GLOMERULAR DISEASES

Table 2 and Table 3 at the last page

GLOMERULAR SYNDROME

1. Acute nephritic syndrome

2. Rapidly progressive glomerulonephritis
3. Chronic renal falure
4. Asymptomatic hematuria/proteinuria

NEPHROTIC SYNDROME
FOCAL SEGMENTAL GLOMERULOSCLEROSIS
• Manifestations •
– Massive proteinuria • Classifications
– Hypoalbuminemia – In association with other known
– Generalized edema conditions
– • HIV, heroin, sickle cell disease,
– Hyperlipidemia and lipiduria massive obesity
– As a secondary event reflecting
MINIMAL CHANGE DISEASE glomerular scarring
– As an adaptive response
– In certain inherited, congenital forms of
NS
– As a primary disease --- idiopathic

TABLE 3 – Classification of Focal Segmental

Glomerulosclerosis (FSGS)*
Primary FSGS (1)  Idiopathic
 Genetic forms
 Obesity
 Sickle cell anemia
 Unilateral renal agenesis
 Reflux nephropathy
Secondary FSGS (1)  Segmental sclerotic
lesions in necrotizing GN,
IgA nephropathy or other
forms of GN
 Low birth weight
 Lithium
 Idiopathic
• Lipoid nephrosis, Nil disease, Idiopathic  With HIV nephropathy
nephrotic syndrome Collapsing variant of  In heroin addicts
• Most common cause of NS in children FSGS (2)  With high dose
• Dramatic response to steroids pamidronate
• Of unknown cause – NSAID, allergic reactions  In renal transplants
• May present with acute renal failure *Synonyms for FSGS include focal glomerulosclerosis, and
• Differentiate from focal segmental focal, segmental glomerulosclerosis and hyalinosis.
glomerulosclerosis Because EM reveals widespread podocyte damage, even in
• LM: few, if any changes glomeruli without sclerosing lesions, a more appropriate
• IF: usually negative; may have mesangial IgM name could be chosen, such as renal disease with diffuse
• EM: widespread effacement of podocyte foot podocyte dysfunction, but no such name is widely used.
processes There are two major morphologic variants of FSGS: a
– Villous hypertrophy of podocytes ”classic” or “usual” form (1) and a collapsing variant (2).
– Absence of deposits In addition, a recent classification describes other
pathologic variants, namely a perihilar variant, a cellular
form, and a tip variant. See text.
• Failure to respond to steroids
• May have microscopic hematuria, hypertension
or renal insufficiency
• Some develop ESRD
• Recurrence after transplantation
• Differ from minimal change disease
 • They have a higher incidence of
hematuria, reduced GFR and HPN  Can be primary or secondary
• Their proteinuria is more often
nonselective  Secondary causes
• They respond poorly to steroids • Drugs
• Many progress to CGN • Underlying malignant tumors
• IMF shows deposition of IgM and C3 in • SLE
sclerotic segment • Infections
• Metabolic disorders
 Some have asymptomatic proteinuria

 Nephrotic syndrome

 Some --- remission

 Others --- ESRD

 Deposits may be formed by the interaction of

autoantibodies with podocyte surface antigens

 LM: normal to extreme diffuse thickening of the cap

wall, foam cells in the interstitium

 LM: some glomeruli with segmental sclerosis
(mesangial matrix material, collapse, BM-like
material) +/- hyalinosis
• Focal segmental consolidation of the tuft with
obliteration of the capillary, often with adhesions
to Bowman’s capsule
• Hyalinosis
• +/- podocyte hypertrophy
• Spikes
 IF: finely granular diffuse cap wall staining --- IgG +/-
C3 and others
 EM: numerous subepithelial deposits +/- spikes of
GBM between
 Course: 1/3 progress, 1/3 remit, 1/3 proteinuria only

 IF: usually negative except IgM +/- C3 in sclerotic

segment

 EM: widespread podocyte foot process effacement

• accumulation in collapsed loop of matrix-like

material

MEMBRANOUS GLOMERULONEPHRITIS
 MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS
 Can be primary or secondary
 Secondary causes
• Chronic immune-complex disorders
– SLE, hepatitis B, hepatitis C,
endocarditis, HIV, schistosomiasis
• Partial lipoid dystrophy associated with C3NeF
• Alpha-1 antitrypsin deficiency
• Malignant diseases
– CLL, lymphoma, melanoma
• Hereditary complement deficiency states
 MPGN types I, II and III
TABLE 4 – Major Conditions with
Pathologic Features that Resemble
 LM: proliferative, mesangial matrix increase, Idiopathic MPGN, Type I
lobulation, tram-tracking, capillary wall thickening
Hepatitis
Usually with Type II mixed
C
 IF: broad cap wall deposits and less often in the cryoglobulinemia
infection
mesangium --- C3 +/- others
Bacterial Visceral abscesses,
infections endocarditis, infected shunts
 EM:
Parasitic
• Type I – massive subendothelial deposits +/- Schistosomiasis, malaria
infections
mesangial deposits
• Lupus nephritis (Class
• Type II – large electron-dense deposits in IV)
• Post streptococcal GN
intramembranous portion
Other (uncommon)
diseases • IgA nephropathy (rare)
• Type III – subepithelial deposits, segmental GBM
in which • Thrombotic
fragmentation features microangiopathy (in
 Course: progressive (many to renal failure) of MPGN chronic stages)
Type I are • Monoclonal
 DX: low complement, nephrotic/nephritic seen In immunoglobulin
some deposition diseases
cases • Idiopathic nodular
glomerulosclerosis (ING)
• Dense deposit disease
(MPGN Type II)

IGA NEPHROPATHY (BERGER’S DISEASE)

 Frequent cause of recurrent gross or microscopic
hematuria
 +/- NS or RPGN
 Initially considered to be benign
 May lead to ESRD
 Reversible ARF from numerous tubular casts and
tubular injury
 LM: any glomerular pattern

 IF: intense mesangial granular IgA

 EM: dense deposits in mesangial paramesangial

areas

 Pathogenesis: deposition in glomeruli of abnormal

forms of circulating IgA resulting from abnormal
glycosylation

• IgA binds to mesangial cells

 • Role of alternative complement pathway – Bacterial, viral and parasitic infections

 No diagnostic serologic test for IgA nephropathy RAPIDLY PROGRESSIVE GN

 Crescentic GN
– Rapid and progressive loss of renal function
associated with severe oliguria and (if
untreated) death from renal failure within
weeks to months
– LM: over 50% of glomeruli with crescents
– IF:
o 1/3 granular (immune complex GN, e.g.
SLE, post-infectious GN)
o 1/3 linear (anti-GBM, e.g. Goodpasture’s
disease)
o 1/3 no deposits (e.g. PAN, Wegener’s,
vasculitis)
– EM: glomerular deposits anywhere
– Course: terrible (progression to ESRD except
post-infectious)

POSTSTREPTOCOCCAL GLOMERULONEPHRITIS
 1-4 weeks after a streptococcal infection of the
pharynx or skin
 6-10 yo but may affect any age
 Group A beta- hemolytic streptococci types 12, 4 and
1
 Acute nephritis syndrome: gross hematuria, edema
and hypertension
 A minority --- severe renal insufficiency
 Low C3
 Glomerular immune deposits represent Ag-Ab
complexes
 LM: proliferative, exudative (PMNs), +/- crescents
 IF: granular GBM --- IgG +/- C3
 EM: subepithelial humps +/- small
subendothelial/mesangial deposits
 Course: resolves in vast majority of cases
 Dx: ASO up, complement down, nephritic syndrome,
HPN

ANTI-GBM DISEASE
 Autoantibodies against the NC1 domain of the alpha
3 chain of type IV collagen (Goodpasture Ag)
 Associated with pulmonary hemorrhage
 LM: crescentic
 IF: strong linear staining along the GBM

 Nonstreptococcal acute GN
 • Benign familial hematuria
• Diffuse thinning of the GBM to between 150 and 225
nm (normal = 300 to 400 nm)

CHRONIC GN

 End-stage pool of glomerular diseases

 A number of cases arise mysteriously without
HEREDITARY NEPHRITIS
antecedent history of any of the well-recognized
• Alport syndrome forms of early GN
– Nephritis accompanied by nerve deafness
and various eye disorders (lens dislocation,
post. Cataracts and corneal dystrophy)
– Males > females, hematuria
– Defective form of BM due to mutations in
genes that encode components of type IV
collagen
• In 80% x-linked inherritance
• In 15% autosomal recessive
• Rarely autosomal dominant
• Skin biopsy (alpha 5)
• Anti-GBM disease after transplantation
• LM: segmental proliferation or sclerosis, fetal-like
glomeruli, mesangial matrix increase
• EM: irregular foci of thickening or thinning with
splitting and lamination of lamina densa
- mainly thinning in female carriers

SYSTEMIC LUPUS ERYTHEMATOSUS

Table 5 – “Original WHO” classification of Lupus

Nephritis (1974)

CLASS Normal glomeruli (by light microscopy,

I immunofluorescence, and electron microscopy)

Purely mesangial disease

a. Normocellular mesangium by light
microscopy
CLASS
II b. Mesangial hypercellularity with
mesangial immune deposits by
immunofluorescence or electron
microscopy

CLASS Focal proliferative glomerulonephritis (<50%

III of glomeruli affected)

THIN BASEMENT MEMBRANE DISEASE CLASS Diffuse proliferative glomerulonephritis (>50%

IV of glomeruli affected)

CLASS Membranous glomerulonephritis

V
*Classification based on glomerular abnormalities only,
evaluated by light, immunofluorescence, and electron
microscopy.
Immune deposits = granular or irregular staining for
immunoglobulins (predominantly IgG) and complement
components, with corresponding electron-dense deposits.
“Proliferative” lesions are characterized by hypercellularity due
to replication of intrinsic cells as well as infiltrating
inflammatory cells, especially monocytes. Other lesions in
Classes III and IV include necrosis, sclerosis, and crescent
formation.

Table 6 - ABBREVIATED INTERNATIONAL SOCIETY OF

NEPHROLOGY/RENAL PATHOLOGY SOCIETY (ISN/RPS)
CLASSIFICATION OF LUPUS NEPHRITIS, OF LUPUS
NEPHRITIS, BASED ON GLOMERULAR ABNORMALITIES,
AS STUDIED BY LIGHT AND IMMUNOFLUORESENCE
MICROSCOPY [66].

Class I Minimal mesangial lupus nephritis; immune deposits

without mesangial hypercellularity

Class Mesangial proliferative lupus nephritis; immune

deposits with mesangial hypercellularity
II
Focal lupus nephritis*; endocapillary hypercellularity, HENOCH-SCHONLEIN PURPURA
Class necrosis  Consists of
III
o Purpuric skin lesions on the extensor
Class Diffuse segmental (IV-S) or global (IV-G) lupus surfaces of the arms, legs and buttocks
nephritis**; various endocapillary lesions, often
IV o Abdominal manifestations – pain, vomiting
crescents
and intestinal bleeding
Class Membranous lupus nephritis***; epimembranous o Nonmigratory arthritis
deposits
V o Renal abnormalities
 LM: proliferative, crescents
Class Advanced sclerosing lupus nephritis> 90% of
glomeruli  IF: mesangial IgA +/- C3 and IgG
VI  Vasculitis in dermis and GIT
* Indicate the proportion of glomeruli with active and with
sclerotic lesions.
** Indicate the proportion of glomeruli with fibrinoid necrosis
and cellular crescents.
***Class V may occur in combination with class III or IV in
which case both will be diagnosed.
****Indicate and grade (mild, moderate, severe) tubular
atrophy, interstitial inflammation and fibrosis, severity of
arteriosclerosis or other vascular lesions.

DIABETIC GLOMERULOSCLEROSIS
 A leading cause of ESRD
 Proteinuria in 50% 12 to 22 years after clinical
appearance of diabetes, decresing GFR and
retinopathy
 Morphology
o Diffuse glomerulosclerosis
 Diffuse increase in mesangial matrix
  Mild mesangial cell proliferation HEREDITARY Transthyretin Neuropathy,
 Overall thickening of GBM FORMS, due to Fibrinogen A α nephropathy,
o Nodular glomerulosclerosis mutations in chain cardiomyopathy
genes Apolipoprotein Nephropathy
 Kimmelsteil-Wilson disease encoding the A,
 Pathognomic of DM proteins Lysozyme
shown, and
 Ovoid or spherical, often laminated, others
hyaline masses situated in the
periphery of the glomerulus
 IF: Bright linear staining along the GBM and TBM
 EM: GBM thickening and increase in mesangial
matrix, often nodular

AMYLOIDOSIS

• Heavy proteinuria or nephrotic syndrome

• LM: normal, nodules, or diffuse thickening of
GBM and mesangium
• IF: non-contributory
• EM: rigid non-branching fibrils (mesangium and
GBM)
• Course: bad prognosis

TABLE 10 – Major Forms of Systemic Amyloidosis

Precursor Common Associated

Type
Protein Features

Monoclonal light Plasma cell dyscrasia or

chains multiple myeloma not
AL (formerly Kappa or lambda always apparent.
called primary) N – terminal Cardiopathy, neuropathy,
region or entire and nephropathy
molecule common

Chronic infections;
formerly common with
tuberculosis or
Amyloid A osteomyelitis
AA(formerly
protein; Familial Mediterranean
called
a phase reactant fever (preventable by
secondary)
protein colchicine) Rheumatoid
arthritis (rare)
Drug addicts
Nephropathy common
TABLE 1. Renal Cystic Diseases

Pathologic Clinical Features Diagrammatic

Inheritance Features or Complications Typical Outcome Representation
Adult Autosomal Large multicystic Hematuria, flank Chronic renal
polycystic dominant kidneys, liver pain, urinary tract failure
kidney cysts, berry infection, renal
disease aneurysms stones, hypertension
beginning at age
40-60yr
Childhood Autosomal Enlarged, cystic Hepatic fibrosis Variable, death in
polycystic recessive kidneys at birth infancy or
kidney childhood
disease

Medullary None Medullary cysts Hematuria, urinary Benign

sponge on excretory tract infection,
Kidney urography recurrent renal
stones

Familial Autosomal Corticomedullary Salt wasting, polyuria, Progressive renal

juvenile recessive cysts, shrunken growth retardation, failure beginning in
nephronophth kidneys anemia childhood
isis

Adult-onset Autosomal Corticomedullary Salt wasting, polyuria Chronic renal

medullary dominant cysts, shrunken failure beginning in
cystic disease kidneys adulthood

Simple cysts None Single or Microscopic hematuria Benign

multiple cysts in
normal-sized
kidneys
Acquired None Cystic Hemorrhage, Dependence on
renal cystic degeneration in erythrocytosis, dialysis
disease end-stage kidney neoplasia
disease

TABLE 2 AND 3. GLOMERULAR DISEASES

TABLE 2 - Major Manifestations of Glomerular Diseases

Nephrotic Syndrome Results from heavy proteinuria (more than 3.5 grams/24hrs) with edema, hypoproteinemia,
especially of albumin, and hyperlipidemia. The term nephrotic range proteinuria is used for
patients who have heavy proteinuria without the full-blown syndrome.

Asymptomatic Virtually any type of glomerular disease can cause proteinuria, and if not severe (less than 3.5
Proteinuria grams/24hrs), is generally asymptomatic. Protein indicator strips are highly sensitive to
albumin, but less so to light chains (as seen in myeloma).
Acute Nephritic
Characterized by hematuria, red blood cell casts, edema, proteinuria, hypertension, oliguria
Syndrome
and azotemia. May remit.

Rapidly Progressive GN Has features of the acute nephritic syndrome, but is characterized further by progressive
(GN) decline of renal function (reduction of glomerular filtration rate of more than 50% in several
days or weeks),

Hematuria is usually arbitrarily defined as having more than four red blood cells per high
Asymptomatic or Gross
power field in the urine sediment. Gross hematuria causes discoloration of the urine (tea-
Hematuria
colored). Most hematuria is not of glomerular origin. The finding of dysmorphic red cells or of
red cells casts in the urinary sediment supports a glomerular origin.
 Systemic hypertension is associated with glomerular diseases and may contribute to disease
Hypertension progression, especially with very high blood pressure levels.

Patients with several forms of glomerular disease (and other forms of renal disease) may
End Stage Renal Disease
present with advanced renal insufficiency, without distinctive manifestations of the underlying
(ESRD)
disease.

TABLE 3 - Major Glomerular Diseases *

Usual Name Usual Presenting Clinical Features

Minimal change disease Nephrotic syndrome
Focal segmental glomerulosclerosis
Proteinuria, often with nephrotic syndrome
(FSGS) * *
Membranous Glomerulonephritis (GN) * * Nephrotic syndrome or heavy proteinuria
IgA nephropathy & Henoch-Schoenlein Purpura Hematuria, with or without proteinuria. HSP also has purpura,
(HSP) arthralgia, GI disturbance
Nephrotic syndrome, or asymptomatic proteinuria with microscopic
Membranoproliferative GN Type I * *
hematuria, occasionally acute nephritic syndrome
Post streptococcal GN Acute nephritic syndrome
Anti-GBM Nephritis Rapidly progressive renal failure, often with lung hemorrhage
Rapidly progressive renal failure, often with lung hemorrhage or
Pauci immune necrotizing and crescentic GN
other extrarenal manifestations of vasculitis or Wegener’s
(ANCA associated)
granulomatosis
Lupus nephritis Diverse renal abnormalities and other manifestations of SLE
Mixed cryoglobulinemic GN (with type II
Purpura, arthralgia, signs of GN
cryoglobulins, usually with hepatitis C infection)
Proteinuria, sometimes with nephrotic syndrome, and chronic
Diabetic glomerulosclerosis
progressive renal failure
Thrombotic microangiopathy (TMA) * * Hemolytic anemia, thrombocytopenia, renal or other organ damage
Monoclonal immunoglobulin deposition diseases
Proteinuria, nephrotic syndrome, renal insufficiency
(MIDD); Fibrillary GN
* Glomerular diseases are sometimes classified as those that primarily affect only the kidney (primary glomerular diseases)
and those in which renal involvement is a manifestation of a systemic disease (secondary glomerular diseases). Several
diseases do not fall neatly into either of these categories. Nevertheless, when a patient presents with features of a
glomerular disease, it is imperative to look for evidence that points to a systemic disease that could account for the renal
manifestations.
* * Indicates a pathologic pattern or process rather than disease entity.