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Glomerular and Cystic
Diseases
Davis Massey, MD PhD
Surgical Pathology
Anna Vinnikova, MD
Nephrology

Learning Objectives
• Know the mechanisms of glomerular injury.
• Know the presented causes of the nephrotic and
nephritic syndrome, their clinical presentation,
clinical course, pathologic findings, and prognoses.
• Know the several types of cystic renal diseases and
their clinical and pathologic findings.
• Know the features of dialysis acquired renal changes.

The Kidney:
Gross Anatomy Review
• Cortex
– Glomeruli
– Proximal and
distal tubules
• Medulla
– Collecting ducts
and loops of
Henle

Immune complex deposit locations
relative to GBM

relative to GBM
Subendothelial
Subepithelial

relative to GBM
Subendothelial
Subepithelial
Intramembranous

Clinical Manifestations of Glomerular
Injury
Major renal syndromes include:
Acute nephritic syndrome : immune complexes
Nephrotic syndrome
Acute renal failure
• due to glomerular, interstitial, vascular injury, ATN or
obstruction
Chronic renal failure
• final common pathway of all chronic renal diseases

Biopsy Work-up
• Glomeruli
– H&E, PAS, silver,
trichrome stains
– Immunofluorescence
– Electron microscopy
• Tubules
• Interstitium
• Vessels

Glomerular Injury: Immune Mechanisms
• In situ immune complex deposition/formation:
– by circulating Ab directed against native glomerular Ag complexes
(membranous glomerulonephritis).
– by circulating Ab directed against or crossreactive with intrinsic Ag native
to the glomerulus (Goodpasture Disease), or directed against or
crossreactive with non-native “implanted” antigen trapped in the
glomerulus.
• Circulating immune complex deposition:
– Complexes not native to the glomerulus, which lodge there due to their
physicochemical properties; these may be exogenous Ag (infectious – Post
Streptococcal glomerulonephritis) or endogenous (host DNA – Lupus
nephritis)
• Cytotoxic Ab:
– direct interaction of Ab with glomerular cell components with a cytotoxic
result
• Cell-mediated damage:
– Sensitized T cells, macrophages
• Alternative complement pathway activation

Glomerular Injury: Immune Mechanisms
• Other mechanisms:
– Ab to visceral epithelial cells (causing proteinuria)
– Toxins (including some drugs)
– Cytokines
– Conditions promoting nephron loss leads to the
“tipping point” (30 – 50%), with eventual renal failure
– The unknown (unidentified circulating factors)

Mediators of Glomerular Injury
• After immune reactants or sensitized T cells localize
to glomerulus, how is damage brought about ?
– Neutrophils releasing proteases in response to
complement activation; T cells, macrophages releasing
other biologically active substances (cytokines and other
proteases)
– Resident glomerular cells such as mesangial cells
stimulated to produce pro-inflammatory mediators
– Soluble mediators of inflammation (chemotactic cytokines,
other cytokines, coagulation factors, etc)

Mechanisms of Glomerular Disease
Progression
• Outcome of damage depends on:
– Initial severity of renal damage
– Nature and persistence of Ag
– Host immune status, age, genetic susceptibilities
• Once any renal disease has destroyed sufficient
nephron mass to reduce GFR to about 30% to 50% of
normal, the tipping point is reached and progression
to ESRD continues steadily regardless of the activity
of the initiating stimulus.

Mechanisms of Glomerular Disease
Progression
• Two major histologic characteristics of
progressive renal damage are 1) focal
segmental glomerulosclerosis (FSGS) which
may be either a primary idiopathic disease
(more later) or a change secondary to other
stimuli (next), and 2) tubulointerstitial fibrosis
(TIF).

Mechanisms of glomerular disease
progression
• Secondary FSGS:
– Glomerulosclerosis caused by maladaptive changes that occur in the
unaffected glomeruli of diseased kidneys; maladaptive changes
include:
• Compensatory glomerular hypertrophy
• Glomerular hypertension (often systemic HTN too)
– These changes damage epithelial and endothelial cells causing
increased glomerular permeability to proteins, accumulation of
proteins in the mesangium promoting unwanted mesangial cell
proliferation, infiltration by macrophages, increases in extracellular
matrix, and inevitable progressive (segmental) sclerosis (“fibrosis”) of
glomeruli, all of which further reduces nephron mass, and promotes
the spiraling toward worsening glomerulosclerosis.

Mechanisms of glomerular disease
progression
• Tubular injury
– Many acute and chronic glomerulonephritides have tubular injury as a
component.
– Tubular injury may be due to ischemia (reduces amt of O2) from
upstream sclerotic glomeruli, acute and chronic inflammation in the
adjacent interstitium, damage to peritubular capillaries, and to
proteinuria which may directly injure tubular epithelium.
• These lead to tubulointerstital fibrosis (TIF).
– TIF contributes to disease progression of both immune and non-
immune glomerular diseases (FSGS, diabetes); TIF often correlates
better with renal function decline than does the severity of glomerular
damage.

Nephrotic Syndrome
• Minimal Change Disease (MCD)
• Focal Segmental Glomerulosclerosis (FSGS)
• Membranous Glomerulonephropathy (MGN)

Minimal Change Disease
Case presentation
• Danielle is a 21 year old VCU student referred
by Student Health for proteinuria. She
developed edema to thighs 3 wks ago. She has
been previously healthy. She takes no
medications except for an occasional Excedrin.
• Exam: BP 101/63, exam normal except for 2+
pitting lower extremity edema bilaterally

Case presentation
• Labs: urine prot 4+, alb 2.2, cholesterol 498,
creat 0.6
• Diagnosis: Nephrotic syndrome
• Patient started on prednisone 60 mg daily.
Returns 1 wk later – edema resolved and urine
protein is down to trace.
• Diagnosis: Minimal Change Disease

Minimal change disease
• Definition: Histopathologic lesion with normal
glomeruli on light microscopy and diffuse foot
process fusion on electron microscopy,
associated with nephrotic syndrome.

• Pathogenesis:
– leading hypothesis: immune dysfunction leads to
release of a cytokine
– the cytokine (“permeability factor”) targets
podocytes, disrupting GBM charge barrier and
causing proteinuria

• Morphology:
– Normal glomeruli by light microscopy (LM)
– Abnormal glomeruli by electron microscopy (EM)
with foot process effacement; no deposits found
– Proximal tubular epithelial cells often filled with
lipid and protein (“lipoid nephrosis”) due to
hyperlipidemia
– Immunofluorescence microscopy (IF) studies are
negative

• Epidemiology:
– Most common cause of primary nephrotic
syndrome in children
– Less common in adults
• Ethiology:
– Primary - idiopathic
– Secondary:
• Drugs: NSAIDs
• Tumors: lymphomas
• Immune modulation: vaccinations

• Clinical characteristics and treatment:
– Abrupt onset of florid nephrotic syndrome
– Normal blood pressure
– Renal function usually remains good
– 90% respond rapidly to corticosteroids, adults are
slower to respond than children
– Relapses are characteristic and respond to re-
treatment

• Clinical characteristics and treatment:
– Frequently relapsing or steroid-resistant cases
respond to other immunosuppressive agents
(mycophenolate, cyclosporine, cyclophosphamide)
– Some become steroid dependent until puberty,
when most cases finally remit
– Long term prognosis is excellent

Case follow-up
• Patient was treated with a 4 months
prednisone taper with complete resolution of
proteinuria. However, 1 mo after stopping
prednisone, her proteinuria increased to 3+,
which indicated a relapse. Started on CellCept
(Mycophenolate), again with resolution of
proteinuria after 1 wk. Pt then treated with
CellCept x 1 year. She remains in complete
remission.

Focal Segmental Glomerulosclerosis
Case presentation
• Robert is a laboratory technician at St Mary’s
Hospital, who has diagnosed himself with
nephrotic syndrome over Christmas break
• He is a 50 year old African American male w
h/o HTN, who developed progressively
increasing lower extremity edema since
summer

Case presentation
• He was seen by his PCP several times, and his
medications were adjusted. However, in spite
of proteinuria on UA, no diagnosis was made
• Medications: verapamil and lasix
• On exam, his BP is 145/91, remainder
unremarkable except for tight 4+ LE edema

Case presentation
• Labs 9 mo prior:
– 2+ protein on UA
– serum albumin 4
– cholesterol 300, LDL 180
• Current labs:
– serum albumin 2.8
– cholesterol 396, LDL 270 and
– creatinine 1.2
– Urinalysis 4+ protein and a few granular casts
– Urine protein/creatinine ratio 12

Case presentation
• Diagnosis: Nephrotic syndrome
• Kidney biopsy was performed, demonstrating
focal segmental glomerulosclerosis

• Definition: Histopathologic lesion with
sclerosis of some but not all (hence focal)
glomeruli that involves a portion (segment) of
the glomerular tuft

• Morpology:
– Sclerotic segments show basement membrane collapse,
increased matrix, trapping of plasma proteins in glomerular
capillary walls by light microscopy
– Effacement of VEC in sclerotic and non-sclerotic segments
by EM; no deposits.
– pronounced tubular atrophy and interstitial fibrosis

segmentally collapsed unaffected

GBM collapse and foot process fusion
less affected segment

• Ethiology and pathogenesis:
– Primary:
• presumed due to a circulating factor (?cytokine) that damages VEC
– Secondary (associated with other conditions):
• HIV, heroin addiction, sickle cell disease, massive obesity.
• maladaptive response to nephron loss
– Inherited
• linked to mutations of the proteins nephrin, podocin, or α-actinin4,
causing “podocytopathy”.

• Epidemiology: most common cause of primary nephrotic
syndrome in African-American adults
• Clinical characteristics:
– Nephrotic syndrome (primary disease or HIV nephropathy) or
nephrotic range proteinuria (most secondary forms)
– Proteinuria is non-selective (can have other proteins other than just
albumin) in contrast with minimal change disease
– Hypertension, reduced GFR
– Slow and variable response to steroids
– Progression to chronic glomerulosclerosis; 50-80% to ESRD within
several years
– Children have better prognosis than adults
– Recurrence post transplant is common in idiopathic FSGS leading to
graft failure

• Treatment:
– Only idiopathic FGSG has a chance to respond to
immunosuppressive treatment. Therefore, it is imperative
to determine whether the disease is primary or secondary
– Primary disease:
• Steroids
• Immunosuppressive cytotoxic agents - Cyclosporine, Tacrolimus,
Mycophenolate
– Primary and secondary disease:
• ACE/ARB and anti-lipid agents
– HIV-associated FSGS
• Antiretroviral medications

Case follow-up
• Patient was started on prednisone. Two weeks
later he was admitted with bacteremia. His
prednisone was tapered and he was started
on cyclosporine. Patient was unable to
tolerate medication, switched to CellCept.
This medication was stopped after several
months due to lack of efficacy.

Case presentation
• His proteinuria increased to 40 g/24 hrs, and
serum creatinine progressively increased to 3.
Patient failed other immunosuppressive
medications, and had multiple infectious
complications. He also had severe
complications of nephrotic syndrome –
resistant anasarca (total body edema), deep
venous thrombosis from hypercoagulable
state, pericardial effusion, and chronic
hypotension due to low plasma oncotic

Case presentation
• He was started on dialysis to control edema,
but could not tolerate fluid removal due to
hypotension. After hospitalization that lasted
4 months, patient finally agreed to have
bilateral renal artery embolization, a
procedure called “chemical nephrectomy”. He
is now hemodialysis-dependent, and has
much improved clinically.

Now let’s see if you’ve been paying
attention…

Patient has nephrotic syndrome,
biopsy below. Which statement about
this disease is INCORRECT:
A. It is the most common
cause of nephrotic
B. It is characterized by
sudden onset of florid
nephrotic syndrome
C. It is poorly responsive
to steroids
D. It can be caused by
NSAIDs

Which statement about this
disease is INCORRECT:
A. It is the most common
cause of nephrotic
B. It is characterized by
sudden onset of florid
nephrotic syndrome
C. It is poorly responsive
to steroids
D. It can be caused by
NSAIDs

Membranous Glomerulonephropathy
Case presentation
• Danny is a 28 yo previously healthy VCU
security guard, who was referred for
evaluation of proteinuria. He noticed LE
edema several weeks prior. He was
hypertensive at 155/90. His serum creatinine
was 0.9, alb 2.2, cholesterol 311 w LDL 173,
Urine - 5g protein/24 hrs.

Case presentation
• Kidney biopsy showed Membranous
Glomerulopathy.
• Clinical course: patient was treated w
immunosuppressive regimen consisting of
prednisone and cyclophosphamide for 6
months, and responded with markedly
decreased proteinuria (0.5 g/24 hrs).

Case presentation
• He was seen in follow-up several years later
and had trace proteinuria and normal
creatinine. He said: “I hope I would never hear
from my membranous nephropathy again”

• Definition: Histopathologic lesion
characterized by glomerular basement
membrane thickening due to immune
complex entrapment, associated with
nephrotic syndrome

normal

• Pathology: light
microscopy: diffuse,
uniform thickening
of basement
membrane with
small subepithelial
projections
("spikes") of
basement
membrane in
capillary loops.

• “Spike” formation on subepithelial (urinary) side of GBM,
(silver stain)

• Immunofluorescence microscopy: diffuse, coarsely granular pattern along
capillary loops.

• Subepithelial electron-dense immune deposits

• Pathogenesis: A chronic immune-complex
nephritis caused by:
– Ab directed against intrinsic GBM Ag (primary)
– circulating Ag-Ab complex entrapment in the GBM
(secondary)
– Both activate complement, which damages
podocytes and makes them leaky

• Epidemiology:
– most common cause of primary nephrotic syndrome in
Caucasian adults
• Ethiology:
– Primary
– Secondary:
• Drugs: penicillamine, captopril, gold
• Malignancy (solid tumors)
• Infection: hepatitis B, syphilis
• Autoimmune disease: systemic lupus erythematosus (SLE), rheumatoid
arthritis (RA)

• Clinical features:
– insidious onset of nephrotic syndrome, usually without
identifiable preceding illness;
– variable, but often indolent course
• Prognosis: “Rule of thirds” (without treatment):
– 1/3 – Spontaneous remission
– 1/3 – Partial remission / slow deterioration
– 1/3 – Progress to ESRD

• Predictors of poorer outcome are:
– tubulointerstitial fibrosis
– elevated cr at diagnosis
– male sex
– hypertension
– older age
– and heavy proteinuria.
• Treatment:
– Steroids alone are not very effective
– Prednisone alternating with Cyclophosphamide
– Cyclosporin

Patient has nephrotic syndrome and
biopsy is depicted below. Which
statement is INCORRECT:
A. It is the most common cause
of idiopathic nephrotic
syndrome in African
American adults
B. It is characterized by slow
and variable response to
steroids
C. It can be associated with HIV
D. In primary form, EM would
show foot process fusion
only in sclerotic segments

Nephritic Syndrome
• Membranoproliferative Glomerulonephritis (usually
combined nephrotic-nephritic)
• Acute Post-streptococcal Glomerulonephritis
• Rapidly Progressive (Crescentic) GN
• IgA Nephropathy

Membranoproliferative Glomerulonephritis
(Type I)
Case presentation
• Harry is a 48 year old African American
male with h/o polysubstance abuse,
admitted to the hospital with generalized
swelling, hypertensive urgency and
pulmonary edema. He was homeless, but
is currently living at Rubicon drug
treatment center.

(Type I)
Case presentation
• His serum cr in 2, serum albumin is 2.5,
urine protein to creatinine ratio is 10, UA
showed proteinuria and hematuria.
Further workup revealed that patient is
positive for hepatitis C and cryoglobulins.

(Type I)
Case presentation
• Kidney biopsy revealed
membranoproliferative
glomerulonephritis (MPGN), type I.
• Patient was not a candidate for treatment
due to poor social situation and history of
non-compliance. His renal function has
deteriorated and he became dialysis-
dependent within 6 months.

Membranoproliferative
Glomerulonephritis (Type I)
• Definition: histopathologic lesion
characterized by mesangial proliferation
and interposition into the glomerular
capillary wall with double contours (“tram
tracking”) of GBM on light microscopy

• Light microscopy:
– glomerular hypercellularity and lobular simplification.
Splitting of GBM ("tram-track“) is characteristic.
• Immunofluorescence microscopy:
• coarse granular staining along capillary loops.
• Electron Microscopy:
• Subendothelial deposits with new formation of GBM
(splitting).

Tramtracking (GBM “splitting”)

Deposits by IF (C3)

• Pathogenesis: deposition of immune
complexes in glomerulus with abnormal
activation of complement, production of
“nephritic factors” and glomerular injury

(Type I)
• Epidemiology:
– Primary – children and young adults, rare
– Secondary – adults, more common
• Ethiology:
– Primary (idiopathic)
– Secondary (seen in association with other
disorders)
• SLE, hepatitis C (often with cryoglobulinemia),
endocarditis
• Malignancy (lymphoma, leukemia)

• Clinical characteristics
– Nephrotic/nephritic
– Depressed serum complement levels
– Few remissions, usually unrelenting course
– 50% with renal failure in 10 years

• Treatment:
– Primary in children – immunosuppression
– Secondary – treat the original disease (antiviral
or antibacterial agents), antiplatelet agents,
immunomodulation in some cases

Which statement regarding the disease
with IF picture below (depicting granular
IgG staining along GBM) is INCORRECT:
A. This is the most common
cause of primary nephrotic
syndrome in Caucasian adults
B. 2/3 of patients will develop
spontaneous or partial
remission without treatment
C. Can be associated with solid
tumors
D. EM would show reduplication
of GBM with “tram tracking”

Nephritic Syndrome
• Membranoproliferative Glomerulonephritis
• Rapidly Progressive (Crescentic) GN
• IgA Nephropathy

Acute Post-Streptococcal Glomerulonephritis
Case presentation
• Wyatt is transferred to VCU from outside
hospital for acute glomerulonephritis. He is a
16 year old Caucasian male with h/o
tonsillectomy at age 5. Ten days prior to
admission he had strep throat with positive
rapid strep test, and was started on
augmentin by his PCP.

Case presentation
• He was referred for admission after he
developed tea colored urine, and was found
to have hematuria, proteinuria and HTN. Pt
reports 20 lbs wt gain in 3 days w periorbital
and upper body edema, and abdominal pain.
He now denies any sore throat.

Case presentation
• SH is significant for tobacco, alcohol and
marijuana use
• Exam: BP 175/77, ps 49. Young athletic wm in
no acute distress. Lungs were clear and heart
was regular, with 2/6 systolic murmur at base.
Abdomen was soft, diffusely tender, with liver
and spleen edges palpable. Trace LE edema.
No rash.

Case presentation
• Labs showed cr 1.3, albumin 2.7, urinalysis
178 rbc and 25 wbc, 3+ protein and several
red blood cell casts. ASO titer and
streptozyme were positive. C3 complement
level was low.
• Diagnosis: Acute post-streptococcal GN.

Case presentation
• Due to worsening renal function, we
performed renal biopsy, which confirmed the
above diagnosis, but also showed acute
interstitial nephritis likely secondary to
augmentin. That medication was stopped,
and patient was treated w diuretic and ace
inhibitor. Patient’s condition improved and he
was discharged to follow-up in renal clinic.

Case presentation
• His creatinine normalized after 1 mo. After 4
months, he was off antihypertensives,
however his UA still showed 3+ blood and 2+
protein. He was lost to follow-up since that
visit.

Acute Proliferative (Poststreptococcal,
Postinfectious) GN
• Definition: acute nephritic syndrome that
develops following infection by nephritogenic
strains of strep or other organisms

Postinfectious) GN
• Epidemiology and ethiology:
– Most common GN in children
– Incidence declines with age
– Usually 1 – 4 weeks post infection casued by
nephritogenic strains of strep (usually group A strep)
– Also reported with pneumococcal and staphylococcal
infections, some viral diseases (mumps, measles,
chickenpox, and hepatitis B and C).

Acute Proliferative (Poststreptococcal, Postinfectious)
GN
– history of infection 1-4 wks prior
– abrupt onset of nephritic syndrome
– oliguria
– hematuria (tea-colored urine)
– Edema : due to kidneys not working
– hypertension
– azotemia

Postinfectious) GN
– urinalysis usually
reveals proteinuria,
red cells, white cells,
and casts
– High antistreptolysin
O (ASO) titers in
post-streptococcal
cases

Glomerulonephritis
• Pathogenesis: Deposition of IgG immune complexes
in capillary loops, with complement (C3) activation.
Pathogenic Ag is unknown. Uncertain whether
circulating Ag-Ab complex or in situ Ag-Ab complex
formation occurs. Implicated antigens are
endostreptosin and nephritis-plasmin-binding
protein.

Postinfectious) GN
• Pathology: light
microscopy: enlarged,
hypercellular glomeruli
with endothelial and
mesangial cell
proliferation. Neutrophils
may be present.
Crescents may be seen.

Postinfectious) GN
• Immunofluorescence microscopy: coarsely
granular (“lumpy-bumpy”) pattern along
capillary loops.

Postinfectious) GN
• Electron microscopy: subepithelial very large
"hump-like" deposits.

Postinfectious) GN

GN
• Treatment: supportive
– Diuretics
– Antihypertensives
– Antibiotics do not change course in post-strep GN
• Prognosis:
– majority (especially children) become clinically
asymptomatic
– some may develop rapidly progressive GN
– adults can progress to chronic GN

Which diagnosis can you suspect from
the light microscopy below:
A. Membranous
nephropathy
B. Minimal change disease
C. FSGS
D. Membranoproliferative
Glomerulonephritis
(MPGN)

Nephritic Syndrome
• Membranoproliferative Glomerulonephritis
• Rapidly Progressive (Crescentic) Glomerulonephritis
(RPGN)
• IgA Nephropathy

Rapidly Progressive Glomerulonephritis
Case presentation
• William is a 50 year old music teacher who is
transferred from outside hospital for rapidly
progressive renal failure with hematuria and
proteinuria. He was very fit and healthy until
several weeks prior to admission, when he
developed a protracted upper respiratory
illness requiring several visits to PCP and
emergency rooms and several courses of
antibiotics.

Case presentation
• He was finally admitted after he was found to
have bilateral pulmonary infiltrates, gross
hematuria and elevated creatinine. His
condition deteriorated and he required
mechanical ventilation for acute respiratory
failure.
• Bronchoscopy was consistent with pulmonary
hemorrhage.

Case presentation
• His renal function deteriorated and he was
started on hemodialysis.
• His C-ANCA were positive at high titer.
• Kidney biopsy was performed and showed
crescentic pauci-immune glomerulonephritis.
• Diagnosis: Wegener’s granulomatosis with
alveolar hemorrhage and rapidly progressive
glomerulonephritis.

Case presentation
• Clinical course: He was treated with
intravenous steroids, cyclophosphamide and
plasmapheresis with gradual improvement in
respiratory and renal function. He recovered
completely and several months later arranged
his music department to give a concert at
MCV Hospital to thank those who saved his
life.

• Definition: acute nephritic syndrome associated with
rapidly deteriorating renal function (over weeks).
Histopathologically this is crescentic GN.
• Ethiology:
1. Anti-GBM disease
2. Immune complex-mediated crescentic GN (any GN that has gone
severe - lupus nephritis, post-infectious GN, IgA nephropathy)
3. Pauci-immune GN
4. 9dont see any immune complexes) (can be found in : vasculitic
diseases – Wegeners granulomatosis, microscopic polyangiitis)

Rapidly Progressive (Crescentic)
Glomerulonephritis
• Clinical features: Rapid and progressive loss of renal
function with severe oliguria and even death from
renal failure within weeks to months is the course in
untreated cases.
• Treatment: heavy immunosuppression with steroids
and cytotoxic agents (cyclophosphamide,
mycophenolate), many times plasmapheresis is used
to remove antibodies quickly
• Prognosis: May be related to the number of
crescents; those with >80% crescents do more
poorly. Recurrence post-transplant is unusual.

Rapidly Progressive (Crescentic) Glomerulonephritis

Anti-GBM Disease
• Type I, also referred to as anti-
GBM disease (Goodpasture’s
disease), in which IF reveals
linear (not granular) deposition
of IgG and C3 along the GBM;
EM shows no deposits; least
common type.

Anti-GBM Disease
• In some cases IgG and C3
may also bind the
pulmonary alveolar
capillary basement
membranes, producing a
syndrome (Goodpasture’s
syndrome) of pulmonary
hemorrhage and renal
failure.

Anti-GBM Disease
• Circulating anti-GBM antibodies are found in the serum.
Plasmapheresis may be used to treat these patients, in order
to remove the circulating Ab.

Immune-Complex-Mediated Crescentic GN
• Type II, or immune-complex-
mediated crescentic GN,
which may be associated
with any immune-complex
type GN including SLE, IgA
nephropathy, or
postinfectious GN.

• IF will reveal a
coarse, granular or
“lumpy-bumpy”
staining pattern.
Treatment is
directed at the
underlying disease.
“Linear” “Granular”

• EM usually shows
deposits

Pauci-Immnune Type GN
• Type III, or pauci-immnune type GN, which as the name
implies shows no anti-GBM Ab or immune-type complexes,
either by IF or EM.

Pauci-Immnune Type GN
• Associated with antineutrophil cytoplasmic antibodies (ANCA)
and are a feature of Wegener granulomatosis, microscopic
polyangiitis, or other vasculitic diseases.

Which statement regarding the disease
depicted on electron micrograph below is
INCORRECT:
A. This disease has poor
prognosis
B. This disease is treated in
supportive fashion with
diuretics and
antihypertensives
C. Light microscopy would
show proliferative GN

IgA Nephropathy (Berger’s Disease)
Case presentation
• Kelly is a 24 year old white female with history of
hypertension and depression, who is 16 wks
pregnant. She is referred by her OB for
proteinuria, hematuria and hypertension. Patient
has a history of gross hematuria following upper
respiratory infections.

Case presentation
• Her BP is 155/90, she has trace LE edema, and her
UA shows 3+ protein and 20 rbc. Her renal
function is normal. She is managed conservatively
with labetalol for BP control and bed rest. Her
proteinuria is monitored and remains stable
throughout the pregnancy. She is delivered via C-
section at 37 weeks gestation.

Case presentation
• 6 weeks post-partum her proteinuria remains
unchanged at 3g/24 hrs. Kidney biopsy is
performed and shows IgA nephropathy with 50%
glomerulosclerosis and moderate interstitial
fibrosis. She is started on ACE-I, fish oil and
prednisone.

• Definition: Histopathologic lesion of a
glomerulonephritis characterized by prominent
IgA deposits in the mesangium detected by IF
microscopy.

• Immunofluorescence microscopy: IgA most prominently
and consistently; diffuse and granular in mesangium.

• Electron microscopy: electron-dense deposits within the
mesangium.

• Pathogenesis:
– Error of IgA production and clearance; those with IgAN have an
abnormally high production of IgA in the marrow, and plasma
clearance of IgA by the liver may be reduced by an abnormal
glycosylation, leading to its deposition as immune complexes in
the mesangium; there it activates complement.
– Possible genetic or acquired abnormality of immune regulation
causing increased mucosal IgA production in response to
respiratory or GI exposure to environmental Ag; IgAN occurs
with increased frequency in those with gluten enteropathy
(celiac disease).
– There may be a familial tendency linked to HLA and
complement phenotypes.

• Epidemiology: the most common primary GN
worldwide
• The classic presentation is gross hematuria,
occurring coincidentally with a upper respiratory
infections. Hematuria subsides and recurs every
few months.
• In the background, there is indolent development
of mild nephritic or nephrotic features
• Very rarely develops crescentic RPGN

• May be associated with Henoch-Schoenlein
purpura, a systemic disorder of children that
includes purpuric skin lesions, abdominal pain
and arthralgia.
• Prognosis: variable, with many patients
maintaining normal renal function for many
years; but slow progression to chronic renal
failure in 40%. Recurrence post-transplant is
frequent.

Look at biopsy slides below. Which
statement about this disease is
INCORRECT:
A. Plasmapheresis should be
started to remove circulating
antibodies
B. This disease can be
associated with pulmonary
hemorrhage
C. This disease is associated
with Antinuclear Cytoplasmic
antibodies (ANCA)
D. This disease clinically
presents as RPGN

Chronic Glomerulonephritis (CRGN)
Case presentation
• Will is a 25 year old VCU student with history
of HTN self-referred to VCU renal clinic to
have his “kidneys checked”. He reports that
he was seen by a private nephrologist in town
2 years prior and had a kidney biopsy, which
showed “chronic changes”. He did not have
insurance and could not afford to pay medical
bills, therefore he has not followed up. He is
not taking any medications.

Case presentation
• Patient is asymptomatic
• Blood pressure is 170/110, and physical exam
is normal apart from trace LE edema. His BUN
is 55 and creatinine 6.2. Urinalysis
demonstrates 3+ protein, 5 rbcs per hpf, and
some broad granular casts. Renal ultrasound
demonstrates 9 cm kidneys bilaterally with
thin echogenic cortex.
• Diagnosis: chronic glomerulonephritis

• Pathology: kidneys are grossly shrunken, and
microscopically show significant and
widespread global glomerular sclerosis, with
interstitial fibrosis and tubular atrophy, “end-
stage kidney”.

• Epidemiology: an important cause of end-
stage renal disease. It is usually first noted in
young to middle-age adults.
• Pathogenesis: usually at time of diagnosis,
glomerular changes of CRGN are so far
advanced that determination of exactly how
they became sclerotic is impossible to work
out. It may therefore be the end-stage of such
processes as FSGS, MGN, RPGN, or MPGN.

• Clinical features and lab findings: usually
insidious onset, and discovered late in its
course with renal insufficiency. Patients
usually have edema, HTN and heavy
proteinuria.

• Treatment
– Control of BP
– Use of ACE inhibitor
– Control of hyperlipidemia
– Avoidance of other nephrotoxic substances
– Cessation of smoking

• Prognosis: poor renal prognosis and patient
needs to be prepared for dialysis or kidney
transplantation

This IF staining pattern is in:
A. Mesangial distribution
B. Granular capillary loop
distribution
C. Linear capillary loop
distribution

Autosomal Dominant Polycystic
Kidney Disease (Adult)
• Autosomal dominant
disease related to defect
on chromosome 16 (PKD-1)
in 85% of cases
• Progressive cystic dilation
of nephrons leading to
renal failure
• ESRD by the 4th
or 5th
decade.

• Polycystin-1 on surface of
tubular epithelial cells (TEC)
probably integral to cell-cell and
cell-matrix interaction in growth
and differentiation.
• Cysts detach from TEC and
continue to proliferate and
secrete fluid thereby enlarging.
• May be asymptomatic until late
stages, when pain may occur.

• Larger masses (up to
4kg) may be apparent
by palpation.
• Hematuria,
proteinuria, polyuria,
hypertension.
• Patients may survive
for years with
azotemia but
ultimately progress to
uremia.

• 40% also have
polycystic liver disease
(from biliary
epithelium)
• Also intracranial berry
aneurysms at the Circle
of Willis; lead to death
in 4 – 10% of cases due
to subarachnoid
hemorrhage

• Mitral valve prolapse in
20 – 50% (usually
asymptomatic)
• 40% die of coronary or
hypertensive heart
disease

• Dialysis or transplant
usually successful,
does not recur
• Nephrectomy if
painful or infected

Autosomal Recessive Polycystic
Kidney Disease (Childhood)
• Rare and distinct from
ADPKD
• Usually presents at birth with
serious complications
• Enlarged kidneys may
interfere with pulmonary
development - stillbirth
• Rapid renal failure may
follow
• Defect on chromosome 6
(PKHD1) which encodes
protein fibrocystin

• Fibrocystin may function in
biliary and renal collecting
duct differentiation
• Kidneys are enlarged with
smooth external surface and
many small cysts on cut
section arranged at right
angles to cortical surface
• Spongelike appearance

• Liver also has cysts
• Progressive hepatic fibrosis
and bile duct proliferation in
older children (“congenital
hepatic fibrosis”)

Simple cysts
• May be multiple
• Usually 1 – 5cm, maybe
bigger
• Translucent, straw colored
fluid
• Commonly found post-
mortem
• By imaging have smooth
contours with no
vascularity, unlike tumors

Acquired (dialysis-associated) cystic
disease
• With prolonged dialysis
may form many cortical
and medullary cysts
• Clear fluid filled
• Probably result from
tubule obstruction due
to fibrosis or
calcification

Acquired (dialysis-associated) cystic
disease
• May develop renal cell
carcinoma in cyst wall
(7% over 10 years)

Pathology Laboratory Images
• Selected images from the path website.
• Understand the pathogenesis/cause.
• OK to memorize the image, but be able to
recognize similar changes in other images.
• You should be familiar with the images you
have seen in lectures and will see in lab.

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