesubendothelial electron-dense
deposits .
splitting" of the GBM (tram track) occurswhen the mesangial cell (which has a
macrophage-like function) goes after
subendothelial immune deposits.
EM-MPGN type I a mesangial cell at the lower left that is
interposing its cytoplasm at the arrow into the basement
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p g y p
membrane leading to splitting" of the GBM (tram track).
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In type II lesions the lamina densa and thesubendothelial space of the GBM aretransformed into an irregular, ribbon-like,extremely electron-dense structure, resultingfrom the deposition of material of unknowncomposition, giving rise to the term dense-deposit disease.
C3 is present in irregular chunky and segmentallinear foci in the basement membranes and in
the mesangium in characteristic circularaggregates (mesangial rings).
IgG ,C1q and C4 are usually absent.
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
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membrane that often coalesce to form a ribbon-like mass of
deposits )arrows)
Clinical Course
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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.
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Dense-deposit disease has a worseprognosis.
It tends to recur in renal transplant
recipients.
The Nephritic Syndrome
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The Nephritic Syndrome
characterized by: (1) hematuriawith dysmorphic red cells and
red blood cell casts in the urine.
(2) some degree ofoliguriaand azotemia. (3) hypertension.
Although there may also be some proteinuriaand even edema, these are usually not as
severe as in the nephrotic syndrome.
Pathogenesis
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Pathogenesis
proliferation of the cells within the glomeruliaccompanied 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 reninrelease from the ischemic kidneys.
Acute Postinfectious (Poststreptococcal)
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Glomerulonephritis
is typically caused by glomerulardeposition of immune complexes
resulting in diffuse proliferation and
swelling of resident glomerular cellsand frequent infiltration of leukocytes,
especially neutrophils.
The inciting antigen may be exogenousor endogenous.
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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
Poststreptococcal GN
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Poststreptococcal GN
It develops in a child 1-4 wks after theindividual 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 islocalized to the pharynx or skin.
Pathogenesis
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Pathogenesis
Ag-Ab complex deposition.
Typical features of immune complex
disease, such as hypocomplementemia
and granular deposits of IgG andcomplement on the GBM are seen.
The relevant antigens are probably
streptococcal proteins but their identityis not established.
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It is also not clear if immune complexesare formed in the circulation or in situ.
Studies indicate that C3 may be
deposited on the GBM before IgG ( theprimary injury might be by complement
activation).
Morphology
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Morphology
LM The most characteristic change in postinfectious GN is a
fairly uniformly increased cellularity of the glomerulartufts that affects nearly all glomeruli( "diffuse" ).
The increased cellularity is caused both by proliferationand swelling ofendothelial and mesangial cells and by aneutrophilic and monocytic infiltrate.
Sometimes there is necrosis of the capillary walls.
"crescents" within the urinary space in response to thesevere inflammatory injury.
Post-streptococcal glomerulonephritis.
This glomerulus is hypercellular and capillary loops
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This glomerulus is hypercellular and capillary loops
are poorly defined.
Post-streptococcal glomerulonephritis is due to increased
numbers of epithelial, endothelial, and mesangial cells as well as
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neutrophils in and around the capillary loops(arrows)
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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.
APGNimmune deposits are distributed in the capillary loops in a
granular, bumpy pattern because of the focal nature of the
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granular, bumpy pattern because of the focal nature of the
deposition process .
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EM shows deposited immune complexes
arrayed as subendothelial,
intramembranous, or, most often,subepithelial "humps" nestled against
the GBM.
Mesangial deposits are also occasionallypresent.
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
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The capillary lumen is filled with a PMN whose nuclear lobes (arrows)and
cytoplasmic granules are visibl(arrows).
EM-Typical electron-dense subepithelial "hump(arrow) and
intramembranous deposits
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intramembranous deposits.BM, basement membrane; CL, capillary lumen; E, endothelial cell; Ep, visceral epithelial cells (podocytes)
Clinical Course
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Clinical Course
abrupt onset . malaise, a slight fever, nausea, and the nephritic
syndrome.
oliguria, azotemia, and hypertension are only mild tomoderate.
gross hematuria.
Some proteinuria is a constant feature of the diseaseand it may occasionally be severe enough toproduce the nephrotic syndrome.
Serum complement levels are low during the activephase of the disease.
serum anti-streptolysin O antibody titers.
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Recovery occurs in most children in epidemic cases. Some children develop rapidly progressive GN due to
severe injury with crescents or chronic renal disease dueto secondary scarring.
The prognosis in sporadic cases is less clear.
In adults 15% to 50% of individuals develop end-stagerenal disease over the ensuing few years or 1 to 2decades.
in children the prevalence of chronicity after sporadic
cases of acute postinfectious GN is much lower.
IgA Nephropathy (Berger
Di )
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Disease)
is one of the most common causes ofrecurrentmicroscopic or grosshematuria
It usually affects children and youngadults.
begins as an episode of grosshematuria that occurs within 1 or 2
days of a nonspecific upper respiratorytract infection.
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the hematuria lasts several days andthen 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.
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Some have considered IgAnephropathy to be a localized variant of
Henoch-Schnlein purpura, also
characterized by IgA deposition in themesangium.
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Henoch-Schnlein purpura is asystemic syndrome involving the skin
(purpuric rash), gastrointestinal tract
(abdominal pain), joints (arthritis), andkidneys.
Pathogenesis
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Pathogenesis
1- It is associated with an abnormality in IgAproduction and clearance.
IgA is increased in 50% of patients with IgAnephropathy due to increased production in themarrow.
circulating IgA-containing immune complexesare present in some individuals.
A genetic influence is suggested by theoccurrence of this condition in families and in
HLA-identical siblings, and by the increasedfrequency of certain HLA and complementphenotypes in some populations
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2-abnormality in glycosylation of theIgA 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.
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4-increased IgA synthesis in responseto respiratory or gastrointestinal
exposure to environmental agents (e.g.,
viruses, bacteria, food proteins) maylead to deposition of IgA and IgA-Ag
complexes in the mesangium, where
they activate the alternative
complement pathway and initiate
glomerular injury.
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5-IgA nephropathy occurs withincreased frequency in individuals with
celiac disease and in liver disease
where there is defective hepatobiliaryclearance of IgA complexes (secondary
IgA nephropathy).
Morphology
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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.
The IgA is deposited mainly in mesangium, which then
increases mesangial cellularity (arrow)
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increases mesangial cellularity (arrow) .
mesangial matrix enlargement is conspicuous and predominates over a
relatively mild mesangial cell proliferation
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relatively mild mesangial cell proliferation.
Mesangial proliferation can be much more intense, global
and diff se
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and diffuse
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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.
IF demonstrates positivity with antibody to IgA.
the pattern is that of mesangial staining
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the pattern is that of mesangial staining.
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EM Electron-dense deposits in the
mesangium.
The deposits may extend to thesubendothelial area of adjacent capillary
walls in a minority of cases usually those
with focal proliferation.
small electrondense mesangial deposits are found even in
glomeruli with a normal appearance by LM
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glomeruli with a normal appearance by LM.
Mesangial involvement is variable, but often characterized by a sub-
membranous concentration of the electrondense deposits (x 4600)
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membranous concentration of theelectrondensedeposits.(x 4600)
Hereditary Nephritis
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y p
Hereditary nephritis refers to a group ofhereditary glomerular diseases caused
by mutations in GBM proteins.
Alport syndrome, in which nephritis isaccompanied by nerve deafness and
various eye disorders, including lens
dislocation, posterior cataracts, andcorneal dystrophy.
Pathogenesis
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g
The GBM is largely composed of type IVcollagen, which is made up of heterotrimers
of3, 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 thedisease manifestations of Alport syndrome.
Morphology
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p gy
Histologically, glomeruli in hereditarynephritis appear unremarkable until late inthe course when secondary sclerosis mayoccur.
Interstitial cells take on a foamyappearance as a result of accumulation ofneutral fats and mucopolysaccharides
(foam cells) as a reaction to markedproteinuria.
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With progression, there is increasingglomerulosclerosis, vascular sclerosis,
tubular atrophy, and interstitial fibrosis.
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
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membranes.
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EM the BM of glomeruli appears thin and
attenuated early in the course.
Late in the course, the GBM developsirregular foci of thickening or
attenuation with pronounced splitting
and lamination of the lamina densa,yielding a "basket-weave" appearance.
thin and attenuated BM in Alport
syndrome
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syndrome
The diagrams below illustrate normal BM(LT) vs the
thickened and 'falling apart' of Alport GBM(RT)
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g p p ( )
BM
Clinical Course
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X-linked as a result of mutation of thegene encoding 5 type IV collagen.
Males > females and are more likely to
develop renal failure. Rarely, inheritance is autosomalrecessive or dominant, linked todefects in the genes that encode 3 or
4 type IV collagen.
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presentation at age 5-20 yrs with grossor microscopic hematuria and
proteinuria.
overt renal failure occurs between 20-50 yrs of age.
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Female carriers of X-linked Alport syndromeor 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 (benignfamilial hematuria, or thin basement
membrane lesion).
Rapidly Progressive (Crescentic)
Glomerulonephritis
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Glomerulonephritis
RPGN is a clinical syndrome and not aspecific etiologic form of GN.
Clinically, it is characterized by rapidand progressive loss of renal functionwith features of the nephriticsyndrome.
With severe oliguria and if untreated
death from renal failure within weeks tomonths.
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The histologic picture is characterizedby the presence of crescents
(crescentic GN).
These are produced in part byproliferation of the parietal epithelial
cells of Bowman's capsule in response
to injury and in part by infiltration ofmonocytes and macrophages.
Pathogenesis
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Primary kidney or systemic disease. In most cases the glomerular injury is
immunologically mediated.
CrGN is divided into 3 groups on thebasis of immunologic findings.
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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 withrenal failure (Goodpasture).
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Anti-GBM antibodies are present in theserum and are helpful in diagnosis.
Plasmapheresis which removes
pathogenic antibodies from thecirculation is beneficial.
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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
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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 theyfill Bowman's space.
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The crescents eventually obliterateBowman's space and compress the
glomeruli.
Fibrin strands are prominent betweenthe cellular layers in the crescents.
Crescents may undergo
scarring(fibrous crescents).
Crescentic GN (PAS stain).
the collapsed glomerular tufts and the crescent-shaped mass of
proliferating cells and leukocytes internal to Bowman's capsule.
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p g y p
IF micrograph of a glomerulus CGN demonstrates
positivity with antibody to fibrinogen.
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IF strong linear staining of deposited IgG
and C3 along the GBM Type I (Anti-GBM
Antibody).
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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.
Immune Complex-Mediated (Type II)
Crescentic Glomerulonephritis
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p
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
Morphology
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LM There is severe injury with segmentalnecrosis and GBM breaks with resultantcrescent formation.
in contrast to type I CrGN (anti-GBM antibodydisease), segments of glomeruli withoutnecrosis show evidence of the underlyingimmune complex GN (e.g., diffuseproliferation and leukocyte exudation in
postinfectious GN or SLE, and mesangialproliferation in IgA nephropathy or Henoch-Schnlein purpura(.
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IF reveal the characteristic granular
("lumpy bumpy") pattern of staining of
the GBM and/or mesangium forimmunoglobulin and/or complement.
Pauci-Immune (Type III)
Crescentic Glomerulonephritis
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p
It is defined by the lack of anti-GBMantibodies or significant immune complexdeposition 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 orWegener granulomatosis.
When pauci-immune CrGN is limited to thekidney it is called idiopathic.
Morphology
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Glomeruli show segmental necrosis andGBM 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 depositsdetectable by electron microscopy.
Clinical Course
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The onset of RPGN is by nephriticsyndrome except that the oliguria and
azotemia are more pronounced.
Proteinuria sometimes approachingnephrotic range may occur.
Some of these persons become anuric
and require long-term dialysis ortransplantation.
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The prognosis can be roughly relatedto the number of crescents.
When No. of crescents in less than 80%
of the glomeruli have a betterprognosis than those with higher
percentages of crescents.
Chronic Glomerulonephritis
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It is an important cause of end-stage renal diseasepresenting as chronic renal failure.
Among all individuals who require chronic hemodialysisor renal transplantation, 30% to 50% have the diagnosisof chronic GN.
It probably represents the end stage of a variety ofentities:
1-CrGNs.
2-FSGS.
3-MGN.
4-IgA nephropathy. 5-MPGN.
6-Idiopathic( 20% of cases).
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Although chronic GN may develop atany age, it is usually first noted in
young and middle-aged adults.
Morphology
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Classically, the kidneys aresymmetrically 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).
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There is also marked interstitial fibrosis,associated with atrophy and dropout of manyof the tubules in the cortex, and diminutionand loss of portions of the peritubularcapillary network.
The small and medium-sized arteries arefrequently thick walled, with narrowedlumina, secondary to hypertension.
Lymphocytic and plasma cells are present in
the fibrotic interstitial tissue. The markedly damaged kidneys are
designated end-stage kidneys.
Chronic GN.A MT stain shows complete replacement of virtually all
glomeruli by blue-staining collagen.
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g y g g
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DISEASES AFFECTINGTUBULES AND
INTERSTITIUM
Tubulointerstitial Nephritis
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Causes : 1- bacterial infection.
2- drugs.
3- metabolic disorders such ashypokalemia.
4- physical injury such as irradiation.
5- viral infections. 6- immune reactions.
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TIN isdivided into : 1-acute
2-chronic
Acute Pyelonephritis
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Acute pyelonephritis, a commonsuppurative inflammation of the kidneyand the renal pelvis.
It is caused by bacterial infection.
It is an important manifestation of urinarytract infection (UTI) :
1- lower UT (cystitis, prostatitis, urethritis).
2- upper UT(pyelonephritis).
3- both.
Pathogenesis
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The principal causative organisms are : 1- Escherichia coliis the most common .
2- Proteus.
3- Klebsiella. 3- Enterobacter.
4- Pseudomonas.
5- Staphylococci and Streptococcus faecalis
(uncommon).
Routes of infection
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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 infectionfrom the lower urinary
tract is the most important and common
route by which the bacteria reach the kidney.
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bladder urine is sterile and remains soas a result of:
1- the antimicrobial properties of the
bladder mucosa. 2- the flushing action associated with
periodic voiding of urine.
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The first step is adhesion of bacteria tomucosal surfaces colonization of the
distal urethra bladder by expansive
growth of the colonies and by movingagainst the flow of urine.
Predisposing factors
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1-urethral instrumentation, includingcatheterization and cystoscopy
2-female sex because of the close
proximity of the urethra to the rectum 3-trauma to the urethra
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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 multiplicationwithout being flushed out or destroyed by the
bladder wall the bacteria ascend along the
ureters to infect the renal pelvis and
parenchyma.
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UTI is particularly frequent amongindividuals with:
- benign prostatic hyperplasia
- uterine prolapse. - neurogenic bladder dysfunction
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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 theincreased susceptibility to infection.
7-vesicoureteral reflux
An incompetent vesicoureteral orifice allows thereflux of bladder urine into the ureters &allowsbacteria to ascend the ureter into the pelvis. .
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The normal ureteral insertion into thebladder is a competent one-way valve that
prevents retrograde flow of urine,
especially during micturition when theintravesical pressure rises.
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VUR is present in 20% to 40% of youngchildren with UTI.
1- congenital defect that results in
incompetence of the ureterovesicalvalve.
2-acquired in spinal cord injury and
with neurogenic bladder dysfunctionsecondary to diabetes.
Acute
pyelonephritis.
Th ti l f
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The cortical surface
is studded withfocal pale
abscesses
Drug-Induced Interstitial
Nephritis
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Two forms of TIN caused by drugs are : 1-Acute Drug-Induced Interstitial
Nephritis
2-Analgesic Nephropathy
Acute TIN
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1-most frequently occurs with syntheticpenicillins (methicillin, ampicillin)
2- other synthetic antibiotics (rifampin),
diuretics (thiazides) 3- nonsteroidal anti-inflammatory
agents
4-other drugs (phenindione,cimetidine).
Pathogenesis
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Many features of the disease suggest animmune mechanism.
Clinical evidence of hypersensitivity is notdose related.
Serum IgE levels are increased in somepersons 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.
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the drugs act as haptens thatcovalently 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.
Morphology
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the interstitium shows pronounced edemaand 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-necrotizinggranulomas with giant cells may be seen.
The glomeruli are normal except in some
cases caused by nonsteroidal anti-inflammatory agents.
Clinical course
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The disease begins about 15 days (range 2-40 days) after exposure to the drug.
It is characterized by fever, eosinophilia&
rashin about 25% of persons, and renal
abnormalities.
Renal findings include hematuria, minimal or
no proteinuria, and leukocyturia (sometimes
including eosinophils).
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A rising serum creatinine or acute renalfailure with oliguria develops in about 50% of
cases, particularly in older patients.
It is important to recognize drug-induced
renal failure, because withdrawal of theoffending drug is followed by recovery
although it may take several months for renal
function to return to normal.
Analgesic Nephropathy
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Consumption large quantities of analgesics maycause chronic interstitial nephritisoften
associated withrenal papillary necrosis.
Although at times ingestion of single types of
analgesics has been incriminated, most peoplewho develop this nephropathy consume
mixtures containing some combination of
phenacetin, aspirin, acetaminophen, caffeine,
and codeine for long periods.
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Aspirin and acetaminophen While they can cause renal disease in
apparently healthy individuals
preexisting renal disease seems to be anecessary precursor to analgesic-
induced renal failure.
Pathogenesis
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The pathogenesis of the renal lesions isnot entirely clear.
Papillary necrosis is the initial event,and the interstitial nephritis in the overlying
renal parenchyma is a secondaryphenomenon.
Acetaminophen, a phenacetin metabolite,
injures cells by both covalent bindingand oxidative damage.
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The ability ofaspirin to inhibit prostaglandinsynthesis 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.
Morphology
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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 PAS-positive basement membrane thickening.
Clinical Course
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Chronic renal failure, hypertension, andanemia.
The anemia results in part from damage tored cells by phenacetin metabolites.
A complication of analgesic abuse isthe increased incidence oftransitional-cell carcinomaof the renal pelvis or
bladder in persons who survive therenal failure.
Acute Tubular Necrosis (ATN)
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ATN is a clinicopathologic entitycharacterized morphologically by damaged
tubular epithelial cells and clinically by acute
suppression of renal function.
It is the most common cause of acute renalfailure.
In acute renal failure, urine flow falls within
24 hours to less than 400 mL/day (oliguria).
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Other causes of acute renal failure include : (1) severe glomerular diseases manifestingas RPGN.
(2) diffuse renal vascular diseases such as
microscopic polyangiitis and thromboticmicroangiopathies.
(3) acute papillary necrosis associated withacute pyelonephritis.
(4) acute drug-induced interstitial nephritis. (5) diffuse cortical necrosis.
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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.
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nephrotoxic ATN poisons including heavy metals (e.g.,
mercury)
organic solvents (e.g., carbontetrachloride)
drugs such as gentamicin and other
antibiotics, and radiographic contrastagents.
Pathogenesis
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(1) tubular injury (2) persistent and severe disturbances in
blood flow resulting in diminished oxygenand substrate delivery to tubular cells.
Tubular epithelial cells are particularlysensitive to anoxia and are also vulnerableto toxins.
Ischemia causes numerous structuralalterations in epithelial cells
L f ll l it ibl l t
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Loss of cell polarityreversible early event.
Redistribution of membrane proteins (e.g., Na+, [Kgr ]+-ATPase) from the basolateral to the luminal surface oftubular cells
Decreased sodium reabsorption by proximal tubules and
hence increased sodium delivery to distal tubules. Vasoconstriction.
Redistribution or alteration of integrins that anchortubular cells to their underlying basement membranes
results in shedding of tubular cells into the urine.
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damage to the tubules and the resultant tubulardebris can block urine outflow and eventuallyincrease intratubular pressure decreasing GFR.
fluid from the damaged tubules could leak into
the interstitium resulting in increased interstitialpressure and collapse of the tubules.
Ischemic tubular cells also express chemokines,cytokines, and adhesion molecules such as P-
selectin that recruit and immobilize leukocytesthat can participate in tissue injury.
Benign Nephrosclerosis
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the term used for the renal changes inbenign hypertension
It is always associated with hyalinearteriolosclerosis.
Some degree of mild benign nephrosclerosisis present at autopsy in many persons olderthan 60 years of age.
The frequency and severity of the lesions are
increased at any age when hypertension ordiabetes mellitus are present.
Pathogenesis
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many renal diseases cause hypertensionwhich 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.
Morphology
the kidneys are symmetrically atrophic each
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the kidneys are symmetrically atrophic, eachweighing 110 to 130 gm, with a surface ofdiffuse, fine granularity that resembles grainleather.
the basic anatomic change is hyaline
thickening of the walls of the small arteriesand arterioles known as hyalinearteriolosclerosis.
This appears as a homogeneous, pinkhyaline thickening at the expense of thevessel lumina with loss of underlying cellulardetail .
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The narrowing of the lumen results inmarkedly decreased blood flow through
the affected vessels and thus produces
ischemia in the organ served
All structures of the kidney show
ischemic atrophy.
Benign nephrosclerosis.arterioles with hyaline deposition, marked thickening of the walls
and a narrowed lumen.
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In advanced cases of benignnephrosclerosis the glomerular tufts
may become globally sclerosed.
Diffuse tubular atrophy and interstitialfibrosis are present.
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The larger blood vessels (interlobar andarcuate arteries) show reduplication of
internal elastic lamina along with fibrous
thickening of the media and the subintima
(fibroelastic hyperplasia).
Clinical Course
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rarely causes severe damage to thekidney except in susceptiblepopulations, such as AfricanAmericans.
all persons with this lesion usuallyshow some functional impairment,such as loss of concentrating ability or
a variably diminished GFR. A mild degree of proteinuria.
Malignant Hypertension andMalignant Nephrosclerosis
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It accounts for only 5% of persons withelevated blood pressure.
It may arise de novo or it may appear
suddenly in a person who had mildhypertension.
In less developed countries it occurs
more commonly.
Pathogenesis
vascular damage to the kidneys
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vascular damage to the kidneys.
most commonly results from long-standingbenign hypertension with eventual injury tothe arteriolar walls.
The result is increased permeability of the
small vessels to fibrinogen and other plasmaproteins, endothelial injury, and plateletdeposition.
fibrinoid necrosis of arterioles and small
arteries and intravascular thrombosis.
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Mitogenic factors from platelets (e.g.,PDGF) and plasma cause intimal
smooth hyperplasia of vessels,
resulting in the hyperplastic
arteriolosclerosistypical of malignant
hypertension and of morphologically
similar thrombotic microangiopathies
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The kidneys become markedlyischemic.
Renin-angiotensin system isstimulated.
angiotensin II causes intrarenalvasoconstriction renal ischemia renin secretion.
Aldosterone levels are also elevated salt retention Bp.
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The consequences of the markedlyelevated blood pressure on the blood
vessels throughout the body are known
as malignant arteriolosclerosis, and the
renal disorder is referred to as
malignant nephrosclerosis.
Morphology
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The kidney is normal-slightly shrunken,depending on the duration and severity of
the hypertensive disease.
Small pinpoint petechial hemorrhagesmay appear on the cortical surface from
rupture of arterioles or glomerular
capillaries giving the kidney a peculiar,
flea-bitten appearance.
fibrinoid necrosis of the arterioles
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fibrinoid necrosis of the arterioles .
In the interlobular arteries and larger arterioles,proliferation of intimal cells produces an onion-skinappearance .
This lesion, called hyperplastic arteriolosclerosis,
causes marked narrowing of arterioles and small arteriesto the point of total obliteration.
Necrosis may also involve glomeruli withmicrothrombi within the glomeruli as well as necroticarterioles.
Malignant hypertension.
Fibrinoid necrosis of afferent arteriole (PAS stain).
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Malignant hypertensionHyperplastic arteriolosclerosis (onion-skin lesion).
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Clinical Course
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malignant hypertension ischaracterized by :
1-diastolic pressures > 120 mm Hg,
2-papilledema 3-encephalopathy
4-cardiovascular abnormalities
5-renal failure
Early symptoms are related to increased intracranial
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Early symptoms are related to increased intracranial
pressureand include headache, nausea, vomiting,and visual impairment, particularly the developmentof scotomas, or spots before the eyes.
At the onset of rapidly mounting blood pressure
there is marked proteinuria and microscopic ormacroscopic hematuria but no significant alterationin renal function.
The syndrome is a true medical emergency thatrequires prompt and aggressive antihypertensive
therapy before irreversible renal lesions develop.
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About 50% of patients survive at least 5years.
90% of deaths are caused by uremia.
10% by cerebral hemorrhage or cardiacfailure.
CYSTIC DISEASES OF THEKIDNEY
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1-Simple Cysts 2-Autosomal Dominant (Adult)
Polycystic Kidney Disease
3-Autosomal Recessive(Childhood) Polycystic Kidney
Disease
4-Medullary Cystic Disease
1-Simple Cysts
Multiple or single cystic spaces that vary widely in
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p g y p y y
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 arediscovered either incidentally or because ofhemorrhage and pain.
Simple renal Cysts
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Dialysis-associated acquired cystsoccur inthe kidneys of patients with end-stage renal
disease who have undergone prolonged
dialysis.
They are present in both cortex and medullaand may bleed causing hematuria.
renal adenomas or even adenocarcinomas
arise in the walls of these cysts.
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
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2-Autosomal Dominant (Adult) PolycysticKidney Disease
Characterized by multiple expanding cysts of
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y p p g yboth kidneys that ultimately destroy theintervening parenchyma.
It is seen in approximately 1: 500-1000persons
Accounts for 10% of cases of chronic renalfailure.
It can be caused by inheritance of one of at
least 2 autosomal dominant genes of veryhigh penetrance.
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1-In 85-90% of families, PKD1, thedefective gene is on the short arm of
chromosome 16.
This gene encodes a large and complexcell membrane-associated protein
called polycystin-1.
2-The PKD2gene (10-15% of cases) on
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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 althoughpatients with PKD2mutations have a slower
rate of disease progression as comparedwith patients with PKD1mutations.
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Clinical presentation
asymptomaticuntil the 4th decadeby which time the
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kidneys are quite large although small cysts start todevelop in adolescence.
The most common presenting complaint is flankpainor a heavy dragging sensation.
Acute distention of a cyst either by intracystichemorrhage or by obstruction may causeexcruciating pain.
palpation of an abdominal mass.
Intermittent gross hematuriacommonly occurs.
hemorrhage.
Complications
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1-hypertension (75% ). 2-urinary infection.
3-Saccular aneurysms of the circle of
Willis are present in 10% to 30% ofpatients (subarachnoid hemorrhage ).
4-end-stage renal failure occurs at
about age 50 .
3-Autosomal Recessive (Childhood)Polycystic Kidney Disease
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autosomal recessive inheritance. It occurs in approximately 1:20,000 live
births.
Perinatal, neonatal, infantile, andjuvenile subcategories have been
defined, depending on time of
presentation and the presence of
associated hepatic lesions.
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Mutations in a gene PKHD1coding fora 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
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Cysts are fairly small but uniformly distributed throughout theparenchyma so that the disease is usually symmetrical in appearance
with both kidneys markedly enlarged.
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4-Medullary Cystic Disease
There are 2 major types of medullary
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j yp ycystic disease:
1-medullary sponge kidney
a relatively common and usually
innocuous condition.
2-nephronophthisis-medullary cysticdisease complex
is almost always associated with renaldysfunction.
Nephronophthisis-medullarycystic disease
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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.
The juvenile form is the most common.
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Approximately 15-20% of individuals withjuvenile nephronophthisis have extra-renalmanifestations:
1- retinal abnormalities, including retinitis
pigmentosa. 2- oculomotor apraxia.
3- mental retardation.
4- cerebellar malformations.
5- liver fibrosis.
The initial manifestations are usually polyuria and
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polydipsia a consequence of diminished tubularfunction.
Progression to end-stage renal disease ensues overa 5-10-year period.
The disease is difficult to diagnose, since there are
no serologic markers and the cysts may be too smallto be seen with radiologic imaging.
cysts may not be apparent on renal biopsy if thecortico-medullary junction is not well sampled.
A positive family history and unexplained chronic
renal failure in young patients should lead tosuspicion of medullary cystic disease.
URINARY OUTFLOWOBSTRUCTION
Renal Stones Urolithiasis
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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
Pathogenesis
R l d f
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Renal stones are composed of: 1-calcium oxalate or calcium oxalate
mixed with calcium phosphate(80%) .
2-10% are composed ofmagnesiumammonium phosphate.
3-6%-9% are eitheruric acid orcystine
stones.
I ll th i i t i
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In all cases there is an organic matrixof mucoprotein that makes up about
2.5% of the stone by weight.
Causes
1 i d i t ti f th
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1-increased urine concentration of thestone's constituents so that it exceeds
their solubility in urine
(supersaturation).
50% of patients who develop calcium
stoneshave hypercalciuria that is not
associated with hypercalcemia.
H l i i
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Hypercalciuria: A. absorptive hypercalciuria.
B. renal hypercalciuria due to primary
renal defect of calcium reabsorption.
I 5% t 10% f th i
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In 5% to 10% of persons there ishypercalcemia and consequent
hypercalciuria.
2 Th f id
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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 i H
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3-urine pH High urine pH favors crystallization of
calcium phosphate and stone
formation.
Magnesium ammonium phosphate
(struvite) stonesalmost always occur
with a persistently alkaline urine due to
UTIs.
U i id t f d i idi i
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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 i f ti
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4-infections The urea-splitting bacteria such as
Proteus vulgarisand the staphylococci
predispose the person to urolithiasis.
5-lack of substances that normally inhibit
i l i it ti
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mineral precipitation.
Inhibitors of crystal formation in urineinclude Tamm-Horsfall protein, osteopontin,pyrophosphate, mucopolysaccharides,diphosphonates, and a glycoprotein callednephrocalcin
No deficiency of any of these substances hasbeen consistently demonstrated inindividuals with urolithiasis.
Stones are unilateral in about 80% of
patients
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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 knownas staghorn calculi.
These massive stones are usually composedof magnesium ammonium phosphate.
Hydronephrosis
R f t dil ti f th l l i
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Refers to dilation of the renal pelvisand 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.
The most common causes are as follows:
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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
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Foreign bodies: Calculi, necrotic apillae Tumors: Benign prostatic hyperplasia,
carcinoma of the prostate,
bladder tumors (papilloma and carcinoma),
contiguous malignant disease (retroperitoneallymphoma, 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.
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