The Kidney

Diseases based on 4 basic anatomic

compartments:
Glomeruli
Tubules
Interstitium
Blood vessels

All forms of CRD destroy all FOUR elements End

stage Renal Disease (ESRD)

Clinical Manifestations of Renal

Diseases:

 Azotemia: of BUN & creatinine due to GFR

Prerenal: Due to renal hypoperfusion
Postrenal: Due to outflow obstruction
Uremia: Clinical s/sxs associated w/ azotemia
Nephritic syndrome: hematuria, proteinuria,

HPN due to glomerular injury

Nephrotic syndrome: >3.5g/day proteinuria,

hypoalbuminemia, edema, hyperlipidemia,

lipiduria due to glomerular injury

Clinical Manifestations of Renal Diseases:

RPGN:
nephritic syndrome w/ rapid decline in GFR
Asymptomatic hematuria/proteinuria:
Mild glomerular injury
Renal tubular defects:
d/o in tubules &/or interstitium manifest w/ polyuria &
electrolyte abnormalities
UTI:
Pyelonephritis or Cystitis
Nephrolithiasis:
Calculi in urinary spaces, associated with renal colic &
hematuria

Renal Failure:
Acute Renal Failure:
New-onset

oliguria or anuria w/ azotemia

Result from injury to any renal anatomic
compartment
Chronic renal Failure:
Prolonged

uremia
End stage of all chronic renal diseases

Renal Failure:
FOUR Stages:
Based on GFR and clinical manifestation:
1)
Diminished renal reserve:

Up to 50% of normal GFR; asymptomatic w/ normal

BUN/Creatinine levels

Renal insufficiency:

2)

20% to 50% of normal GFR; azotemia often w/ anemia &

hypertension
Polyuria due to decreased concentrating ability

3)

Chronic renal failure:

4)

Less than 20% of normal GFR

Edema, metabolic acidosis, Hyperkalemia
Often w/ overt uremia

End-stage renal disease:

Less than 5% of normal GFR

Glomerular Diseases

 Primary GN:
Kidney as principal organ involved

Secondary GN:
Kidney damaged by a systemic disease

Manifestations & glomerular histologic changes

are similar b/w primary & secondary GN

Pathogenesis of Glomerular Injury:

Immune mechanisms underlie MOST forms of

Glomerular injury
Immunoglobulin deposition, directly or Ag-Ab

complexes along w/ activated complement &/or

recruited inflammatory cells

 Immune complex deposition involving

intrinsic & in situ renal antigens

Intrinsic

matrix or cellular (endothelial, mesangial,

or epithelial) Ags or w/ circulating Ags trapped in
the glomerulus

a) Heymann nephritis:

Experimental rat model of GN

Involves immunization w/ renal tubular proteins
Antibodies to Megalin protein Ag on visceral epith
cells
Results in complement activation & shedding of
immune complexes Subepithelial deposits
Granular pattern of IF staining
Closely follow Membranous GN in humans

b) Abs against planted Ags:

Circulating molecules localize to the kidney

Affinity for GBM where they become trapped

Abs induce a discrete, granular pattern of Ig &

complement IF staining

c) Anti-GBM Ab-induced GN:

Autoimmune disease in w/c antibodies are directed

against intrinsic fixed Ags of the GBM
Goodpasture syndrome: Abs against
noncollagenous domain of 3 chain of Type IV
collagen
Linear IF staining pattern

 Circulating Immune Complex GN:

Injury caused by trapping of circulating Ag-Ab complexes w/in
glomeruli
Followed by activation of complement & inflamm cells bearing
Fc receptors
Ag can be endogenous or exogenous
IC deposits can be subendothelial, subepithelial, or mesangial
IF staining: granular pattern

 Cell-mediated Immunity in GN:

Sensitized T cells
Direct cytoxicity or released cytokines caused foot processes
effacement or epithelial detachment
Presents with proteinuria

Mediators of Glomerular Injury:

Activated complement fragments are chemotactic
Ig localized in glomeruli interact w/ Fc-receptor-

bearing cells
Activated T cells also secrete chemokines that

recruit cellular effectors

 Cells responsible for Glomerular injury:

Neutrophils

& monocytes: proteases, O2-derived

free radicals, & arachdonic acid metabolites
Macrophages, lymphocytes, NK cells:
cytokines, cytotoxic cell mediators, growth factors
Platelets: aggregate & release eicosanoids & growth
factors
Resident glomerular cells (mesangial):
cytokines, growth factors, chemokines, O2 free
radicals, eicosanoids, & endothelin

 C5b-C9:

MAC w/c causes cell lysis & induces

mesangial cell activation
Eicosanoids, NO, Endothelin: affect vascular
flow
Cytokines, TNF, & chemokines: influence
inflamm cell adhesion & recruitment
PDGF: influences mesangial cell proliferation

 TGF-

& FGF: affect matrix deposition

VEGF: maintains endothelial integrity & regulates
capillary permeability
Coagulation proteins: esp fibrin, stimulate
parietal epithelial cell proliferation (crescent
formation)

Mechanisms of Progression in Glomerular

Diseases:
Regardless of etiology, once GFR is reduced to 30%
to 50% of normal, progression to ESRF proceeds at
a relative constant state.

 TWO major features of progressive renal damage:

1)

FSGS: Adaptive change on unaffected glomeruli

Compensatory hypertrophy
Proteinuria & segmental glomerulosclerosis
Total glomerular scarring & uremia
Endothelial/epithelial injury lead to protein
accumulation, macrophage recruitment, mesangial cell
activation, increased matrix synthesis

2) Tubulointerstitial fibrosis: component of many

forms of acute & chronic GN
Renal fxn correlates better w/ extent of tubulointerstitial damage
than w/ severity of glomerular injury
Result from ischemia & inflammation in the surrounding
interstitium
Direct injury to & activation of tubular cells brought by
proteinuria
Elaboration of proinflammatory cytokines & growth factors
from activated tubular cells

NEPHRITIC SYNDROME:
1) Acute Proliferative Glomerulonephritis:

Postreptococcal, Postinfectious

Immune-complex mediated d/o caused by deposition of Ag-Ab

complexes containing proteins from certain bacterial
infections

 Morphology: Acute Proliferative GN

Diffuse GN w/ global hypercellularity due to Neutrophil &
monocyte infiltration
Endothelial, Mesangial, Epithelial proliferation
IF: granular mesangial & GBM IgG, IgM, & C3 deposits
EM: subepithelial humplike deposits

 Clinical course: Acute Proliferative GN

Nephritic syndrome 1 to 4 wks after pharyngeal or cutaneous
strep infection
GABHS (types 1, 4, & 12)
Anti-streptococcal Ab titers are
Serum complement C3 concentrations are
>95% of children recover quickly
<1% develop rapidly progressive disease

2) Rapidly Progressive (Crescentic) GN:

Rapid, progressive renal decline

Divided into THREE broad groups based on immunologic
findings
Associated w/ know disorders; 50% idiopathic

 Type I RPGN:
20%

of RPGN; Anti-GBM disease characterized by

linear IgG (& C3) GBM deposits
Anti-GBM Abs may cross-react w/ pulmo alveolar
BM to produce pulmo hemorrhages (Goodpasture
syndr)
High prevalence of certain HLA haplotypes
Solvent exposures or virus infection implicated as
inciting trigger in susceptible hosts

 Type II RPGN:
25%

of RPGN; immune-mediated dse

Complication of any IC nephritides, including
postinfectious GN
Micro: crescent formation, glomerular cellular
proliferation
IF: granular staining

 Type III RPGN:

Pauci-immune

type; >50% of RPGN

characterized by absence of Anti-GBM Abs or IC
Circulating Antineutrophil Cytoplasmic Ab (ANCA)
Associated w/ systemic vasculitis
Idiopathic cases: >90% of cases have ANCA titers

 Morphology: RPGN
Distinctive crescents formed by parietal cell proliferation &
inflammatory cell migration into Bowman space
Crescents may undergo sclerosis
IF: linear staining in anti-GBM disease (Type I); granular
deposits in IC disease (Type II); little or no staining in
pauci-immune disease (Type III)
EM: distinct ruptures in GBM; subepithelial deposits also
occur in Type II disease

 Clinical course: RPGN

All forms present w/ hematuria, RBC casts, moderate
proteinuria, variable HPN, & edema
Goodpasture syn: recurrent hemoptysis
Renal involvement usu progressive culminating in severe
oliguria
Functional recovery occur in intensive plasma pheresis w/
steroids & cytotoxic agents

NEPHROTIC SYNDROME:
Excessive glomerular permeability to plasma

proteins; Proteinuria >3.5 g/day

Primarily LMW proteins (albumin)
More severe injury include HMW proteins in
addition to albumin (heavy proteinuria)
Hypoalbuminemia, colloid osmotic pressure,
systemic edema
Na+ & H2O retention, Hyperlipidemia, lipiduria,
vulnerability to infection, thombotic complications

1) Membranous nephropathy (MGN):

Common cause of adult nephrotic syndrome

Idiopathic in 85% of cases; remainder occurs in assoc w/

malignancy, SLE, drug exposures (NSAIDS, penicillamine,
captopril), infections, or autoimmune (thyroiditis) d/o

 Pathogenesis: MGN
Chronic

IC-mediated disease
Abs can be against self Ags or exogenous proteins or
haptens
Lesions similar to those seen in Heymann nephritis
Capillary leakiness due to complement activation
w/c activates epithelial & mesangial cells to liberate
proteases & oxidants

 Morphology: MGN
Micro:

diffuse thickening of capillary wall

(membranous); Tubular cells w/ reabsorption
droplets; interstitial chronic inflamm; glomerular
sclerosis
IF: diffuse GBM granular staining for Ig &
complement
EM: subepithelial GBM deposits w/c incorporates
into the GBM & assume intramembranous location

 Clinical features: MGN

Insidious

onset of Nephrotic syndrome

HPN &/or hematuria in 15% to 35% of cases
Course usually indolent
Proteinuria persists in 60% of patients
Only 10% die or progress to RF in 10 yrs
40% progress to renal insufficiency

2) Minimal-Change Disease
Major

cause of Nephrotic syndrome in children

Peak incidence b/w ages 2 & 6 yrs
Occasionally follows RTI or routine immunization
Also associated w/ Atopic d/o & HL (other
lymphomas & leukemias)

 Pathogenesis: MCD
Hypothesis:

immune dysfunction & elaboration of

one or more circulating cytokines that affect visceral
epithelial cells

Loss

of glomerular polyanions that form part of

normal permeability barrier increased leakiness!

 Morphology: MCD
Micro:

IF:

normal glomeruli

No immune deposits

EM:

diffuse effacement of foot processes (fusion) of

visceral epithelial cells

 Clinical features: MCD

Most

characteristic feature dramatic response

to corticosteroid therapy

Heavy

proteinuria (Albuminuria) but excellent long

term prognosis

3) Focal Segmental Glomerulosclerosis:

Primary

(idiopathic) d/o
Secondary to other known d/o (heroin abuse, HIV
infection, SCD, obesity)
After glomerular necrosis due to other causes (IgA
nephropathy)
Adaptive response to loss of renal tissue (chronic
reflux, analgesic abuse, unilateral agenesis)
Secondary mutations of proteins that maintain
glomerular filtration barrier

 Pathogenesis: FSGS
Primary

lesion is visceral epithelial damage

(effacement or detachment)
Part of pathologic continuum w/ MCD(?)
Circulating cytokines or genetic defects of slit
diaphragm complex are implicated
Glomerulosclerosis & hyalinosis stem from
entrapment of plasma proteins & matrix synthesis

 Morphology: FSGS
Micro:

characterized by sclerosis of some, but not

all, glomeruli (focal); in affected glomeruli, only a
portion of capillary tuft is involved (segmental)

IF:

IgM & C3 in sclerotic areas or mesangium

EM:

both sclerotic & non-sclerotic areas reveals

diffuse foot process effacement w/ focal epithelial
detachment

 Clinical course: FSGS

Proteinuria

(non-selective), hematuria, GFR, &

HPN
Idiopathic

FSGS responds variably to steroids &

progression to CRF in >20% of cases

Recurs

in 25% to 50% of renal allograft recipients

 HIV-associated

Nephropathy: severe collapsing

glomerulopathy variant of FSGS
Collapse

of entire glomerular tuft & striking cystic dilation of

tubular segments w/ assoc inflammation & fibrosis

Proliferation

& hypertrophy of glomerular visceral

epithelium assoc w/ Endothelial tubuloreticular
inclusions

4) Membranoproliferative Glomerulonephritis:
Accounts
Can

for 10% to 20% of Nephrotic syndrome

be idiopathic or secondary to another disorder

or agent

 Pathogenesis: MPGN has two forms

Type

I: most common; likely consequence of AgAb complex deposition & complement activation
Ags

in the complexes can originate from infection, SLE, or

malignancy
Can also be idiopathic
Type
Due

II: dense-deposit disease

to activation of alternate complement pathway

Most have C3 nephritic factor in serum autoAb
against C3 convertase

 Morphology: MPGN
Micro:
thickened

capillary loops & glomerular cell proliferation

glomeruli appear lobular due to mesangial proliferation

double contour appearance

IF:
Type

I: occasional granular subepithelial & mesangial Ig

& C3, C1q, & C4 deposits
Type II: irregular granular or linear deposits of C3 on
either side of GBM w/ occasional circular mesangial
deposits; absent IgG, C1q, & C4

EM:

Type I: Subendothelial electron-dense deposits

Type II: Characteristic lainar, ribbon-like electron-dense

deposits in the GBM proper

 Clinical features: MPGN

Adolescence

& young adults w/ Nephrotic syndrome

Occasionally w/ hematuria
Progression slowed by steroids
50% develop CRF w/in 10 yrs
High recurrence rate in transplant recipients,
particularly in patients w/ type II disease

ISOLATED URINARY
ABNORMALITIES:
1) IgA Nephropathy (Berger Disease):
Most

common type of GN worldwide

Major cause of recurrent glomerular hematuria
Pathogenesis:
Genetic/acquired

defects in immune regulation w/

mucosal IgA secretion in response to
ingested/inhaled Ags

systemic IgA or qualitative alterations in IgA

leads to augmented deposition in the
mesangium & activation of alternate
complement pathway

Increased frequency in Celiac disease or w/ liver

pathology

Similar IgA deposits occur in HenochSchonlein purpura

 Morphology:
Micro:
glomeruli

can appear nearly normal, showing only subtle

mesangial hypercellularity or can have focal
proliferative/sclerotic lesions

IF:
IgA,

C3, & Properdin deposition is typical

EM:
Electron-dense

deposits in mesangium

 Clinical features:
Gross

hematuria ff. respiratory, GI, or urinary

infection
Hematuria lasts for several days, subsides, & recurs
CRF develops in 10% to 40% over a period of 20 yrs
Older age of onset, heavy proteinuria, HPN,
crescents, & vascular sclerosis Poorer prognosis
Recurrence of IgA deposits is common in allografts;
15% re-develop clinical disease

2) Alport syndrome:
Hereditary

nephritis: heterogenous grp

associated w/ glomerular injury
Alport syndrome: hematuria progressing to CRF,
assoc w/ nerve deafness, lens dislocation, cataracts,
corneal dystrophy

 Pathogenesis:
Manifestations

due to defective assembly of Type IV

collagen in GBM
X-linked form (85%) is due to mutations in the 5
chain
Autosomal forms due to mutations in 3 or 4
subunits
Abnormal type IV collagen affects function of GBM,
eye lens, & cochlea.

 Morphology:
Early

lesions detectable by EM
Diffuse GBM thinning; interstitial cells stuffed w/
fats & mucopolysaccharides
Disease progression: features of FSGS, tubular
atrophy, interstitial fibrosis
Fully developed disease: irregularly thickened
GBM w/ pronounced splitting of lamina dense, often
w/ basket-weave appearance

3) Thin Basement Membrane Lesion (Benign

Familial Hematuria)
Familial

asymptomatic hematuria
Proteinuria present but renal function is normal
Excellent prognosis
Disorder due to mutations in Type IV collagen 3 or
4 chains, resulting in GBM only 150 to 250 nm
thick (normal is 300 to 400 nm)

CHRONIC GLOMERULONEPHRITIS:
Common end stage; some arise w/o clear

antecedent
Percentages that progress to Chronic GN:
Poststreptococcal GN = 1% to 2%
RPGN = 90%
Membranous GN = 30% to 50%
FSGS = 50% to 80%
MPGN = 50%
IgA Nephropathy = 30% to 50%

 Morphology: Chronic GN
Gross:
symmetrically

contracted kidneys
Diffusely granular surface
Thinned-out cortex
Micro:
Glomeruli

completely effaced by hyalinized CT

Marked tubular atrophy
Marked arteriolar sclerosis

 Dialysis
Arterial

changes:

intimal thickening
Acquired cystic changes
Calcium urate crystal deposition

 Clinical course: Chronic GN

Hypertension
Secondary

manifestations of Uremia

Pericarditis
Uremic

gastroenteritis
Secondary hyperparathyroidism w/ nephrocalcinosis
Renal osteodystrophy

GLOMERULAR LESIONS ASSOCIATED

WITH SYSTEMIC DISEASES:
1) Henoch-Schonlein purpura:
Occur

at any age but typically b/w ages of 3 & 8 yrs

Purpuric skin lesions (vasculitis)
Abdominal symptoms (pain, vomiting, bleeding)
Arthralgia
GN w/ some hematuria, nephritic/nephrotic
syndrome

Glomerular lesions:

focal mesangial proliferation to crescentic GN

always w/ Mesangial IgA deposition

Overall prognosis usually excellent

Recurrent hematuria can persist for years

2) Bacterial Endocarditis-Associated GN:

Due

to IC deposition
Hematuria; Nephritic syndrome & RPGN may occur
Continuum from focal necrotizing GN to diffuse GN,
to Crescentic GN
IF & EM: granular IC deposition

3) Diabetic Nephropathy:
Leading

end-stage RF in 40% of Type 1 & Type 2 DM

Glomerular disease leading to proteinuria w/ or w/o
Nephrotic syndrome
Hyalinizing

arteriolar sclerosis - susceptibiliy

to Pyelonephritis & Papillary necrosis
Capillary

BM thickening
Diffuse mesangial sclerosis
Nodular glomerulosclerosis (Kimmelstiel-Wilson disease)

 Pathogenesis: DM Nephropathy
Hyperglycemia

& Insulin deficiency lead to

biochemical alterations in the GBM
Non-enzymatic glycation of proteins
Hemodynamic changes result in GFR, glomerular
capillary pressure, & glomerular hypertrophy w/c
culminates in Glomerulosclerosis

4) Amyloidosis:
Amyloid

of any type; Deposited in glomeruli & in

vessel walls producing heavy proteinuria
ESRD occurs

5) Other Systemic Disorders: Goodpasture

syndrome, Polyarteritis nodosa, Allergic vasculitis,
Wegener granulomatosis

From Focal segmental necrotizing GN to Crescentic GN

Essential mixed cryoglobulinemia = MPGN
Plasma cell dyscracias = light-chain deposition disease

Tubular & Interstitial

Diseases

ACUTE KIDNEY INJURY (Acute Tubular

Necrosis)
Most common cause of ARF
Accounts for 50% of ARF in hospitalized patients
Characterized by renal tubular epithelial cell injury
Causes:
1) Ischemia:
2) Direct toxic injury:
3) Acute tubulointerstitial nephritis: hypersensitivity
response to drugs
4) Urinary obstruction:

 Pathogenesis: ATN
Reversible/irreversible

tubular damage leading to

renal function
a) Arteriolar vasoconstriction
b) Tubular obstruction
c) Back-leak of tubular fluids
d) Glomerular ultrafiltration

 Morphology: ATN
Ischemic

AKI:

Patchy

tubular necrosis w/ lesser degrees of tubular injury

Involves prox tubule straight segments & thick asc. LOH
Nephrotoxic
Variable

AKI:

degrees of tubular injury & necrosis

Mostly in proximal tubules
Distal tubules & collecting ducts contain cellular & protein
casts
Interstitial edema w/ variable inflammatory infiltrate

 Clinical course: ATN

Highly

variable but proceeds thru 3 stages:

Initiation phase (up to 36 hours):
Dominated

by inciting event
Slight decline in urine output
Rise in BUN
Maintenance
Oliguria

phase:

(40 to 400 mL/day)

Salt & H2O overload
Hyperkalemia
Metabolic acidosis
Rising BUN

 Recovery

phase:

Rising

urine volumes (up to 3 L/day) w/ H2O, Na+, K + losses

Renal tubular function restored
Concentrating ability improves

Prognosis:
Good

in most cases of Nephrotoxic AKI

Poor for AKI secondary to overwhelming sepsis or
other causes of multi-organ failure

TUBULOINTERSTITIAL NEPHRITIS:
Absence of hallmarks of nephritic or

nephrotic syndrome & by features of tubular

dysfunction

1) Pyelonephritis & UTI:

Most

common organisms: Gm (-) bacilli from GIT

More common in women:
Shorter

urethra
Hormonal changes affecting mucosal bacterial adherence
Absence of prostatic antibacterial compounds
Other

risk factors: Long term catheterization,

Vesicoureteral reflux, DM, Pregnancy,
immunosuppression, UT obstruction, BPH,
tumors, & calculi

 Pathogenesis:
Most

commonly the result of ascending infection

from the bladder
Sequence of events:
Colonization

of distal urethra & introitus

Multiplication of bacteria in the bladder
Vesicoureteral reflux
Si/Sx:
UTI:

dysuria, frequency
Pyelonephritis: flank pain, fever, WBC casts

2) Acute pyelonephritis:
Patchy,

suppurative inflammation, tubular necrosis,

intratubular neutrophil casts
Morphology:
Abscesses
Papillary

necrosis
Pyonephrosis
Perinephric abscesses
Renal scars w/ fibrotic deformation of cortex, calyx, pelvis

 Clinical

features:

Uncomplicated

pyelonephritis follows a benign course w/

Antibx therapy
Recur or progress in the presence of Vesicoureteral reflux,
obstruction, immunocompromise, DM, etc
Polyomavirus Infection in renal allografts
(immunocompromised host)

3) Chronic pyelonephritis & Reflux Nephropathy:

Tubulointerstitial

inflammation, renal scarring,

dilated & deformed calyces
TWO forms:
a) Reflux nephropathy:
most

common
begins in childhood from infections superimposed on
congenital vesicoureteral reflux & intrarenal reflux
Unilateral or bilateral

b) Chronic obstructive pyelonephritis

Chronic obstruction predisposes to infection

Parenchymal atrophy

 Morphology:
Both

types associated w/ broad scars, deformed

calyces, tubulointerstitial inflammation, fibrosis
Secondary FSGS & vascular HPN
Clinical features:
Symtoms

of acute pyelonephritis or can have silent,

insidious onset
Proteinuria & FSGS is a poor prognostic sign

4) Tubulointerstitial Nephritis Induced by Drugs

& Toxins:
A) Acute drug-induced interstitial nephritis:
Idiosyncratic

hypersensitivity reaction
Roughly 2 wks after exposure
Drugs bind to tubular cellular/matrix components & induce
Ab (IgE) & T-cell-mediated immune reactions
Morphology:
Edema,

patchy tubular necrosis, tubulointerstitial infiltrates

Occasionally w/ well-formed granulomas

 Clinical

features:

Fever
Eosinophilia
Skin

rash,
Hematuria,
Mild proteinuria
Sterile pyuria,
Azotemia
ARF
***Drug withdrawal usually leads to full recovery

B) Analgesic nephropathy:
Excessive

intake of Phenacetin-containing analgesic

mixtures
Ingestion of Aspirin, Phenacetin, or Acetaminophen in
isolation rarely causes disease
Pathogenesis:
Papillary

necrosis due to direct toxicity & ischemia

Drug metabolites (Phenacetin & Acetaminophen) deplete
tubular cells of Glutathione & induce oxidative metabolites
Aspirin inhibit formation of vasodilatory prostaglandins

 Morphology:
Analgesic

nephropathy characterized by chronic

tubulointerstitial nephritis w/ papillary necrosis

Clinical

features:

Polyuria,

increased stone formation due to tubular acidosis

Anemia

GI

symptoms
HPN
UTI in 50% of cases & papillary necrosis
Increased risk of Transitional Cell Ca

C) Nephropathy associated w/ NSAIDS:

Due to combination of:
Decreased

synthesis of vasodilatory prostaglandins

Hypersensitivity interstitial nephritis
Cytokine elaboration leading to podocyte foot process
effacement
Membranous nephropathy of uncertain etiology

D) Other Tubulointerstitial Diseases:

1)
2)
3)

Urate nephropathy Hypercalcemia & nephrocalcinosis

Light-chain cast nephropathy

Bence Jones proteinuria & cast nephropathy

Amyloidosis

Light-chain deposition diseases

Hypercalcemia & hyperuricemia

Vascular Diseases

Kidney diseases & systemic disorders affect

renal blood vessels

1) Benign Nephrosclerosis:
Pathology

assoc w/ renal arteriolar sclerosis

Arteriolar stenosis sec to wall thickening,
hyalinization from deposition of insudated proteins
& BM matrix synthesis
Large musc arteries: Fibroelastic hyperplasia w/
medial & intimal thickening
Diffuse ischemic atrophy of nephrons
Kidneys small w/ diffuse granular surfaces (scarring)

 Renal

failure & mild proteinuria

Progression to CRF correlated to:
Severity

of HPN,
Present comorbidities
African origin

Arteriolar Nephrosclerosis:

Fibroelastic Hyperplasia:

2) Malignant HPN & Accelerated Nephrosclerosis:

Assoc w/ accelerated HPN
Most are superimposed on preexisting benign essential
HPN, Chronic renal dse, or Scleroderma

Pathogenesis:
Initial vascular insult, endothelial injury, platelet deposition,
permeability Fibrinoid Necrosis & IV thrombosis
Renal ischemia w/ stimulation of Renin-Angiotensin & other
vasoconstrictive systems, aldosterone-driven salt/H2O retention
escalating BP

Morphology:

Fibrinoid necrosis of arterioles, hyperplastic arteriopathy

(onion-skin), necrotizing GN, & glomerular thrombotic
microangiopathy

Clinical features:

Systolic pressure >200 mm Hg & diastolic BP > 120 mm

Hg
Proteinuria
Hematuria
Papilledema
Encephalopathy
Cardiovascular abnormalities
Renal failure

 Plasma renin, Angiotensin, & Aldosterone levels

Anti-HPN treatment: 75% survive 5 years
One-half recover pre-crisis renal function

3) Renal Artery Stenosis:

Unilateral

stenosis accounts for 2% to 5% of pts w/

renal HPN
Stenosis induce excessive renin secretion
70% caused by Obstructive Atheromatous Plaque
Remainder due to Fibromuscular Dysplasia
Usu

in young women (20 & 40 yo)

Non-arteriosclerotic intimal, medial, or adventitial
hyperplasia
Revascularization

cases

surgery cures 70% to 80% of

4) Thrombotic Microangiopathies:
Charac.

by microangiopathic hemolytic anemia,

renal failure, & intravasc coagulation
Endothelial injury w/ platelet activation &
aggregation
Classes:
a)

b)
c)

Typical (childhood) HUS: consumption of

bacteria contaminated food (Shiga toxin)
Atypical HUS: mutations in complement-regulatory
proteins, APAs, contraceptives, drugs, radiation, etc.
TTP: inherited/acquired deficiencies of ADAMTS13
metalloproteinase that regulate vWF function

 Morphology:
HUS: Endothelial injury
TTP: Platelet activation
Thromboses in the interlobular afteries, afferent
arterioles, & glomeruli, together necrosis & thickening of
vasc walls
Similar changes seen in Malignant HPN

5) Other Vascular Disorders:

a) Atheroembolic Renal Dse:
Cholesterol

crystals & debris embolize from atheromatous

plaque after manipulation of diseased aortas

b) SCD Nephropathy:
Sickling

in the hypertonic, hypoxic medulla leads to

vascular occlusion w/ hematuria, concentrating ability,
proteinuria

c) Diffuse Cortical Necrosis:

Complication

of obstetric emergency, septic shock, or

extensive surgery; Unkown etiology

d) Renal Infarcts:
End-organ

arterial blood supply w/o significant collateral

circulation; most infarcts are asymptomatic

Diffuse Cortical Necrosis

Renal Infarct

Congenital Anomalies

 Approx 10% of newborns w/ significant

malformations
20% pedia CRF stem from Renal dysplasias &

hypoplasias
Most arise from acquired development defects

rather than as heritable lesions

Agenesis of the Kidney:

Renal Hypoplasia:

Ectopic Kidney:

Horseshoe Kidney:

 Multicystic Renal Dysplasia:

Sporadic d/o resulting from abnormal metanephric
differentiation
Unilateral / Bilateral
Enlarged, multicystic w/ abnormal lobar
organization
Histo:
Immature

ducts surrounded by undifferentiated

mesenchyme, often w/ cartilage formation
Most are assoc w/ obstructive abnormalities of ureter &
lower UT

Cystic Diseases of the

Kidney

1) Autosomal Dominant (Adult) Polycystic Kidney

Disease:
Accounts for 5% to 10% of CRF
High penetrance & most often bilateral
Pathogenesis:

PKD1

mutations: 85% of cases (Polycystin 1); cell-cell or

cell-matrix interactions
PKD 2 mutations: Polycystin 2; regulation of intracellular
Ca++

 Morphology:
Massively

enlarged kidneys w/ cysts up to 3 or 4 cm in diam

Cyst arise anywhere along the Nephron & compress
Interstitial inflammation & fibrosis
Clin

features:

Most

patients are asymptomatic until renal insufficiency

supervenes
Cystic dilation or hemorrhage can cause pain &/or
hematuria, & HPN, polyuria, proteinuria
40% have scattered liver biliary cysts
20% to 25% have MVP

2) Autosomal Recessive (Childhood) Polycystic

Kidney Disease:
Perinatal & juvenile presentation
Associated w/ hepatic lesions caused by mutations of
PKHD1, encoding for Fibrocystin
Morphology:

Enlarged

kidney w/ multiple, cylindrically dilated collecting

ducts oriented at right angles to cortex & filling both cortex
& medulla
Congenital hepatic fibrosis

 Medullary Sponge Kidney:

Seen in adults w/ multiple cystic dilations in medullary
collecting ducts

Usually discovered incidentally by radiographic studies

Predispose to renal calculi

 Nephronophthisis & Adult-Onset Medullary Cystic

Disease:
Family of progressive renal disorders characterized by
small medullary cysts
Cysts concentrated at the cortimedullary junction
FOUR variants:

Sporadic,

nonfamilial (20%)
Familial juvenile nephronophthisis (50%); auto recessive
Renal-Retinal dysplasia (15%); auto recessive
Adult-onset medullary cystic disease (15%); auto dominant

 Features:
Children present w/ polyuria, Na+ wasting, tubular
acidosis, ff by progression to CRF over 5 to 10 yrs
Considered in children w/ unexplained CRF, (+) family
hx, & chronic tubulointerstitial nephritis in biopsy

Pathogenesis:
Seven gene loci identified
Initial injury to distal tubules w/ BM disruption leading
to chronic progressive tubular atrophy & interstitial
fibrosis

3) Acquired (Dialysis-Associated) Cystic Disease:

End-stage

kidneys of patients undergoing prolonged

renal dialysis
Multiple cortical & medullary cysts due to
obstruction from calculi &/or interstitial fibrosis
Cysts:
Often

contains Ca oxalate crystals; lined by atypical,

hyperplastic epithelium that can undergo malignant
transformation

 Simple cyst:
Single

or multiple cysts of the cortex (rarely medulla)

Lined by low cuboidal epihtelium
Range from 1 cm to 10 cm in size
Smooth walls, filled w/ clear, serous fluid
Hemorrhage can cause flank pain
Calcification w/ irregular contours may mimic Renal
Cell Carcinoma

Urinary Tract
Obstruction

 Obstructive uropathy:
Increase

susceptibility to infection & stone formation

Unrelieved pbstruction = Renal atrophy
Hydronephrosis:
Pelvis

& calyceal dilation assoc w/ progressive renal atrophy

of the kidney following outflow obstruction
Causes: Congenital anomalies, Urinary calculi, Prostatic
hypertrophy, Tumors, Inflammation, Sloughed papillae or
blood clots, Normal pregnancy, Uterine prolapse &
cystocele, Funcitonal disorders

 Morphology:
Sudden/complete

obstruction: GFR leads to modest

pelvis & calyceal dilation, w/ mild parenchymal
atrophy
Subtotal/intermittent obstruction: Progressive
dilation ensues
Obstruction also triggers interstitial inflammation &
fibrosis

 Clinical features:
Early

symptoms ar consequences of underlying

obstruction (Renal colic)
Unilateral: can remain silent for long periods
Bilateral,

partial: polyuria, tubular acidosis, salt

wasting, renal calculi, tubulointerstitial nephritis, atrophy, &

HPN
Bilateral,

complete: oliguria or anuria

Urolithiasis (renal Calculi,

Stones)

 Arise at any level in the Urinary tract, although most

are formed in the kidney

Hereditary associations: charac by excessive
production or secretion of stone-forming substances
Pathogenesis:

concentrations of stone substances

Changes in urinary pH
urine volume
Bacterial infection
Loss of inhibitors of crystal formation

 FOUR types of renal calculi:

1) Calcium-containing stones (70%): Calcium

oxalate & calcium phosphate
2) Triple phosphate/struvite (15% to 20%):
made up of magnessium ammonium phosphate;
usually assoc w/ Bacterial infection
3) Uric acid stones (%5 to 10%): form from acidic
urine
4) Cysteine (1% to 2%): caused by genetic defects in
renal amino acid resorption

 Clinical features:
Obstruction
Ulceration
Bleeding
Pain
Renal infection

Calcium oxalate crystals

Struvite crystals

Uric acid crystals

Cysteine crystals

Tumors of the Kidney

Benign Tumors of the Kidney:

1) Renal Papillary Adenoma:
Small,

yellow cortical tumors

Histo: vacuolated epithelial cells; form tubules &
complex branching papillary structures
Indistinguishable from LG Papillary Renal Cell Ca
Size cut-off: 3 cm; separates from those that
metastasize from those that rarely do

2) Angiomyolipoma:
Hamartomatous

lesion made up of vessels, smooth

muscle, & fat

Seen in 25% to 50% of cases w/ Tuberous
sclerosis
Clinical significance: Spontaneous hemorrhage

3) Oncocytoma:
Epithelial

tumor composed of eosinophilic cells

arising from collecting duct intercalated cells
Represent %5 to 15% of resected renal neoplasms
Can grow up to 12 cm in diameter
EM: cytoplasm packed w/ mitochondria

Malignant Tumors of the Kidney:

1) Renal Cell Carcinoma:
Represent

3% of all visceral cancers & 85% of renal

cancers in adults
Incidence: 50 to 70 years; 2:1 male preponderance
Tobacco is the most significant risk factor
4% autosomal dominant:
von

Hippel-Lindau (VHL) syndrome: 50% to 70% of patients

Hereditary papillary carcinoma: multiple, bilateral tumors

Classification & Pathogenesis:

a) Clear cell (non-papillary) Ca:

Most

common type (70% to 80%)

95% are sporadic

b) Papillary Carcinoma:
10%

to 15%
Both familial & sporadic forms

Clear Cell Renal Ca:

Solitary & large, bright

yellow-gray
Gray-white necrosis, w/ foci
of hemorrhagic discoloration
Renal vein invasion
Solid, trabecular, or tubular
Polygonal cells w/ clear
cytoplasm
Delicate arborizing
vasculature

Papillary Carcinoma:
Multifocal & bilateral
Hemorrhagic & cystic
Cuboidal cells in papillary

configuration
Often w/ interstitial foam
cells & psamomma bodies

Clear Cell RCCa:

Papillary Carcinoma:

c) Chromophobe Renal Ca:

Represent

5% of renal cancers
Derived from collecting duct intercalated cells
Excellent prognosis

d) Collecting Duct (Bellini Duct) Ca:

Represent

only 1% of renal cancers

Arise from medullary collecting duct cells

Chromophobe Renal Ca:

Bellini Duct Ca:

Pale, eosinophilic cells w/

Low-grade malignancy

perinuclear halos
bubble wrap appearance
Arranged in sheets around

blood vessels

Chromophobe Renal Ca:

Collecting Duct (Bellini Duct)

Carcinoma:

 Clinical Features: Renal Cell Carcinoma

Classic Triad: Flank pain, palpable mass, hematuria
May produce Paraneoplastic syndrome:
Prognosis: depend on size, extent of spread at diagnosis
Tends to metastasize before symptoms are felt; 45% of
patients survive 5 years
w/o metastasis, 5-yr survival is 70%

2) Urothelial Carcinomas of the Renal Pelvis:

5% to 10% of renal tumors originate from renal pelvic
urothelium
Manifest relatively early due to hematuria or obstruction
Histo: same w/ Urothelial tumors in the UB
Often multifocal; 50% w/ concomitant bladder tumor

5-yr survival: varies from 50% to 100% for LG

superficial tumors to 10% w/ HG infiltrating tumors

END