Kidney (Part 1)

GENERAL PATHOLOGY: THE KIDNEY (PART 1)
Lectured By: Aije Bruzon-Hortel, MD

2nd Semester | AY 2021-2022
MORPHOLOGIC COMPONENTS Glomeruli Tubules Interstitium Blood Vessels
CLINICAL MANIFESTATIONS OF AZOTEMIA

RENAL DISEASES • Biochemical abnormality
• Elevation of BUN and Creatinine levels
• Decreased GFR
Ø PRERENAL AZOTEMIA – hypoperfusion of the kidneys that
impairs renal function in the absence of parenchymal
damage
Ø POSTRENAL AZOTEMIA – urine flow is obstructed distal to
the kidney
Ø UREMIA – failure of renal excretory fxn and a host of
metabolic and endocrine alterations resulting from renal
damage
NEPHRITIC SYNDROME
• A clinical entity caused by glomerular dse.
• Acute onset of either grossly visible hematuria or microscopic
hematuria w/ dysmorphic red cells and red casts on U/A
Ø Diminished GFR; mild to moderate proteinuria, HTN
NEPHOROTIC SYNDROME
• d/t glomerular dse
• Characterized by heavy proteinuria (3.5gm/day);
hypoalbuminemia, severe edema, hyperlipidemia, lipiduria
ASYMPTOMATIC HEMATURIA OR PROTENURIA

• A manifestation of subtle or mild glomerular dse.
ACUTE KIDNEY INJURY

• Rapid decline in GFR (hrs-days), w/ concurrent dysregulation of
fluid & electrolyte balance & retention of metabolic waste
products normally excreted by the kidney (urea and creatinine)
• Severe forms: oliguria and anuria (reduced or no urine flow)
• Result from glomerular, interstitial, vascular, or acute tubular
injury
GENERAL PATHOLOGY: THE KIDNEY (PART 1) | I Glomerular Diseases

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CHRONIC KIDNEY DISEASE

• Chronic renal failure
• Presence of a diminished GFR that is persistently
<60ml/min/1.73m2 for at least 3 mo., from any cause, and/or
persistent albuminuria
• End result of all chronic renal parenchymal dse.
END STAGE RENAL DISEASE (ESRD)

• <5% of normal GFR
• Terminal stage of uremia
RENAL TUBULAR DEFECTS

• Polyuria, nocturia, and electrolyte disorders
• Result of dse. that either directly affect tubular structure or
cause defects in specific tubular fxns (inherited or acquired
URINARY TRACT OBSTRUCTION

• Bacteriuria & pyuria
• May affect the kidney (pyelonephritis) or bladder (cystitis)
TUMORS
• Anatomic location & nature of the lesion
NEPHROLITHIASIS
• Manifested by spasms of severe pain (renal colic) & hematuria
GLOMERULUS
Filtering membrane:
✓ Fenestrated endothelial cell – prevents

filtration of blood cells but allows all
component of blood plasma to pass
through
✓ Glomerular BM – prevents filtration of
larger proteins
✓ Filtration slit between pedicels or
podocytes /visceral epithelial cell –
prevents filtration of medium sized
proteins

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CLASSIFICATIONS OF Primary Kidney is the only or predominant organ involved

Glomerulonephritis
GLOMERULAR DISEASES
Secondary Systemic disorders w/c also affect the glomerulus
Glomerulonephritis
Glomerulopathy Renal disorders w/c do not have a cellular inflammatory
component
PATHOLOGIC RESPONSES OF HYPERCELLULARITY

THE GLOMERULUS TO INJURY Characterized by an increase in the number of cells in the glomerular
(1) Hypercellularity tuft’s d/t:
(2) Basement Membrane (1) Proliferation of mesangial cells
Thickening (2) Infiltration of leukocytes à the presence of WBCs can contribute
(3) Hyalinosis to the hypercellularity of the glomerular tufts
(4) Sclerosis (3) Formation of crescents
Infiltration of Mesangial Cells

Normal Glomerulus Affected Glomerulus
✓ Capillary loops can be appreciated ✓ Increased number of mesangial cells
✓ In b/w the capillaries there is a thin ✓ Capillary loops cannot be appreciated well
mesangium wherein there is an oval shaped b/c of widened mesangial cells

nucleus (mesangial cells)
Infiltration of Leukocytes
Lobulated nuclei are indicative of

neutrophilic invasion
✓ Typical nuclei density ✓ High density of nuclei present

✓ No WBC invasion ✓↑ number of WBCs
Formation of Crescents

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✓ Capsule lined by simple squamous ✓ Proliferation of the epithelium à crescent

epithelium aka parietal epithelium formation in the Bowman’s space
✓ Glomerular tuft is also lined by simple ✓ Composition: cells from parietal and
squamous epithelium aka visceral epithelium visceral epithelium
✓ There is a space b/w these two structures
✓ Injury could lead to the proliferation of
epithelial cells
BASEMENT MEMBRANE THICKENING

Characterized as thickening of the capillary walls by light microscopy
(1) Deposition of electron-dense amorphous materials
(2) Increased synthesis in the BM
(3) Formation of additional layers of the BM
Deposition of Amorphous Electron-Dense Material

EM: Normal Glomerular Subepithelial electron-dense LM: Capillary Wall
Wall deposits “humps” Thickening
✓ Take note of the “hump” ✓ Capillary walls are darkly

on the epithelial side stained
✓ This is d/t BM thickening ✓ Special stain (H&E)
✓ Electron-dense = dark
Increased Synthesis of the Protein Components of the BM
EM: Normal Glomerular Widening of the mesangium LM: Thickened GBM w/
Wall Nodular Mesangial
Expansion
✓ Glomerular membrane is ✓ Appreciated the thickness

normally quite thin of the BM
Formation of Additional Layers of BM Matrices
EM: Normal Glomerular Subepithelial & LM: Thickening of capillary
Wall intramembranous material walls
deposited in BM
✓ Linearity à thin and one ✓ Matrix duplication ✓ Mesangium appears to be

line ✓ Subendothelial deposits widened d/t thickened
(most common) capillary walls

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HYALINOSIS
• Accumulation of material that is homogenous and eosinophilic
by light microscopy
• A consequence of endothelial or capillary wall injury & typically
the result of various forms of glomerular damage
Hyalinosis
✓ Not to be confused w/ crescent formation

✓ There is hypercellularity present in crescent formation
✓ Instead, replacement with eosinophilic material
✓ Composition: Hyaline – extracellular, amorphous material composed of plasma proteins
that have insudated from the circulation into the glomerular structures
SCLEROSIS
• Deposition of extracellular collagenous matrix confined either in
the mesangial areas or involve the capillary loops or both
• Sclerosis process may result to obliteration of some or all of the
capillary lumens in the affected glomeruli
Sclerosis
✓ Pinkish deposition represents the collagenous matrix

✓ Composition: deposition of collagen
CATEGORIES OF HISTOLOGIC CHANGES

• Capillary loop or mesangial – affects predominantly the
capillary of mesangial regions
• Diffuse – all of the glomeruli in the kidney
• Global – entirety of individual glomeruli
• Focal – involves only a fraction of glomeruli in the kidney
• Segmental – affecting a part of each glomerulus

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PATHOGENESIS OF Immune Mechanisms underlie most forms of primary glomerulopathy &

GLOMERULAR INJURY many of the secondary glomerular disorders
2 FORMS OF ANTIBODY-ASSOCIATED INJURY

(1) Injury by antibodies reacting in situ w/in the glomerulus by
binding
Ø Intrinsic – insoluble fixed glomerular antigens
Ø Extrinsic – molecules planted w/in the glomerulus
(2) Injury resulting from deposition of circulating antigen-antibody
complexes in the glomerular capillary wall or mesangium
DISEASES CAUSED BY IN SITU Immune complexes are formed locally by antibodies that react w/
FORMATION OF IMMUNE intrinsic tissue antigen or w/ extrinsic antigens “planted” in the
COMPLEXES glomerulus from the circulation
• The deposited circulating immune complex in the glomerulus
initiate complement or Fc receptor mediate leukocyte activation
à glomerular injury
HEYMANN NEPHRITIS
• Experimental membranous nephropathy in rats
• Localized immune rxn is induced by immunizing rats w/ an
antigen w/c is now known as megalin present in the epithelial
cell foot processes
• In humans, the known antigen is M-type phospholipase α2
receptor
• Rxn of Ab w/ Ag produce immune complex deposits along the
subepithelial aspects of the BM
Immunofluorescence microscopy:
• Pattern of immune deposits: Granular (reflective of the very
localized Ab-Ab interaction)
ANTIBODIES AGAINST PLANTED Ab’s can react in situ w/ Ag’s that are not normally present in the
ANTIGEN glomerulus but are “planted” there
• Planted Ag can be cationic molecules binding to anionic
molecules of the glomerulus
• DNA bacterial products w/c are deposited in the mesangium b/c
of their large size
Ø Ex. Infants fed w/ cow’s milk
DISEASES CAUSED BY Ab Ab bind to intrinsic Ag homogenously distributed along the entire length
DIRECTED AGAINST NOMRAL of the GBM
COMPONENTS OF THE GBM
GOODPASTURES SYNDROME
• Anti-GBM Ab are produced in response to a normal component
of the GBM w/c is a non-collagenous domain of a3 chain of
collagen type IV

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• These Ab may cross-react w/ the BM of the lung alveoli à

simultaneous lung and kidney lesions w/c is common in
Goodpasture’s syndrome
• Results in a diffuse linear pattern of staining for the Ab by
immunofluorescence techniques
GLOMERULONEPHRITIS Glomerular injury is caused by the trapping of circulating Ag-Ab
RESULTING FROM DEPOSITION complexes w/in the glomeruli
OF CIRCULATING IMMUNE • Antigens that trigger the formation of circulating immune
COMPLEXES complexes
Ø Endogenous – SLE, IgA nephropathy
Ø Exogenous – post-streptococcal glomerulonephritis
MECHANISMS OF GLOMERULAR Immune complexes elicit a local inflammatory rxn that produces injury
INJURY FOLLOWING IMMUNE (1) Binding of complement
COMPLEX FORMATION (2) Engagement of Fc receptors (WBC, mesangial cells) as
mediators
Electron microscopy: electron dense deposits

a. Mesangium
b. b/w EC & GBM
c. b/w outer surface of GBM & podocytes
Immunofluorescence microscopy: granular deposits

a. GBM
b. Mesangium
c. Both
Degraded by infiltrating leukocytes, mesangial cells, endogenous

proteases
Factors affecting the glomerular localization of Ag, Ab, IC:

(1) Molecular charge of reactants
1. Highly cationic – cross GBM, reside subepithelially
2. Highly anionic macromolecules – trapped subendothelially

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3. Neutral – accumulates in mesangium

(2) Size of reactants
1. Large molecules – not nephritogenic
CELL MEDIATED IMMUNITY IN Evidence includes:

GLOMERULONEPHRITIS • Sensitized T cells cause glomerular injury
• Involved in the progression of some glomerulonephritides
Ø Presence of activated macrophages, T cells, & their products
Proof of GN in humans
• Lacking
HOW DOES THE GLOMERULAR

DAMAGE ENSUE?
EPITHELIAL CELL INJURY Loss of podocytes à protein leakage

• FSGS
• Diabetic nephropathy
The postulated sequence is a consequence of antibodies specific to epithelial cell antigens,

toxins, cytokines, or other factors causing injury; this results in foot process effacement and

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sometimes detachment of epithelial cells and protein leakage through defective glomerular
basement membrane and filtration slits.
MECHANISMS OF PROGRESSION Once any renal disease, glomerular, or otherwise, destroys fxning
IN GLOMERUAL DISEASES nephrons & reduces the GFR to about 30-50% of normal, progression to
ESRF proceeds at a steady rate, independent of the original stimulus or
activity of the underlying disease
2 Major Histologic Chracteristics of Progressive Renal Damage
FOCAL SEGMENTAL GLOMERULOSCLEROSIS

• Progressive fibrosis involving portions of some glomeruli
develops after many types of renal injury & leads to proteinuria
and increasing fxnl impairement
TUBULOINTERSTITIAL FIBROSIS
• Tubulointerstitial injury, manifested by tubular damage and
intersitial inflammation, is a component of many acute & chronic
glomerulonephritides
NEPHRITIC SYNDROME ACUTE PROLIFERATIVE GN

Characterized by inflammation in
the glomeruli Poststreptococcal, Postinfectious
• Chracterized histologically by diffuse proliferation of glomerual
cells associated with influx (exudation) of leukocytes
• Typically caused by immune complexes
Poststreptococcal GN
• A prototypical glomerual disease of immune complex etiology
Etiology & Pathogenesis

• Caused by immune complexes containing streptococcal antigens
& specific Ab, w/c are formed in situ
Morphology
• Glomeruli: enlarged, hypercellular

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If microscopy: granular deposits in the mesangium; focal & sparse

deposits
Laboratory Findings
• Increased antistreptococcal antibody titers
• Decreased serum C3
RAPIDLY PROGRESSIVE • Characterized by rapid and progressive loss of renal fxn

(CRESCENTIC) GN associated w/ severe oliguria & signs of nephritic syndrome
• Immunologically mediated
A syndrome associated w/ severe
glomerular injury, but does not
denote a specific etiologic form of
glomerulonephritis
NEPHROTIC SYNDROME Pathophysiology

• Caused by a derangement in glomerular capillary walls resulting
in increased permeability to plasma proteins
MEMBRANOUS NEUROPATHY
• Characterized by diffuse thickening of the glomerual capillary
wall d/t the accumulation of deposists containing Ig along the
subepithelial side of the BM
Characteristic Histologic Findings:

• Thickened walls of the capillaries
• Black staining of the capillary loops w/c correponds to the
thickened BM of the capillaries
• Spikes that project into the urinary space

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MINIMAL CHANGE DISEASE • Benign disorder

• Chracterized by diffuse effacement of foot processes of visceral
epithelial cells (podocytes), detectablie only by electron
microscopy, in glomeruli that appear virtually normal by light
micrscopy
LM: normal glomeruli
• Normal BM & absence of proliferation

• Effacement of foot processes (arrows) & absence of deposits
Ø Principal lesion
FOCAL SEGMENTAL
GLOMERULOSCLEROSIS
Segmental sclerosis in one of three

glomeruli
C/cx: Most common cause of

nephrotic syndrome in adults
• Glomerual tuft appears normal in the first picture

• Increased eiosinophilia in the second picture along w/ decreased
nuclei bc the area is sclerotic
• The cells were replaced by collagen fibers hence less nuclei are
seen in the slide

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MEMBRANOPROLIFERATIVE GN • Best considered a pattern of immune-mediated injury rather

than a specific disease
• In most cases of type I MPGN there is evidence of immune
complexres in the glomerulus & activation of both classical &
alternative complement pathways
• Hypercellular – d/t E
• GBM thickening – double
contour track appearance
d/t duplication or splitting
of BM
• Lobular architecture
Silver stain – BM & mesangial

matrix
TYPE I
• Subendothelial deposists
TYPE II
• Intramembranous deposits
ISOLATED GLOMERULAR IgA NEPHROPATHY (BERGER DISEASE)

ABNORMALITIES • Characterized byt the presence of prominent IgA deposists in the
mesangial regions & recurrent hematuria
• The most common type of glomerulonephritis worldwide
• Diagnosis is made only by the detection of IgA deposition
Histologic Findings LM: Mesangioproliferative GN; focal proliferative GN

• Mesangial widening à very narrow urinary space
• Endocapillary proliferation
• Proliferation of mesangial cells & matrix
IF: Mesangial deposition of IgA
• Deposits must be IgA to confirm Berger Disease diagnosis

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HEREDITARY NEPHRITIS
A group of heterogenous familial renal diseases assocaited w/ mutations
in collagen genes that manifest primarily w/ glomerual injury
• X-linked inheritance
• Autosomal inheritance
CHRONIC GLOMERULONEPHRITIS
End-stage glomerular disease that may result from specific types of GN
or may develop w/o antecedent history of any of the well recognized
forms of acute GN
Microscopic findings
• Mason’s trichrome stains collagens or fibrosis à blue

• Blue structures – fibrotic/sclerotic glomeruli
• Few renal tubules and they are atrophic
• Interstitium is fibrotic and there are a lot of mononuclear
inflammatory cells
• Common among HTN px eventually will affect arteris and
arterioloes in glomerulus à sclerotic à narrowing of lumen

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GENERAL PATHOLOGY: THE KIDNEY (PART 1)

Lectured By: Aije Bruzon-Hortel, MD

MORPHOLOGIC COMPONENTS Glomeruli Tubules Interstitium Blood Vessels

CLINICAL MANIFESTATIONS OF AZOTEMIA

ASYMPTOMATIC HEMATURIA OR PROTENURIA

ACUTE KIDNEY INJURY

GENERAL PATHOLOGY: THE KIDNEY (PART 1) | I Glomerular Diseases

CHRONIC KIDNEY DISEASE

END STAGE RENAL DISEASE (ESRD)

RENAL TUBULAR DEFECTS

URINARY TRACT OBSTRUCTION

✓ Fenestrated endothelial cell – prevents

GENERAL PATHOLOGY: THE KIDNEY (PART 1) | I Glomerular Diseases

CLASSIFICATIONS OF Primary Kidney is the only or predominant organ involved

PATHOLOGIC RESPONSES OF HYPERCELLULARITY

Infiltration of Mesangial Cells

✓ Capillary loops can be appreciated ✓ Increased number of mesangial cells

mesangium wherein there is an oval shaped b/c of widened mesangial cells

Lobulated nuclei are indicative of

✓ Typical nuclei density ✓ High density of nuclei present

GENERAL PATHOLOGY: THE KIDNEY (PART 1) | I Glomerular Diseases

✓ Capsule lined by simple squamous ✓ Proliferation of the epithelium à crescent

BASEMENT MEMBRANE THICKENING

Deposition of Amorphous Electron-Dense Material

✓ Take note of the “hump” ✓ Capillary walls are darkly

✓ Glomerular membrane is ✓ Appreciated the thickness

✓ Linearity à thin and one ✓ Matrix duplication ✓ Mesangium appears to be

GENERAL PATHOLOGY: THE KIDNEY (PART 1) | I Glomerular Diseases

✓ Not to be confused w/ crescent formation

✓ Pinkish deposition represents the collagenous matrix

CATEGORIES OF HISTOLOGIC CHANGES

GENERAL PATHOLOGY: THE KIDNEY (PART 1) | I Glomerular Diseases

PATHOGENESIS OF Immune Mechanisms underlie most forms of primary glomerulopathy &

2 FORMS OF ANTIBODY-ASSOCIATED INJURY

GENERAL PATHOLOGY: THE KIDNEY (PART 1) | I Glomerular Diseases

• These Ab may cross-react w/ the BM of the lung alveoli à

Electron microscopy: electron dense deposits

Immunofluorescence microscopy: granular deposits

Degraded by infiltrating leukocytes, mesangial cells, endogenous

Factors affecting the glomerular localization of Ag, Ab, IC:

GENERAL PATHOLOGY: THE KIDNEY (PART 1) | I Glomerular Diseases

3. Neutral – accumulates in mesangium

CELL MEDIATED IMMUNITY IN Evidence includes:

HOW DOES THE GLOMERULAR

EPITHELIAL CELL INJURY Loss of podocytes à protein leakage

The postulated sequence is a consequence of antibodies specific to epithelial cell antigens,

GENERAL PATHOLOGY: THE KIDNEY (PART 1) | I Glomerular Diseases

2 Major Histologic Chracteristics of Progressive Renal Damage

FOCAL SEGMENTAL GLOMERULOSCLEROSIS

NEPHRITIC SYNDROME ACUTE PROLIFERATIVE GN

Etiology & Pathogenesis

GENERAL PATHOLOGY: THE KIDNEY (PART 1) | I Glomerular Diseases

If microscopy: granular deposits in the mesangium; focal & sparse

RAPIDLY PROGRESSIVE • Characterized by rapid and progressive loss of renal fxn

NEPHROTIC SYNDROME Pathophysiology

Characteristic Histologic Findings:

GENERAL PATHOLOGY: THE KIDNEY (PART 1) | I Glomerular Diseases

MINIMAL CHANGE DISEASE • Benign disorder

LM: normal glomeruli

• Normal BM & absence of proliferation

Segmental sclerosis in one of three

C/cx: Most common cause of

• Glomerual tuft appears normal in the first picture

GENERAL PATHOLOGY: THE KIDNEY (PART 1) | I Glomerular Diseases