RENAL PATHOLOGY           

                    
                    
                   

Greg Balko, MD
May 27, 2009
SET 1
SET 1
 Nephrotic Syndrome

– Proteinuria > 3.5 gm/day, due to excessive permeability of

glomerular capillary wall.
– Leads to hypoalbuminemia, decreased colloid oncotic pressure
and edema.
– Accompanied by sodium and water retention, hyperlipidemia,
vulnerability to infection and thrombotic complications.
– Causes of the nephrotic syndrome:
• Amyloidosis.
• diabetic glomerular disease.
• foot process disease.
• minimal change glomerulopathy.
• focal-segmental glomerulosclerosis.
• membranous glomerulopathy.
• membranoproliferative glomerulonephritis*.
 Nephritic Syndrome (Nephritis)
• Features:
– Acute inflammation of glomeruli.
– Hematuria (including red cell casts).
– Mild to moderate proteinuria.
– Oliguria, hypertension and mild edema.
• Many causes including:
– Post-streptococcal glomerulonephritis.
– RPGN syndromes.
– Membranoproliferative glomerulonephritis.*
– Bacterial endocarditis.
– Lupus.
– Cryoglobulinemia.
– Wegener's granulomatosis.
– Polyarteritis.
– IgA nephropathy.
 Acute Diffuse Proliferative
Glomerulonephritis
• Acute post-streptococcal
glomerulonephritis is the most
common cause of this reaction
pattern.
• This produces the nephritic
syndrome (hematuria, red cell
casts, moderate proteinuria and
edema) in children two weeks
following a respiratory or skin
infection with a "nephritogenic
strain" of group A, beta-hemolytic
streptococci.
• The cause is deposition of
circulating immune complexes
which fix complement and attract
PMN's.
 Acute Diffuse
Proliferative
Glomerulonephritis

• There is swelling and

proliferation of glomerular
endothelial cells.
• This chokes off their blood
supply, making the
glomeruli hypercellular and
bloodless.
• This explains the oliguria,
edema, and hypertension.
• Deposits of circulating
immune complexes fix
complement and attract
neutrophils.
 Acute Diffuse
Proliferative
Glomerulonephritis

• Immunofluorescence: coarse
granular deposits containing
immunoglobulin and
complement.
• Electron microscopy:
granules are large, dense,
hump-shaped deposits
located subepithelially (i.e.,
on the epithelial side of the
GBM).
 Acute Diffuse Proliferative
Glomerulonephritis: Post-streptococcal GN

• Children: 95% recover.

• Adults:
– epidemic form: good prognosis.
– sporadic form: 40% develop rapidly
progressive disease, chronic renal failure.
 Minimal Change Disease (Lipoid
Nephrosis)
• This is a relatively benign disorder.
• The most frequent cause of nephrotic
syndrome in children.
• It is characterized by diffuse
effacement of foot processes of
epithelial cells in glomeruli that appear
virtually normal by light microscopy.
• The peak incidence is between 2 and 6
years of age.
• The disease sometimes follows a
respiratory infection or routine
prophylactic immunization.
• Its most characteristic feature is its
usually dramatic response to
corticosteroid therapy.
 Minimal Change
Disease (Lipoid
Nephrosis)
• The glomeruli are normal by
light microscopy.
• EM: visceral epithelial cells,
show a uniform and diffuse
effacement of foot processes,
these being replaced by a rim
of cytoplasm often showing
vacuolization, swelling, and
hyperplasia of villi.
• This change, often incorrectly
termed "fusion" of foot
processes, actually represents
simplification of the epithelial
cell architecture with
flattening, retraction, and
swelling of foot processes.
 Minimal Change
Disease (Lipoid
Nephrosis)
• The visceral epithelial changes
are completely reversible after
corticosteroid therapy,
concomitant with remission of
the proteinuria.
• The cells of the proximal
tubules are often laden with
lipid and protein, reflecting
tubular reabsorption of
lipoproteins passing through
diseased glomeruli (thus, the
historical term lipoid
nephrosis).
• Immunofluorescence studies
show no immunoglobulin or
complement deposits.
 RPGN Type I:
Goodpasture’s
Syndrome
• Example of type I RPGN; anti-GBM
antibody-induced disease.
• Cells accumulate in Bowman’s space,
form crescents.
• The Goodpasture antigen is a peptide
within the noncollagenous portion of
the α3-chain of collagen type IV.
• What triggers the formation of these
antibodies is unclear in most
patients.
• There is linear deposition of
antibodies and complement
components along the GBM.
• Nephritic syndrome:
– hematuria.
– red cell casts, moderate
proteinuria.
– hypertension and edema.
– recurrent hemoptysis.
 RPGN Type I:
Goodpasture’s
Syndrome
• The kidneys are enlarged and
pale, often with petechial
hemorrhages on the cortical
surfaces.
• The histologic picture is
dominated by the formation of
distinctive crescents.
• Crescents are formed by
proliferation of parietal cells
and by migration of
monocytes and macrophages
into the urinary space.
• The crescents eventually
obliterate Bowman space and
compress the glomerular tuft.
 RPGN Type I: Goodpasture’s Syndrome

• The anti-GBM antibodies

cross-react with pulmonary
alveolar basement
membranes to produce the
clinical picture of
pulmonary hemorrhage
associated with renal
failure.
 RPGN Type I:
Goodpasture’s
Syndrome
• Electron microscopy: distinct
breaks in the GBM, allowing
leukocytes, proteins, and
inflammatory mediators into
the urinary space, where they
trigger the crescent
formation.
• By immunofluorescence
microscopy, Goodpasture’s
syndrome cases show linear
fluorescence for
immunoglobulin and
complement.
 Rapidly Progressive
Glomerulonephritis
• All three types of RPGN may
be associated with a well-
defined renal or extrarenal
disease, but in many cases
(approximately 50%), the
disorder is idiopathic.
• Of the patients with this
syndrome, about one fifth
have anti-GBM antibody-
induced disease without lung
involvement; another one
fourth have immune
complex-mediated disease
RPGN; and the remainder are
of the pauci-immune type.
• The common denominator in
all types of RPGN is severe
glomerular injury.
 Membranous
Nephropathy
• The most common cause of the
nephrotic syndrome in adults.
• In about 85% of patients, no
associated condition can be
identified (idiopathic).
• Other cases occur secondary to
systemic diseases:
– Drugs (penicillamine, captopril,
gold, NSAIDs).
– Underlying malignant tumors,
particularly carcinoma of the
lung and colon and melanoma.
– SLE.
– Infections (chronic hepatitis B,
hepatitis C, syphilis,
schistosomiasis, malaria).
– Other autoimmune disorders,
such as thyroiditis.
 Membranous
Nephropathy
• Microscopic: uniform, diffuse
thickening of the glomerular
capillary wall.
• Basement membrane material
is laid down between these
deposits, appearing as
irregular spikes protruding
from the GBM.
• These spikes are best seen by
silver stains, which color the
basement membrane black.
Membranous
Nephropathy

• Electron microscopy:
irregular dense deposits
between the basement
membrane and the
overlying epithelial cells.
 Membranous Nephropathy

• Immunofluorescence
microscopy: granular
deposits contain both
immunoglobulins and various
amounts of complement .
• The course of the disease is
variable but generally
indolent.
• Although proteinuria persists
in more than 60% of patients,
only about 10% die or
progress to renal failure
within 10 years, and no more
than 40% eventually develop
renal insufficiency.
SET 2
SET 2
Hypertensive Vascular Disease
 Hypertensive Vascular Disease

• Benign hypertension (diastolic

> 90 mm Hg): leads to chronic
damage.
• Malignant hypertension
(diastolic > 130 mm Hg):
vascular necrosis &
hemorrhage w/ acute cardiac
& renal failure.
• Distinction not clear cut in
some cases.
 Benign Nephrosclerosis
• Increased flow of protein into
vessel walls.
• Due to sustained, prolonged
hypertension.
• Hyaline arteriolarsclerosis*:
– small arteries & arterioles:
thickened, scarred
– reduplication of the internal
elastic lamina.
– accumulation of plasma
proteins near the BM.
• Eventual insufficiency and failure
if hypertension becomes
moderate, or if superimposed
upon an underlying disease
(diabetes).
• Blacks more susceptible.
Benign Nephrosclerosis: Hyaline
Arteriolarsclerosis
 Malignant Nephrosclerosis
• Malignant hypertension
(diastolic > 130 mm Hg).
• Rapidly progressive, accelerated
nephrosclerosis.
• Affects the heart, brain, kidneys:
– papilledema.
– encephalopathy.
– cardiovascular.
abnormalities
– renal failure.
• Microvascular changes:
– fibrinoid necrosis.
– smooth muscle proliferation.
Malignant Nephrosclerosis
Malignant Nephrosclerosis
 Diabetic Nephropathy

• The kidneys are prime

targets of diabetes.
• Renal failure is second only
to myocardial infarction as
a cause of death from this
disease.
• Three lesions are
encountered:
– glomerular lesions.
– renal vascular lesions,
mainly
arteriolosclerosis.
– pyelonephritis,
including necrotizing
papillitis.
 Diabetic Nephropathy

• The most important

glomerular lesions:
– capillary basement
membrane thickening.
– diffuse mesangial
sclerosis.
– nodular
glomerulosclerosis.
• The glomerular capillary
basement membranes are
thickened throughout their
entire length.
 Diabetic Nephropathy

• Diffuse mesangial
sclerosis: diffuse increase
in mesangial matrix and is
always associated with
basement membrane
thickening.
• It is found in most patients
with disease of more than
10 years' duration.
• When glomerulosclerosis
becomes marked, patients
manifest the nephrotic
syndrome.
 Diabetic Nephropathy
• Nodular glomerulosclerosis:
Kimmelstiel-Wilson lesion -
ball-like deposits of a
laminated matrix situated in
the periphery of the
glomerulus.
• Contain trapped mesangial
cells.
• Seen in 15% to 30% of long-
term diabetics.
• Nodular form is
pathognomonic of diabetes.
• Diffuse mesangial sclerosis
may also be seen in
association with old age and
hypertension.
 Diabetic Nephropathy

• Both the diffuse and

nodular forms of
glomerulosclerosis induce
sufficient ischemia to
cause overall fine scarring
of the kidneys, marked by a
finely granular cortical
surface.
 Diabetic Nephropathy

• Renal atherosclerosis and

arteriolosclerosis
constitute part of the
macrovascular disease in
diabetics.
• The changes in the arteries
and arterioles are similar
to those found throughout
the body.
• Hyaline arteriolosclerosis
affects both the afferent
and efferent arteriole.
• Efferent arteriolosclerosis
is rarely, if ever,
encountered in individuals
who do not have diabetes.
 Diabetic Nephropathy

• Both acute and chronic

pyelonephritis occur in in
diabetics.
• They are more common in
diabetics than in the general
population, and, once
affected, diabetics tend to
have more severe
involvement.
• One special pattern of acute
pyelonephritis, necrotizing
papillitis (or papillary
necrosis), is much more
prevalent in diabetics than in
nondiabetics.
Systemic Lupus
Erythematosus
 Systemic Lupus Erythematosus
• The kidney is a frequent target
of injury in SLE.
• The principal mechanism of
injury is immune complex
deposition in renal structures,
including glomeruli, tubular
and peritubular capillary
basement membranes, and
larger blood vessels.
• Other forms of injury may
include a thrombotic process
involving the glomerular
capillaries and
extraglomerular vasculature,
thought to be caused by
antiphospholipid antibodies.
 Systemic Lupus Erythematosus

• Antinuclear antibody, an
antibody to nucleosomal DNA-
histone complexes, is very
sensitive but not specific.
• Anti-ds (double stranded) DNA is
more specific for lupus. This test
may correlate with the degree of
activity of lupus, in general,and
with the level of nephritis.
• Antiphospholipid antibody is
present in 30% of patients with
SLE. This is associated with
thromboembolic complications.
 Systemic Lupus Erythematosus

• World Health Organization (WHO) classification of lupus

nephritis:
– minimal or no detectable abnormalities (class I), rare,
seen in renal biopsies from less than 5% of SLE
patients.
– mesangial lupus glomerulonephritis (class II).
– focal proliferative glomerulonephritis (class III).
– diffuse proliferative glomerulonephritis (class IV).
– membranous glomerulonephritis (class V).
• None of these patterns is specific for lupus.
Set 3
Set 3
 Acute Tubular Necrosis

• Acute renal failure associated

with dysfunction and necrosis
of tubular epithelial cells.
• Classification:
– ischemic: shock, sepsis,
burns, transfusion, other.
– toxic: drugs, metals,
poisons, solvents, other.
• Pathology: variable, focal to
extensive epithelial necrosis.
• Pathogenesis:
– vasoconstriction,
obstruction, tubular
leakage of filtrate. Ischemic ATN: characterized
by swollen kidneys with a pale
cortex and congested
medulla.
 Acute Tubular Necrosis

• Pathogenesis: sloughing and necrosis of epithelial cells results in cast formation. The
presence of casts leads to obstruction and increased intraluminal pressure, which
reduces glomerular filtration. Afferent arteriolar vasoconstriction, caused in part by
tubuloglomerular feedback, results in decreased glomerular capillary filtration
pressure. Tubular injury and increased intraluminal pressure cause fluid backleak
from the lumen into the interstitium.
 Acute Tubular
Necrosis
• Microscopic: some tubular
cells are necrotic whereas
others are flattened, stretched
out and regenerating.
• Distal convoluted tubules and
collecting ducts contain
hyaline casts.
•
Acute Tubular
Patterns of damage:
– Ischemic: Necrosis
• necrosis is patchy.
• relatively short lengths of
tubules are affected.
• straight segments of the
proximal tubules and
ascending limbs of
Henle’s loop are most
vulnerable.
– Toxic:
• necrosis of proximal
tubule segments with
many toxins.
• necrosis of distal tubule
may also occur.
• In both types, the lumens of the
distal convoluted tubules and
collecting ducts contain casts.
 Acute Drug-Induced Interstitial
Nephritis
• A well-recognized adverse reaction to a constantly
increasing number of drugs.
• Most frequently occurs with synthetic penicillins
(methicillin, ampicillin), other synthetic antibiotics
(rifampin), diuretics (thiazides), NSAIDs, and miscellaneous
drugs (allopurinol, cimetidine).
• Begins about 15 days after exposure and is characterized
by fever, eosinophilia, and rash in about 25% of patients,
and renal abnormalities (hematuria, mild proteinuria, and
leukocyturia often including eosinophils).
• A rising serum creatinine level or acute renal failure with
oliguria develops in about 50% of cases, particularly in
older patients.
 Acute Drug-Induced Interstitial
Nephritis

• Interstitium is affected:
edema and infiltration by
mononuclear cells,
principally lymphocytes and
macrophages.
• Eosinophils and neutrophils
may be present.
• With some drugs (e.g.,
methicillin, thiazides),
interstitial granulomas with
giant cells may be seen.
 Acute Drug-Induced Interstitial
Nephritis

• Interstitium is affected:
edema and infiltration by
mononuclear cells,
principally lymphocytes and
macrophages.
• Eosinophils and neutrophils
may be present.
• With some drugs (e.g.,
methicillin, thiazides),
interstitial granulomas with
giant cells may be seen.
 Acute Drug-Induced Interstitial
Nephritis

• "Tubulitis," the infiltration

of tubules by lymphocytes,
is common.
• Variable degrees of tubular
necrosis and regeneration
are present.
• The glomeruli are normal
except in some cases
caused by NSAIDs, when
minimal change disease
and the nephrotic
syndrome develop
concurrently.
 Acute
Pyelonephritis
• Causes:
– ascending infection -
vesicoureteral reflux into
the renal pelvis and
papillae; E. coli, Proteus,
Enterobacter.
– hematogenous seeding -
due to septicemia or
endocarditis;
Staphlococcus and E.
coli.
• Patchy process, pinpoint
microabscesses on cortical
surface.
 Acute
Pyelonephritis
• Common in patients with:
– incompetent ureteral
valves.
– diabetes.
– immunocompromise.
• Patchy suppurative
inflammation, tubular
necrosis, neutrophilic casts.
• Abscesses and papillitis
more common in diabetics.
• Flank pain, fever, dysuria,
pyuria and bacteriuria.
 Chronic Pyelonephritis
• Chronic tubulointerstitial inflammation with renal scarring.
• Important cause of end-stage renal disease.
• Two forms:
– reflux-associated: common, congenital vesicourtehral reflux or
intrarenal reflux.
– obstructive: posterior urethral valves, ureteral calculi or abnormalities.
 Chronic
Pyelonephritis
• Characteristic morphologic
features are seen on gross
examination:
– irregular scarring.
– coarse, discrete,
corticomedullary scar
overlying a dilated,
blunted, or deformed
calyx.
– most in upper and lower
poles consistent with
the frequency of reflux
in these sites.
 Chronic
Pyelonephritis
• Microscopic:
– changes involve
predominantly tubules and
interstitium.
– tubules show atrophy in
some areas and
hypertrophy in others.
– thyroidization: dilated
tubules may be filled with
colloid casts.
– varying degrees of chronic
inflammation and fibrosis.
– a variety of glomerular
changes may be present.
• Clinical: recurrent infections,
tubular dysfunction,
hypertension, chronic renal
failure.
SET 4
SET 4
 Renal Cell Carcinoma

• 85% of renal cancers in adults.

• M>F; 50-60’s.
• VHL gene implicated in
carcinogenesis of both familial
and sporadic tumors.
• Spherical, yellow-gray-white
mass with necrosis and
hemorrhage.
• Invasion of renal vein is
common.
• Prognosis depends on size and
extent of spread.
• 25% show metastasis at time of
diagnosis.
 Renal Cell Carcinoma

• Clear cell variant (70-80%):

– solid sheets, cords and tubules.
– round to polygonal cells with
clear to granular cytoplasm.
– They can be familial, associated
with VHL disease, or in most
cases (95%) sporadic.
– In 98% of these tumors, whether
familial, sporadic, or associated
with VHL, there is loss of
sequences on the short arm of
chromosome 3.
• Papillary carcinoma accounts for
10% to 15%.
 Renal Cell Carcinoma

• Classic triad: hematuria, costovertebral pain, palpable

mass.
• May produce systemic symptoms:
– polycythemia.
– hypercalcemia.
– hypertension.
– hepatic dysfunction.
– feminization, masculinization.
– Cushing’s syndrome.
– eosinophilia, amyloidosis.
 Wilms Tumor
• The most common primary
renal tumor of childhood and
the fourth most common
pediatric malignancy in the
United States.
• Usually diagnosed between
ages 2 and 5 years.
• ~ 5% to 10% involve both
kidneys, either simultaneously
(synchronous) or one after the
other (metachronous).
• Large, solitary, well-
circumscribed mass that is soft,
homogeneous, and tan to gray
with occasional foci of
hemorrhage, cyst formation,
and necrosis.
 Wilms Tumor
• Tumor risk is increased in association with three recognizable
groups of congenital malformations associated with distinct
chromosomal loci.
– WAGR syndrome:
• aniridia, genital anomalies, and mental retardation
• 33% chance of developing Wilms tumor.
• deletions of 11p13, tumor-associated gene, WT1.
– Denys-Drash syndrome:
• gonadal dysgenesis (male pseudohermaphroditism) and early-
onset renal failure.
• patients are at a much higher risk for Wilms tumor (>90%)
• missense mutation of WT1 gene located at chromosome 11p13.
– Beckwith-Wiedemann syndrome:
• characterized by enlargement of body organs (organomegaly),
macroglossia, hemihypertrophy, omphalocele, and abnormal large
cells in adrenal cortex (adrenal cytomegaly).
• The genetic locus that is involved in these patients is in
chromosome 11 distal to the WT1 locus.
 Wilms Tumor

• Triphasic appearance:
– Blastemic component:
tightly packed blue cells.
– Stromal component:
fibrocytic or "spindle-
shaped" cells.
– Epithelial component:
abortive tubules.
• Good prognosis; excellent
results are obtained with a
combination of nephrectomy
and chemotherapy in most
cases.
• Survival for 2 years usually
implies a cure.
Multiple Myeloma
• Plasmacytoma: a
tumor composed of
mature and
immature plasma
cells.
• Occurs in older
patients .
• Lytic bone lesions.
• Circulating and
urinary monoclonal
immunoglobulins.
• Grave prognosis.
 Multiple Myeloma

• Nonrenal malignant tumors,

like multiple myeloma, affect
the kidneys in a number of
ways.
• The most common target is
the tubulointerstitum.
• Overt renal insufficiency
occurs in half the patients
with this disease.
• Factors contributing to renal damage:
– Bence Jones proteinuria and cast
nephropathy. Bence Jones (light- Multiple
chain) proteins are directly toxic to
epithelial cells and combine with the
Myeloma
urinary glycoprotein (Tamm-Horsfall
protein) under acidic conditions to
form large tubular casts that
obstruct the tubular lumina and also
induce a characteristic inflammatory
reaction around the casts (cast
nephropathy).
– Amyloidosis: accumulations of light
chains with predisposition to form
amyloid fibrils.
– Light-chain deposition disease.
Light chains deposit in the GBM and
mesangium causing glomerulopathy
or in tubular basement membranes,
which may cause tubulointerstitial
nephritis.
• Hypercalcemia and hyperuricemia are
often present in these patients.
 Multiple Myeloma

• Tubulointerstitial changes:
– Bence Jones tubular casts
appear as pink amorphous
masses, sometimes
concentrically laminated,
often with a fractured
appearance, filling and
distending the tubular
lumens
– Some of the casts are
surrounded by multinucleate
giant cells that are derived
from mononuclear
phagocytes.
– The adjacent interstitial
tissue usually shows a
nonspecific inflammatory
response and fibrosis.