PATHOGENESIS OF GLOMERULAR

AND TUBULO-INTERSTITIAL DISEASES

Dr. dr. Ni Wayan Winarti, Sp.PA, Subsp.URL(K)

Prodi/Dep/KSM Patologi Anatomik
FK Unud/RSUP Prof. Dr. IGNG Ngoerah Denpasar
April, 2023
INTRODUCTION
The study of kidney 🌍The early manifestations tend to be distinct
diseases → four basic 🌍Some components seem to be more vulnerable to
components of kidney specific forms of injury
🌓Glomeruli • Most glomerular diseases are mostly immunologically
🌓Tubules mediated
• Tubular and interstitial disorders are frequently caused by
🌓Interstitial tissue toxic or infectious agents
🌓Blood vessels • Primary disorders of the blood vessels → affect all the
structures supplied by these vessels

All forms of chronic kidney disease, whatever the origin, ultimately

damage all four components of the kidney → end-stage kidneys
 Clinical manifestation of kidney ds
🌔Azotemia
🌔Uremia
🌔Syndromes due to
glomerular ds
🌔Acute kidney injury
🌔Chronic kidney ds
🌔ESRD
🌔Renal tubular defects
🌔UT obstruction & renal
tumors
🌔UTI
🌔Nephrolithiasis
 Clinical manifestation of kidney ds
🌔Azotemia Azotemia
🌔Uremia • Biochemical abnormality that refers to an elevation of BUN and
🌔Syndromes due to creatinine levels → decreased GFR
glomerular ds • Causes: Renal, Prerenal, Postrenal
🌔Acute kidney injury
🌔Chronic kidney ds Uremia
🌔ESRD • Azotemia + clinical signs and symptoms and biochemical
abnormalities
🌔Renal tubular defects
• Characterized by
🌔UT obstruction & renal • failure of renal excretory function
tumors • metabolic and endocrine alterations resulting from renal
🌔UTI damage.
• Frequently manifest secondary involvement of GI, peripheral
🌔Nephrolithiasis nerves, heart
 Clinical manifestation of kidney ds
🌔Azotemia The nephritic syndrome
• Grossly visible or microscopic hematuria with dysmorphic red cells and
🌔Uremia red cell casts on urinalysis
🌔Syndromes due to • Diminished GFR
glomerular ds • Mild to moderate proteinuria
• Hypertension
🌔Acute kidney injury
🌔Chronic kidney ds The nephrotic syndrome
🌔ESRD • Heavy proteinuria (>3.5 gm/day)
• Hypoalbuminemia
🌔Renal tubular defects • Severe edema
🌔UT obstruction & renal • Hyperlipidemia
tumors • Lipiduria
🌔UTI
🌔Nephrolithiasis Asymptomatic hematuria or/and proteinuria
• Due to subtle or mild glomerular abnormalities
 Clinical manifestation of kidney ds
🌔Azotemia Acute kidney injury
• Characterized by
🌔Uremia • Rapid decline in GFR (within hours to days)
🌔Syndromes due to • Dysregulation of fluid and electrolyte balance
glomerular ds • Retention of metabolic waste products, including urea and creatinine
• In severe forms → oliguria or anuria
🌔Acute kidney injury • It can result from glomerular, interstitial, vascular or acute tubular
🌔Chronic kidney ds injury
🌔ESRD
Chronic kidney disease
🌔Renal tubular defects
• GFR that is persistently < 60 ml/minute/1.73 m2 for at least 3 months,
🌔UT obstruction & renal from any cause, and/or persistent albuminuria
tumors • Mild (clinically silent) to severe (prolonged uremia)
🌔UTI
🌔Nephrolithiasis End-stage renal disease (ESRD)
• GFR < 5% of normal → the terminal stage of uremia
 Clinical manifestation of kidney ds
🌔Azotemia
🌔Uremia Renal tubular defects
🌔Syndromes due to • Dominated by polyuria, nocturia, and electrolyte disorders
glomerular ds (e.g., metabolic acidosis)
🌔Acute kidney injury • Caused by:
🌔Chronic kidney ds • Diseases that directly affect tubular structures (e.g., the
🌔ESRD nephronophthisis-medullary cystic disease complex)
🌔Renal tubular defects • Diseases that cause defects in specific tubular functions
• inherited (e.g., familial nephrogenic diabetes, cystinuria, renal
🌔UT obstruction & renal tubular acidosis)
tumors • acquired (e.g., lead nephropathy)
🌔UTI
🌔Nephrolithiasis
 Clinical manifestation of kidney ds
🌔Azotemia
Urinary tract obstruction and renal tumors
🌔Uremia
• Varied clinical manifestations based on the specific anatomic
🌔Syndromes due to location and nature of the lesion
glomerular ds
🌔Acute kidney injury
Urinary tract infection
🌔Chronic kidney ds • characterized by bacteriuria and pyuria
🌔ESRD • may be symptomatic or asymptomatic
🌔Renal tubular defects
🌔UT obstruction & renal Nephrolithiasis (renal stones)
tumors • manifested by spasms of severe pain (renal colic) and hematuria
🌔UTI • often recurrent
🌔Nephrolithiasis
 GLOMERULAR DISEASES
(GLOMERULONEPHRITIS/GLOMERULOPATHIES)
Glomerulus
 Classification of GNs
Primary GN : kidney is the only Secondary GN : associated with
or predominant organ involved systemic ds or hereditary disorders
 Pathogenesis of GN

Most forms of primary

GN and many of the
secondary GN are
underlied by immune
mechanisms

Some non-immune
mechanisms
→ Evidence: the presence of activated
macrophages and T cells and their products
in the glomerulus in some forms of GNs
→ Roles of sensitized T cells in some form of
GNs:
➢ cause glomerular injury
➢ involved in the progression

Example in C3 glomerulopathies
 Glomerular injury
Morphological alteration
-Hypercellularity
-Thickening of GBM CLINICAL SYNDROMES
-Hyalinosis
-Sclerosis
MEDIATORS
Complement activation
• induce leukocyte influx
(complement-neutrophil–
dependent injury)
• formation of C5b-C9
(membrane attack complex)
• cell lysis
• stimulates mesangial cells
to produce oxidants,
proteases, and other
mediators
Chemokines
• Monocyte
chemoattractant protein
1 → monocyte and
lymphocyte influx
Eicosanoids, nitric oxide, Cytokines, particularly IL-1
angiotensin, and endothelin and TNF
• involved in the hemodynamic • produced by infiltrating
leukocytes and resident
changes glomerular cells
• induce leukocyte adhesion and a
variety of other effects
Growth factors
• Platelet-derived growth factor (PDGF)
Coagulation system
→mesangial cell proliferation. • The presence of fibrin and thrombin →
• TGF-β, connective tissue growth factor,
may be a stimulus for crescent
formation
and fibroblast growth factor → ECM
deposition and hyalinization
• Vascular endothelial growth factor
(VEGF) → maintain endothelial integrity
and regulate capillary permeability
Epithelial Cell Injury (podocytopathies)

• Can be induced by immune or non immune

mechanism
• Antibodies to podocyte antigens
• Toxins, e.g. puromycin aminonucleoside
• Certain cytokines
• Certain viral infections such as human
immunodeficiency virus (HIV)
• Circulating factors
• Stereotypic morphologic changes in the
podocytes
• Effacement of foot processes
• Vacuolization
• Retraction and detachment of cells from the
GBM
• Clinically : proteinuria
Mechanisms of Progression in Glomerular
Diseases
The outcome of such injury depends on several factors, including
• the severity of renal damage
• the nature and persistence of the antigens
• the immune status, age and genetic predisposition of the host
 The effect of glomerular injury by cells and mediators can be seen
morphologically, and manifest in various clinical syndromes

Morphology
(pathologic response)
• Hypercellularity
• Thickening of basement
membrane
• Hyalinosis
• Sclerosis

Both primary and secondary GNs show similar morphology and clinical syndromes
Pathologic Responses of the Glomerulus to
Injury
🌗 Hypercellularity
Increase in the number of cells in the
glomerular tufts
• Proliferation of mesangial or endothelial
cells.
• Infiltration of leukocytes, including
neutrophils, monocytes, and, in some
diseases, lymphocytes.
• Both together are called endocapillary
proliferation.
• Formation of crescents
Proliferating glomerular epithelial cells
(predominately parietal but including some
visceral cells) and infiltrating leukocytes.
Pathologic Responses of the Glomerulus to
Injury
🌗Basement Membrane Thickening
• By light microscopy, best seen in
sections stained with periodic acid-
Schiff (PAS).
• By electron microscopy
• Deposition of amorphous electron-dense
material
• Increased synthesis of the protein
components of the basement membrane
• Formation of additional layers of
basement membrane matrices
Pathologic Responses of the Glomerulus to
Injury
🌗Hyalinosis and Sclerosis
🌍Hyalinosis
• Hyalin is an extracellular, amorphous material
composed of plasma proteins that have
insudated from the circulation into glomerular
structures
• LM: homogeneous and eosinophilic material
• May obliterate the glomerular capillary
lumens
🌍Sclerosis
• Deposition of extracellular collagenous matrix
• May be confined to mesangial areas, capillary
loops, or both.
• May result in obliteration affected glomeruli
Classification of GNs
Primary GNs
Named based on morphology and
immunopathogenesis
Secondary GNs
Named based on underlying ds
🌼Acute proliferative GN
🌼Crescentic GN
🌼Minimal change ds
🌼Focal Segmental Glomerulosclerosis
🌼Membranous Nephropathy
🌼Membranoproliferative GN
🌼IgA nephropathy
🌼Chronic GN
🌸Lupus Nephritis
🌸Diabetic nephropathy
🌸HIVAN
🌸etc
 Acute Proliferative Glomerulonephritis

• HPA pattern: diffuse proliferation of glomerular cells due to influx of

leukocytes
• IF: immune complex
• Exogenous Ag: APSGN, other infections
• Endogenous Ag: LN
• Classic example: Acute Post Streptococcal Glomerulonephritis (APSGN)
• Commonest clinical sign : nephritic syndrome
• Pathogenesis: circulating immune complex (initiated by exogenous antigen)
APSGN Streptococcal infection
Nephritic syndrome

Immune complex formation & deposition in GBM

Activation of complement system Low serum complement

Immune injuries

GBM fractures Hematuria

Cellular proliferation
Proteinuria
Capillary lumen obliteration

Glomerular blood flow decreased GFR decreased Distal sodium reabsorbtion

Oligouria
Azotemia
Retention of water and sodium

Blood volume increased Hipertensi

Edema
Glomerular enlargement + IgG deposit Subepithelial hump deposit
hypercellular
APSGN
 Crescentic Glomerulonephritis
• Rapidly progressive glomerulonephritis (RPGN)
• Nephritic syndrome with progressive loss of renal function → oligouria-anuria
GNs with Nephrotic Syndrome

1 5

3
 MINIMAL CHANGE DISEASE (MCD)

• Glomerular ds with:
• No or little abnormality on LM
• No deposit on IF
• Podocytes foot process effacement (FPE) on EM
• Pathogenesis: podocytopathy
• >>> in children → responsive to steroid therapy
 FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)
• Characterizes morphologically by focal and segmental lesion on glomerulus/i
• Focal : <50% of all glomeruli
• Segmental : <50% of glomerular tuft
• Causes: idiopathic, infections, adaptive response, etc
• Pathogenesis: podocytopathy

Segmental scar, attachment to BC, IgM, C3 entrapment in lesion FPE

random area
 MEMBRANOUS GLOMERULONEPHRITIS (MGN)
• Characterized by:
• GBM thickening + spike formation (LM)
• IgG + C3 positive staining (IF)
• Deposit (EM)
• Adult > children
• 75% idiophatic
• 25% associated with drug, malignancies, SLE, infection, other autoimmune ds (immune mediated
podocytopathy)
 MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS (MPGN)
& C3-RELATED GLOMERULONEPHRITIS

MPGN, morphologically characterized by:

• Thickening of glomerular capillary wall (duplication)
• Hyper cellularity in the glomerular capillary tuft
• Often: lobular configuration due to mesangial proliferation and expansion
3 histological pattern : MPGN I, II, III
✓Similar pattern of complement abnormality can lead to different
pathologies
✓Similar pathologic pattern can be caused by different complement
abnormalities

Immune deposits
• C3 predominant → C3 glomerulopathy
• C3 >2+ others (IF) + hyperdense deposits (EM) → DDD
• C3 ≤ 2+ others (IF) + intermediate dense deposits (EM) → other C3 GN
• C3 equal with/< others → MPGN-IC
• Idiopathic
• Identifiable cause (Lupus, infection, etc)

Note: C3 Glomerulopathy not always show MPGN pattern

 IgA NEPHROPATHY

• GN with dominant/codominant IgA deposit in mesangium in absence of

systemic ds
• LM: varied
• Mesangial cell proliferation &/ matrix expansion (most frequent)
• Focal segmental inflammation of glomeruli
• Crescent +/- necrosis
• Interstitial inflammation with eosinophils
• Normal glomerulus
• IF: IgA mesangial deposit (100%)
• C3(90%), IgG, IgM (50%), C1q (10%)
• EM: amorphous electron dense deposit in mesangium; occasionally
subepithelial/subendothelial
 IgA NEPHROPATHY

Oxford Classification: MEST + C

M=Mesangial proliferation (M0-M1); E=Endocapillary hypercellularity (E0-E1); S=Segmental Glomerulosclerosis (S0-S1); T=IFTA (T1-T3)
C=Crescent (C0-C1)
 CHRONIC GLOMERULONEPHRITIS

• End-stage glomerular disease

• May result from specific types of GN
• May develop without antecedent
history of any of the well-recognized
forms of acute GN
• Clinical manifestation: uremia
• insidious and slowly progressive
• death in years or decades
Diseases Affecting Tubules and Interstitium
🌒Most forms of tubular injury also involve the
interstitium → discussed together
🌒Two major forms of tubulo-interstitial diseases:
1. Ischemic or toxic tubular injury → acute tubular injury
2. Inflammatory involvement of the tubules and
interstitium → tubulointerstitial nephritis
 Acute Tubular Injury

🌿Acute tubular injury (ATI) is a clinicopathologic entity characterized by:

➢Clinically : acute renal failure
➢Morphologically : tubular injury/necrosis
(Old term : Acute tubular necrosis (ATN))
🌿ATI accounts for some 50% of cases of acute kidney injury (AKI) in
hospitalized patients

🌿Two form of ATI

1. Ischemic ATI
2. Toxic ATI
Ischemic ATI
Due to decreased or interrupted blood flow, include:
🌟Diffuse involvement of the intrarenal blood vessels
➢ Microscopic polyangiitis
➢ Malignant hypertension
➢ Microangiopathies
🌟Systemic conditions associated with thrombosis
➢ Hemolytic Uremic Syndrome [HUS]
➢ Thrombotic Thrombocytopenic Purpura [TTP]
➢ Disseminated Intravascular Coagulation [DIC]
🌟Decreased effective circulating blood volume, as occurs in
hypovolemic shock
Nephrotoxic ATI
Caused by direct toxic injury to the tubules
🌟Endogenous agents
• Myoglobin
• Hemoglobin
• Monoclonal light chains
• Bile/ bilirubin
🌟Exogenous agents
• Drugs → gentamicin and other antibiotics
• Radiocontrast dyes
• Heavy metals → mercury
• Organic solvents → carbon tetrachloride
Why tubular epithelial cells are sensitive to ischemia
and vulnerable to toxins?
• Increased surface area for tubular reabsorption
• Active transport systems for ions and organic acids
• High rate of metabolism and oxygen consumption that is required
to perform transport and reabsorption functions
• The capability for resorption and concentration of toxins
• Ischemic type:
• Patchy
• Most velnerable part: PST Ascending
HL
• Toxic type
• Extensive necrosis of PCT
• Distal tubules and ascending HL may
involved

Both types: DCT and CD contain casts

• Epithelial cells necrosis →
occlusion of lumens by necrotic
cells
• Tubulorhexis (damage of tubular
basement membrane)
• DCT and CD → hyaline
cast/Tamm Horsfall cast
• Regenerative epithelial cells (flat
epithelial cells with enlarged
hyperchromatic nuclei)
• Edema and inflammatory cells at
interstitium
Tubulointerstitial Nephritis

• Inflammatory injuries of the

tubules and interstitium
• often insidious in onset
• principally manifest by azotemia

• Primary vs Secondary
• Secondary :
• As progression of glomerular or
renal vascular ds
• Systemic disorder that affect kidney

TIN that caused by bacterial

infection commonly affect pelvis
and calices → pyelonephritis
 Pyelonephritis

• Inflammation affecting the tubules,

interstitium, and renal pelvis
• >85% gram (-) bacteria from GIT
• Routes :
• Hematogenous
• Ascending
• Predisposing factors for ascending infection:
• Urinary obstruction
• Vesicoureteral and intrarenal reflux
• Acute vs chronic
 - Tubular epithelial
cells necrosis
- Leukocyte (PMN)
casts
ACUTE PN
- Leukocytes
infiltrate at
interstitial
- Edema

- Tubular pithelial
cells atrophy
- Hyaline casts
CHRONIC PN
- MN cells
infiltrate at
interstitial
- Fibrosis
 Tubulointerstitial Nephritis Induced by Drugs and Toxins

1. Trigger an interstitial Immunologic reaction

immunologic reaction
2. Cause acute tubular injury
3. Cause subclinical but
cumulative injury to tubules
→ chronic renal insufficiency
• Type I or type IV hypersensitivity reaction
• Type I : eosinophils
• Type IV : mononuclear/granulomatous reaction, positive
skin test (methicillin and thiazide)
• The drugs function as haptens and covalently
bind to some plasma membrane or
extracellular component of tubular cells →
immunogenic

NSAIDs can cause tubulointerstitial nephritis and/or glomerular injury, (minimal

change disease or membranous nephropathy)
Clinical Features
• Begins about 15 days after exposure Morphology
to the drug
• Characterized by
• Fever
• Eosinophilia (which may be transient)
• Rash (in about 25% of individuals)
• Renal abnormalities
• Urinary findings
• Hematuria, minimal or no proteinuria,
and leukocyturia (sometimes including
eosinophils).
• Rising serum creatinine or acute kidney
injury with oliguria develops in about 50%
of cases, particularly in older patients
 SUMMARY
Pathogenesis of Glomerulonephritis and Acute Tubular Injury
• GNs are mainly mediated by immune mechanism, while ATI by ischemia and
toxic agents
• Clinical manifestations of GNs including: Nephrotic syndrome, Nephritic
syndrome, Asymptomatic hematuria/proteinuria, Rapidly progressive GN,
Chronic renal failure
• Pathologic alteration in GNs: hypercellularity, thickening of GBM, hyalinosis
and sclerosis
• Primary GNs are named after its pathologic features and
immunopathogenesis; secondary GNs based on the underlying ds
• ATI, a most common form of AKI, characterized clinically by decreased of GFR
and oligouria