PATTERNS OF RENAL INJURY

THE CLINICAL SYNDROMES

1. The acute Nephrotic Syndrome

2. The Acute Nephritic Syndrome

3. Rapidly Progressive Glomerulonephritis

4. Asymptomatic Hematuria / Proteinuria

5. The Chronic Nephritic Syndrome

(Chronic Renal Failure)
 THE BASIC STRUCTURAL PATTERNS OF
GLOMERULAR INJURY
1.- Epithelial Cell Disease (Minimal Change Disease)
2.- Focal Segmental Glomerulosclerosis
3.- Membranous Nephropathy
4.- Diffuse Proliferative Glomerulonephritis
5.- Membranoproliferative Glomerulonephritis
6.- Crescentic Glomerulonephritis
7.- Focal Proliferative and Necrotizing
Glomerulonephritis
8.- Mesangial Proliferative Glomerulonephritis
9.- Basement Membrane Abnormalities
10.- Focal Global Glomerulosclerosis, tubulointersitial
inflamation/fibrosis, arteriosclerosis
 THE CLINICAL SYNDROMES
1. The acute Nephrotic Syndrome

2. The Acute Nephritic Syndrome

3. Rapidly Progressive Glomerulonephritis

4. Asymptomatic Hematuria / Proteinuria

5. The Chronic Nephritic Syndrome

(Chronic Renal Failure)
THE NEPHROTIC SYNDROME

Proteinuria (>3.5g/day)
Hypoalbuminemia
Hyperlipidemia
Lipiduria
Edema
Bland urine sediment
 THE BASIC STRUCTURAL PATTERNS OF
GLOMERULAR INJURY
1.- Epithelial Cell Disease (Minimal Change Disease)
2.- Focal Segmental Glomerulosclerosis
3.- Membranous Nephropathy
4.- Diffuse Proliferative Glomerulonephritis
5.- Membranoproliferative Glomerulonephritis
6.- Crescentic Glomerulonephritis
7.- Focal Proliferative and Necrotizing
Glomerulonephritis
8.- Mesangial Proliferative Glomerulonephritis
9.- Basement Membrane Abnormalities
10.- Focal Global Glomerulosclerosis, tubulointersitial
inflamation/fibrosis, arteriosclerosis
THE ACUTE NEPHROTIC SYNDROME

The structural abnormality shared by

all nephrotic conditions or diseases
with heavy proteinuria is diffuse
simplification or “fusion” of the foot
processes of the glomerular visceral
epithelial cells.
 NORMAL MORPHOLOGY

AFOG

SILVER STAINING
NORMAL MORPHOLOGY
PODOCYTE
 MINIMAL CHANGE DISEASE
DIFFUSE EPITHELIAL CELL DISEASE
Dr Helmut Rennke
Minimal Change Disease: high power LM of a glomerulus.
Notice normal cellularity and normal thickness of the GBM
 SILVER STAINING

PAS
MCD – diffuse effacement
of podocytic foot processes

Prawidłowe wypustki
 FOCAL AND SEGMENTAL GLOMERULOSCLEROSIS
(FGS)
1. IDIOPATHIC OR PRIMARY FGS
-background: due to the presence of circulatory factor that damages podocytes
-manifestation: acute nephrotic syndrome (+/- erythrocyturia), edema
-morphologically: diffuse, global fusion of podocytic foot processes, progressive tuft
sclerotisation

2. SECONDARY FGS
-background:
- viruses,
- drugs,
- genetical bacground,
- compensatory mechanisms secondary to relevant or irrelevant deficit in the
number of nephrons
-manifestation: typically slowly rising proteinuria, usually with erythrocyturia
-morphologically: focal, segmental fusion of podocytic foot processes,
progressive tuft sclerotisation
FSGS LM shows characteristic segmental collapse of the tuft (between
9 and 1 o'clock) with adhesion to the capsule and hyaline accumulation
(most prominent at 9 o'clock).
 Vascular pole
FSGS

Adhsion to Bowman’s capsule,

SILVER STAINING
segmental sclerotizations

PAS

Vascular pole
Primary FSGS: EM, low power, showing diffuse obliteration and simplification of foot processes
(fusion) in a glomerulus not involved by the segmental collapse.
This is indistinguishable from minimal change.
Secondary FSGS: low power LM of a patient with unilateral renal agenesis, slight obesity, and
slowly increasing proteinuria that has reached nephrotic range recently. Patient does not have
hypoalbuminemia or edema. Four enlarged glomeruli are present. One of them (focal), second
from left, has a segmental area of capillary collapse. Notice also a small area of tubules
(center, upper half) with thickened basement membranes and slight interstitial fibrosis. .

PAS
Secondary FSGS, unilateral renal agenesis: The "fusion" occurs in general much more
focally in these secondary forms of FGS when compared to the more diffuse obliteration of foot
processes in the primary forms.

Preserved foot
processes

fused foot processes

MEMBRANOUS GLOMERULOPATHY
(GLOMERULONEPHRITIS)
 SILVER STAINING

MEMBRANOUS GN

„SPIKES” ON THE
OUTER ASPECT OF
GBM

PAS
 Membranous nephropathy: Immunofluorescence microscopy.
fine granular fluorescence pattern along the peripheral capillary wall

IgG, light chain lambda, kappa

Membranous nephropathy. Numerous, sometimes confluent electron dense deposits in the
subepithelial space (asterisks) are separated from each other by "spikes" of matrix material (arrows)
that extend from the basement membrane toward the epithelial cells. This gives the appearance of the
deposits being partially incorporated into the basement membrane.

* *
*

*
*
 CONDITIONS ASSOCIATED
WITH MEMBRANOUS NEPHROPATHY
1.- IDIOPATHIC MEMBRANOUS NEPHROPATHY
- Ag: phospholipase A2receptor (PLA2R) (may be shown in a biopsy)
in patient;’s blood: anti PLA2R

2.- AUTOIMMUNE DISEASES

- SLE and RA
- Hashimoto's disease, Grave's disease,
- MCTD,
- Sjögren's syndrome,
- primary biliary cirrhosis,
- bullous pemphigoid,
- dermatitis herpetiformis,
- ankylosing spondylitis,
- small bowel enteropathies
 CONDITIONS ASSOCIATED WITH
MEMBRANOUS NEPHROPATHY
3.- INFECTIOUS OR PARASITIC DISEASES
- Hepatitis B and C
- Syphilis
- Filariasis, schistosomiasis,malaria, leprosy, enterococcal
endocarditis

4.- DRUGS
- Au, Hg, Penicillamine, Captopril,
- NSAIDs
- Hydrochlorothiazide, Trimethadione,
- Chlormethiazole
 THE CLINICAL SYNDROMES
1. The Nephrotic Syndrome

2. The Acute Nephritic Syndrome

3. Rapidly Progressive Glomerulonephritis

4. Asymptomatic Hematuria / Proteinuria

5. The Chronic Nephritic Syndrome

(Chronic Renal Failure)
 THE ACUTE NEPHRITIC
SYNDROME

Hematuria
(red cell casts, dysmorphic RBCs)
Oliguria
Azotemia
Hypertension
Edema
 THE ACUTE NEPHRITIC
SYNDROME
Diseases characterized by the acute
nephritic syndrome are associated invariably
with deposition of immune complexes in the
more proximal layers of the glomerular
capillary wall, in close proximity to the
endothelial cell surfaces.
 THE BASIC STRUCTURAL PATTERNS OF
GLOMERULAR INJURY
1.- Epithelial Cell Disease (Minimal Change Disease)
2.- Focal Segmental Glomerulosclerosis
3.- Membranous Nephropathy
4.- Diffuse Proliferative Glomerulonephritis
5.- Membranoproliferative Glomerulonephritis
6.- Crescentic Glomerulonephritis
7.- Focal Proliferative and Necrotizing
Glomerulonephritis
8.- Mesangial Proliferative Glomerulonephritis
9.- Basement Membrane Abnormalities
10.- Focal Global Glomerulosclerosis, tubulointersitial
inflamation/fibrosis, arteriosclerosis
Diffuse proliferative glomerulonephritis.
Notice the significant increase in the intracapillary cellularity and the presence of
neutrophils within the capillaries in the glomerulus.

PAS
Diffuse proliferative glomerulonephritis:
High power LM of a hypercellular glomerulus; numerous capillaries contain
inflammatory cells, mostly neutrophils. Notice the red blood cells in a distal tubule,
to the left of the glomerulus (arrow).

H&E
 DIFFUSE PROLIFERATIVE GLOMERULONEPHRITIS.
IMMUNOMORPHOLOGICAL PICTURE

IgG, C3

IgM, C3
Type of injury:
DIFFUSE PROLIFERATIVE GN HUMP
Disease:
ACUTE POSTSTREPTOCOCAL GN

neutrophils

IgG, C3
 Ig, C3
Type of injury:
DIFFUSE PROLIFERATIVE GN

Disease:
GN IN A COURSE OF HCV INFECTION
 Diffuse proliferative glomerulonephritis
E in a patient with recent hepatitis C
infection.
Ultrastructural details of subendothelial
deposits.
Immune deposits are present exclusively
D in the subendothelial space.
D Early formation of a second basement
membrane (arrows) by the displaced
endothelium has resulted in an early
double contour.
 CONDITIONS ASSOCIATED WITH DIFFUSE
PROLIFERATIVE GLOMERULONEPHRITIS

• Acute Postinfectious Glomerulonephritis:

bacterial: streptococcal, staphylococcal, pneumococcal, and typhoid fever
viral: varicella, mumps, ECHO and Coxsackie, infectious mononucleosis,
hepatitis B, hepatitis C with cryoglobulins, measles
Other: syphilis, leptospirosis, toxoplasmosis, falciparum malaria

Diffuse proliferative lupus nephritis

Dense Deposit Diseases early phase
Essential mixed cryoglobulinemia, early phase
Some cases of glomerulopathies related to monoclonal gammapathies
 MEMBRANOPROLIFERATIVE
GLOMERULONEPHRITIS (MPGN)
Membranoproliferative glomerulonephritis:
Light microscopy of a glomerulus with predominantly mesangial hypercellularity and occasional
polymorphonuclear leukocytes in the capillaries. There is also prominent thickening (double contours)
of the capillary wall.
Clinical manifestation: CHRONIC nephrotic syndrome and nephritic syndrome
Membranoproliferative glomerulonephritis:
Light microscopy of a glomerulus with prominent thickening (double contours) of the capillary wall.
NO increase in cellularity.
Clinical manifestation: CHRONIC nephrotic syndrome.
 Membranoproliferative glomerulonephritis.
newly synthesized thin basement membrane (arrows) ,
a broad layer with subendothelial electron dense deposits (asterix)

C
US *
* *
* *
* ENDOTHELIUM

C
 CONDITIONS ASSOCIATED WITH A
MEMBRANOPROLIFERATIVE PATTERN OF INJURY
1. IMMUNE DEPOSITS-MEDIATED DISEASES (glomerulonephritis)
2. THROMBOTIC ANGIOPATHIES
3. DEPOSITION DISEASE

1. IMMUNE COMPLEX-MEDIATED DISEASES

Chronic infections:
- Viral: hepatitis B, hepatitis C and essential mixed cryoglobulinemia
- Bacterial: endocarditis, infected ventriculo-atrial (or jugular) shunt, multiple
visceral abscesses, leprosy, meningococcal meningitis
- Protozoa: malaria, schistosomiasis
- Other infections: mycoplasma, ?Borreliosis, Leishmaniasis; parasitic diseases
Miscellaneous:
- Chronic liver disease (cirrhosis and alpha1-antitrypsin deficiency)
- glomerulopathies related to monoclonal gammapathies
 CONDITIONS ASSOCIATED WITH A
MEMBRANOPROLIFERATIVE PATTERN OF INJURY
1. IMMUNE DEPOSITS (IMMUNOLOGICAL COMPLEXES OR COMPLEMENT)
MEDIATED DISEASES:

Chronic infections:
- Viral: hepatitis B, hepatitis C and essential mixed cryoglobulinemia
- Bacterial: endocarditis, infected ventriculo-atrial (or jugular) shunt, multiple visceral
abscesses, leprosy, meningococcal meningitis
- Protozoa: malaria, schistosomiasis
- Other infections: mycoplasma, ?Borreliosis, Leishmaniasis; parasitic diseases

Autoimmune diseases:
- SLE
- Sjögren syndrome
- Rheumatoid arthritis
- Inherited complement deficiencies
Idiopathic forms of MPGN
AMYLOIDOSIS
CLINICAL PICTURE:

NON-NEPHROTIC PROTEINURIA NEPHROTIC SYNDROME

TWO MAIN TYPES:

AMYLOIDOSIS AL: related to
plasma cell dyscrasias
(bad prognosis),
AMYLOIDOSIS AA: related to
chronic inflammatory
processes

Less common:
congo stain
HEREDITARY AMYLOIDOSIS
AMYLOIDOSIS
AMYLOIDOSIS

Amyloid forms fibrils

(electron
microscopy)
 THE CLINICAL SYNDROMES
1. The Nephrotic Syndrome

2. The Acute Nephritic Syndrome

3. Rapidly Progressive Glomerulonephritis

4. Asymptomatic Hematuria / Proteinuria

5. The Chronic Nephritic Syndrome

(Chronic Renal Failure)
 RAPIDLY PROGRESSIVE
GLOMERULONEPHRITIS

Rapid decline in renal function

(over several days or few weeks)

Active urine sediment

Usually no edema and no hypertension

 RAPIDLY PROGRESSIVE
GLOMERULONEPHRITIS
Clinical conditions that evolve with rapidly
progressive decline in renal function and an
active urine sediment are usually
characterized by an inflammatory process
that results in the formation of cellular
crescents within Bowman’s space
(crescents).
 THE BASIC STRUCTURAL PATTERNS OF
GLOMERULAR INJURY
1.- Epithelial Cell Disease (Minimal Change Disease)
2.- Focal Segmental Glomerulosclerosis
3.- Membranous Nephropathy
4.- Diffuse Proliferative Glomerulonephritis
5.- Membranoproliferative Glomerulonephritis
6.- Crescentic Glomerulonephritis
7.- Focal Proliferative and / or Necrotizing GN
8.- Mesangial Proliferative Glomerulonephritis
9.- Basement Membrane Abnormalities
10.- Focal Global Glomerulosclerosis, tubulointersitial
inflamation/fibrosis, arteriosclerosis
 CLINICAL CONDITIONS ASSOCIATED WITH
FOCAL PROLIFERATIVE AND NECROTIZING
GLOMERULONEPHRITIS

- IgA nephropathy/ Henoch-Schoenlein purpura

- Various vasculitides, early phase.
- Early idiopathic crescentic glomerulonephritis,
including Goodpasture's syndrome
- Immune complex-mediated diseases
Lupus nephritis, WHO class III
Postinfectious Glomerulonephritis (SBE)
FOCAL PROLIFERATIVE AND NECROTIZING
GLOMERULONEPHRITIS
FOCAL PROLIFERATIVE AND NECROTIZING
GLOMERULONEPHRITIS
 Type III RPGN
HE
Pauci-immune
ANCA (+)
necroticans GN

SEGMENTAL TUFT NECROSIS

Fibrinogen within glomeruli

CRESCENTIC GN
BREAKS in GBM
CRESCENTIC GN

HE

PAS
PAUCI IMMUNE
FOCAL GN:

CHRONIC LESIONS
CRESCENTIC GLOMERULONEPHRITIS IN A PHASE
OF CRESCENT FIBROSIS
 CRESCENTIC GLOMERULONEPHRITIS IN A PHASE
OF CRESCENT FIBROSIS
low power light microscopy, showing the diffuse nature of the condition (most glomeruli are involved
with some degree of "extracapillary proliferation“ (crescent formation) outside the tuft but inside
Bowman's capsule
 CRESCENTIC GLOMERULONEPHRITIS IN A PHASE
OF CRESCENT FIBROSIS
Organizing stage of the disease. This image shows a fibro-cellular crescent. Notice the
collapsed and fragmented capillary tuft (arrows)

COLLAPSED
GLOMERULAR
TUFT
CRESCENTIC GN:
active and chronic lesions
Crescentic glomerulonephritis: chronic stage, with fibrosed crescents that have obliterated and fragmented the glomerular tuft.
The remnants of the original tufts can be recognized as strongly positive PAS material within the pale-staining scar tissue that
represents the acellular and now completely organized crescent.
Anti-GBM WITH IMMUNOLOGIC
COMPLEXES

PAUCI IMMUNE
CRESCENTIC GLOMERULONEPHRITIS
- Type I, anti-GBM disease
- Type II, immune complex-mediated
post-infectious GN, IgA nephropathy, MPGN,
Systemic diseases (SLE, RA, H-S purpura)
-Type III, pauci immune (ANCA-associated)
Vasculitides (ANCA-associated):
microscopic form of polyarteritis nodosa,
Wegener's granulomatosis
Churg-Strauss syndrome
Drug-induced vasculitides

.
 ANTI GBM DISEASE/GOODPASTURE’S SYNDROME

IgG, linear desposits along GBM

immunofluorescence microscopy reacted for IgG. Characteristic linear staining in a ribbon-like
pattern along the GBM in a case of anti-GBM antibody-mediated glomerulonephritis.
 PATHOGENESIS OF ANCA-ASSOCIATED VASCULITIS

Upon stimulation PMNs actively

release webs of nuclear derived
chromatin fibres called NETs into the
extracellular space.

These NETs are decorated with

histones and antimicrobial cytoplasmic
proteins, including PR3 and MPO, and
are able to capture and kill microbes
extracellularly.

The current evidence suggests that

NETs are directly involved in
endothelial damage and thrombosis as
well as ANCA induction.

Schönermarck U, et al. NDT(2015) 30: i46–i52

 SMALL VESSEL VASCULITIS
PAUCI IMMUNE
- RENAL INVOLVEMENT

Necrotizing arteritis
Necrotizing GN
SMALL VESSEL VASCULITIS
PAUCI IMMUNE
- RENAL INVOLVEMENT

ARTERIAL
WALL
NECROSIS

FIBRINOGEN
 SMALL VESSEL VASCULITIS
PAUCI IMMUNE
- RENAL INVOLVEMENT
ACUTE PHASE
 SMALL VESSEL VASCULITIS
PAUCI IMMUNE
- RENAL INVOLVEMENT
Chronic, occlusive phase elastica

Fibrotic tissue
 THE CLINICAL SYNDROMES
1. The Nephrotic Syndrome

2. The Acute Nephritic Syndrome

3. Rapidly Progressive Glomerulonephritis

4. Asymptomatic Hematuria / Proteinuria

5. The Chronic Nephritic Syndrome

(Chronic Renal Failure)
 ASYMPTOMATIC HEMATURIA/
NON NEPHROTIC PROTEINURIA

Hematuria or proteinuria
(persistent microhematuria)
Usually normal renal function
(early during the course)
Usually no hypertension or edema
 ASYMPTOMATIC HEMATURIA/
NON NEPHROTIC PROTEINURIA

These conditions are characterized

morphologically either by focal necrotizing
and/or inflammatory lesions of the glomeruli
or by basement membrane anomalies that
result in greater capillary fragility.
 THE BASIC STRUCTURAL PATTERNS
OF GLOMERULAR INJURY
1.- Epithelial Cell Disease (Minimal Change Disease)
2.- Focal Segmental Glomerulosclerosis
3.- Membranous Nephropathy
4.- Diffuse Proliferative Glomerulonephritis
5.- Membranoproliferative Glomerulonephritis
6.- Crescentic Glomerulonephritis
7.- Focal Proliferative and Necrotizing
Glomerulonephritis
8.- Mesangial Proliferative Glomerulonephritis
9.- Basement Membrane Abnormalities
10.- Focal Global Glomerulosclerosis, tubulointersitial
inflamation/fibrosis, arteriosclerosis
 MESANGIOPROLIFERATIVE
GLOMERULONEPHRITIS

- IgA Nephropathy
- Idiopathic Mesangioproliferative GN
- Recovery phase of a postinfectious
glomerulonephritis
- SLE WHO Class II, mesangial form,
and other IC-mediated diseases
- Some of the deposition diseases
Mesangioproliferative glomerulonephritis.
There is prominent expansion of the mesangium by matrix and cells.( PAS)
IGA NEPHROPATHY
THE MOST COMMON TYPE POF CHRONIC GLOMERULONEPHRITIS
IN THE WORLD,
particularly common in Asia

Immunofluorescence microscopy: There is characteristic deposition of IgA

in a mesangial pattern in all glomeruli.

IgA
IgA nephropathy. This electron micrograph shows preservation of the structural details
of the peripheral capillary wall, in particular notice the well preserved interdigitating foot
processes. The mesangium contains numerous, large, confluent electron dense deposits
(arrows). CL+capillary lumen; US=urinary space; Ep=visceral epithelial cell.
CLINICAL CONDITIONS ASSOCIATED WITH
GLOMERULAR BASEMENT MEMBRANE
ABNORMALITIES
Hereditary nephritis:
Classical Alport syndrome
Autosomal recessive hereditary nephritis
Autosomal dominant hereditary nephritis
Thin basement membrane disease (TBMD)
Alport syndrome.
Notice the extreme fragmentation of the lamina densa, resulting in a
characteristic “basket weave” pattern.
Alport syndrome.
Notice the extreme fragmentation of the lamina densa, resulting in a
characteristic “basket weave” pattern.
TBMD Alport syndrome
GBM thinner than normal GBM malformation
 THE CLINICAL SYNDROMES
1. The Nephrotic Syndrome

2. The Acute Nephritic Syndrome

3. Rapidly Progressive Glomerulonephritis

4. Asymptomatic Hematuria / Proteinuria

5. The Chronic Nephritic Syndrome

(Chronic Renal Failure)
CHRONIC NEPHRITIC SYNDROME
Azotemia
Active urine sediment (variable)
Proteinuria (variable)
Past history of RPGN, nephrotic syndrome,
or nephritic syndrome
Hypertension
 CHRONIC RENAL FAILURE
CHRONIC NEPHRITIC SYNDROME
The structural equivalent of this syndrome is
chronic renal disease, with secondary FSGS,
tubular atrophy, interstitial fibrosis, and variable
degree of arterial and arteriolar sclerosis. A more
precise diagnosis can often be established by
immunohistochemical and ultrstructural studies.
 THE BASIC STRUCTURAL PATTERNS OF
GLOMERULAR INJURY
1.- Epithelial Cell Disease (Minimal Change Disease)
2.- Focal Segmental Glomerulosclerosis
3.- Membranous Nephropathy
4.- Diffuse Proliferative Glomerulonephritis
5.- Membranoproliferative Glomerulonephritis
6.- Crescentic Glomerulonephritis
7.- Focal Proliferative and Necrotizing
Glomerulonephritis
8.- Mesangial Proliferative Glomerulonephritis
9.- Basement Membrane Abnormalities
10.- Focal Global Glomerulosclerosis, tubulointersitial
inflamation/fibrosis, arteriosclerosis
MORPHOLOGICAL PICTURE OF END STAGE KIDNEY
- FSGS,
- tubulointerstitial inflammation and scarring
- arteriosclerosis
CKD: examples

CHRONIC PYELONEPHRITIS

KIDNEY’S
CAPSULE

HE
CKD: examples
REFLUX NEPHROPATHY AND CHRONIC
PYELONEPHRITIS
CORTICAL
ATROPHY

CHRONIC
INFLAMMATION AND
FIBROSIS

HE
CKD: examples
ADVANCED DIABETIC KIDNEY DISEASE and
ARTERIONEPHROSCELROSIS
CKD: examples
MYLOMA KIDNEY
- chronic kidney disease
- caused by pathologic protein released by
neoplastic plasma cells

Pathologic protein fills tubular

lumens and Bowman’s capsule,

Chronic tubulointerstitial
inflammation and scarring
MYLOMA KIDNEY

Light chains (usually kappa)