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8/23/2019 All Slides Drmaha

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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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y y g


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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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