PATHOGENESIS

OF
GLOMERULAR
AND TUBULO-
INTERSTITIAL
INJURY
I WAYAN JULI SUMADI
Dept. of Pathology Anatomy
School of Medicine
Udayana University
Email:
juli_sumadi@unud.ac.id
 Pathogenesis of Glomerular Injury
Glomerular disease
Nephritic syndrome
Nephrotic syndrome
Chronic glomerulonephritis
Pathogenesis of Tubulo-interstitial injury
Acute Tubular Necrosis/Injury
Tubulo-Interstitial Nephritis
Normal structure of the glomerulus
 Glomerular capillaries contain fenestrated epithelium.
Holes in the endothelial surface are important in the filtration
process.

Glomerular basement membrane (GBM)

Composed of type IV collagen
Heparan sulfate produces the negative charge of the GBM.
Albumin: strong negative charge and is not permeable.
Loss of the negative charge causes loss of albumin in the urine--
-Called selective proteinuria (e.g., minimal change disease)
Causes of GBM thickening
Deposition of immunocomplexes
Examplemembranous glomerulopathy
Increased synthesis of type IV collagen
Examplediabetes mellitus (DM)
 Visceral epithelial cells (VEC)
VEC: responsible for GBM synthesis
Contain podocytes (foot-like processes) and
slit pores between the podocytes
Serve as a distal barrier for preventing
protein loss in the urine
Fusion of the podocytes is present in any
cause of the nephrotic syndrome.
 Mesangial cells
Support the glomerular capillaries
Can release inflammatory mediators and proliferate
in disease
ExampleIgA glomerulopathy has mesangial
immunocomplex deposits

Parietal epithelial cells

Lining cells of Bowman capsule
Proliferation causes crescents that encroach upon
and destroy the glomerulus.
GLOMERULAR DS
Classification
of Glomerular
disease
Classification of glomerular disease
How many glomeruli?
Focal = only some glomeruli
Diffuse = all glomeruli affected
How much of a single glomerulus?
Segmental = only part of the glomerulus
Global = the entire glomerulus
Primary vs Secondary
primarily renal disease vs renal complication of systemic
disease
 Nomenclature and Description of Glomerular Disorders

TERM DESCRIPTION

Focal glomerulonephritis Only a few glomeruli are abnormal

Diffuse glomerulonephritis
Proliferative glomerulonephritis
Membranous glomerulonephritis
Membranoproliferative
glomerulonephritis
Focal segmental glomerulosclerosis
Crescentic glomerulonephritis
Primary glomerular disease
All glomeruli are abnormal
>100 nuclei in affected glomeruli
Thick GBM, no proliferative change
Thick GBM, hypercellular glomeruli
Fibrosis involving only a segment of the involved
glomerulus
Proliferation of parietal epithelial cells around
glomerulus
Involves only glomeruli and no other target organs
(e.g., minimal change disease)

Secondary glomerular disease Involves glomeruli and other target organs (e.g., SLE)

GBM, Glomerular basement membrane; SLE, systemic lupus erythematosus.

Pathogenesis of glomerular disease
Immune mediated
Immune complex (IC) formation/deposition
Intrinsic glomerular antigens (anti-GBM)
Circulating antigens deposited in glomerulus (Membranous GN)
Circulating immune complexes deposited in glomerulus (PSAGN)
Activation of complement
Cytokine release
Neutrophil / macrophage recruitment and activation
Activation of coagulation system
Antibody-mediated glomerular injury can result either from the deposition of circulating immune complexes
(A) or, more commonly, from in situ formation of complexes exemplified by anti-GBM disease (B) or
Heymann nephritis (C).
Pathogenesis of glomerular disease
Immune mediated
Subepithelial immune complexes
less inflammation
BM alterations +/- podocyte damage
Proteinuria
Subendothelial immune complexes inflammatory GN
more inflammation and cellular proliferation
Vessel damage
Haematuria
BM complexes
Rapidly progressive glomerulonephritis
Pathogenesis of glomerular disease
T cell mediated and
complement pathway
Activation of complement
inflammatory GN like
picture but no immune
deposits

Epithelial cell injury

Toxins / cytokines /
unknown factors
Loss of foot processes
Detachment from BM
Proteinuria
 Pathologic Responses of the Glomerulus
to Injury

hypercellularity crescent formation

 Pathologic Responses of the Glomerulus
to Injury

Basal membrane thickening Hyalinosis

Presentation of glomerular disease

NEPHROTIC SYNDROME

NEPHRITIC SYNDROME

CHRONIC
GLOMERULONEPHRITIS
 Glomerular diseases associated with
nephrotic syndrome
Primary
Minimal change disease
Membranous GN
Focal segmental glomerulosclerosis (FSGS)

Secondary
Diabetic nephropathy
Amyloidosis
 Nephrotic Syndrome
Glomerular injury is due to cytokines not neutrophils
Cytokines damage podocytes, causing them to fuse
together.
Cytokines destroy the negative charge of the GBM.
Clinical and laboratory findings
Key finding is proteinuria >3.5 g/24 hours.
Hypoalbuminemia
Generalized pitting edema and ascites due to
hypoalbuminemia cause a decrease in plasma oncotic
pressure.
Hypercholesterolemia/hyperlidiemia and lipiduria
Hypoalbuminemia increases synthesis of cholesterol (unknown
mechanism).
 Minimal change disease
Most common cause of nephrotic syndrome in
children; more common in girls than boys;
occurs in ~15% of adults with nephrotic
syndrome
T-cell cytokines cause the GBM to lose its
negative charge; selective proteinuria
(albumin not globulins)
 Minimal change disease
Light microscopy (LM) Normal
Immunofluorescence (IF) Normal (no
immune deposits)
Electron microscopy (EM) Fusion of
podocyte foot processes
 Glomerular diseases associated with
nephritic syndrome
Primary
Postinfectious / Diffuse proliferative GN
Membranoproliferative GN
IgA nephropathy (Mesangioproliferative GN)
Crescentic GN

Secondary
HSP
Systemic vasculitis
SLE
Systemic sclerosis
 Nephritic syndrome
Glomerular injury is primarily due to neutrophils
Clinical and laboratory findings:
Hypertension due to salt retention
Edema
Oliguria (~400 mL urine/day), due to decreased GFR
from inflamed glomeruli, tubular function intact
Hematuria (RBCs are present with irregular
membranes)
Glomeruli become inflamed from IC deposition causing
damage to RBC membranes (dysmorphic RBCs)
RBC casts are a key finding
Proteinuria is >150 mg/day, but <3.5 g/day
Acute Proliferative (Poststreptococcal,
Postinfectious) Glomerulonephritis
Most common type of postinfectious GN
Usually follows group A streptococcal infection
Subepithelial IC deposits with granular IF
ICs activate the complement system
Diffuse proliferative pattern with neutrophil infiltration
Clinical finding:
Hematuria 13 weeks following group A streptococcal
infection
periorbital edema (sodium retention); edema can
occasionally be more extensive and produce pitting in
dependent areas (e.g., ankles)
hypertension is usually transient
Acute proliferative glomerulonephritis. A, Normal glomerulus. B, Glomerular hypercellularity is due
to intracapillary leukocytes and proliferation of intrinsic glomerular cells. C, Typical electron-dense
subepithelial hump and a neutrophil in the lumen. D, Immunofluorescent stain demonstrates
discrete, coarsely granular deposits of complement protein C3, corresponding to humps
illustrated in part C.
 Chronic glomerulonephritis
End stage glomerular diseases:
Membrano-proliferative GN
Focal Segmental Glomerulosclerosis
Membranous nephropathy
Ig A nephropathy
may develop without antecedent history
TUBULOINTERSTITIAL DS
 Ischemic

Acute tubular
necrosis (ATN)
Nephrotoxic

Tubulointersti Acute
tial ds pyelonephritis

Chronic
Pyelonephritis
Tubulointerstitial
nephritis (TIN)
TIN caused by
drug and toxin
Acute Tubular Necrosis/Injury (ATN/I)
Acute tubular injury/necrosis(ATN) is a
clinicopathologic entity characterized clinically
by acute renal failure (ARF) and morphologic
evidence of tubular necrosis.
ATN is the most common cause of ARF.
ATI can be caused by:
Ischemia (syok, DIC, malignant hypertension, etc)
Direct toxic injury (bile, radiocontrast, drugs, etc)
 Ischemic ATN
Most often caused by prerenal azotemia due to
hypovolemia
Ischemia damages endothelial and tubular cells.
Nephrotoxic type
Aminoglycosides most common cause (e.g.,
gentamicin), Radiocontrast agents, Heavy metals
Primarily damages the proximal tubule cells
Acute Tubular Necrosis (ATN)
 Acute Tubular Necrosis/Injury (ATN/I)
Clinical Findings
Oliguria, in most cases (~400 mL/24 hours)
Pigmented renal tubular cell casts
Hyperkalemia, metabolic acidosis
Increased serum BUN and creatinine
 Acute Tubular Necrosis/Injury (ATN/I)
The prognosis of ATI depends on the
magnitude and duration of injury
Nephrotoxic ATI: current supportive care, 95%
recover.
Syok, burns, multi organ failure: mortality rate
> 50%
 Tubulointerstitial nephritis (TIN)
Acute Pyelonephritis:
Pyelonephritis is defined as inflammation affecting the
tubules, interstitium, and renal pelvis.
Epidemiology
More common in women than men
Women have a short urethra (subject to ascending
infection).
Escherichia coli most common cause
Risk factors
Indwelling urinary catheter
Urinary tract obstruction
Diabetes mellitus, pregnancy
Pathogenesis

> >> Escherichia coli

<< Proteus, Klebsiella, Enterobacter
Two routes
(1) through the bloodstream
(hematogenous infection)
(2) from the lower urinary tract (ascending
infection)
Ascending Infection:
1. Colonization of the distal urethra and
introitus (in the female) by coliform
bacteria

2. From the urethra to the bladder:

instrumentation, shorter urethra in
females, urethral trauma during
sexual intercourse

3. From the bladder to the kidneys:

Urinary tract obstruction and stasis of
urine, vesicoureteral reflux, intrarenal
reflux
 Acute Pyelonephritis:
Clinical Features
pain at the costovertebral angle, fever and
malaise
dysuria, frequency, and urgency
The urine contains many leukocytes (pyuria)
leukocyte casts : renal involvement
Gold standard dx: urine culture
 Chronic Pyelonephritis
Chronic tubulointerstitial
inflammation and
scarring involve the
calyces and pelvis
Pathogenesis
VUR starting in young girls
Lower urinary tract
obstruction -- Produces
hydronephrosis
ExamplesBPH, renal
stones
 Tubulointerstitial Nephritis Induced
by Drugs and Toxins
Common drug associations
Penicillin, particularly methicillin
Rifampin, sulfonamides
NSAIDs, diuretics
Pathogenesis
Combination of type I and type IV hypersensitivity
Occurs ~2 weeks after beginning a drug
 Abrupt onset of
fever, oliguria, and
rash
Withdrawal of the
drug reverses the
disease.
Laboratory findings
BUN/Cr increase
Eosinophilia and
eosinophiluria
(highly predictive)
 References
Vinay Kumar, Abdul K Abbas, Robbins and
Cotran Pathologic Basis of Disease, 9th Ed,
Elsevier, 2015
Goljan EF, Rapid Review of Pathology, 4th Ed,
Elsevier, 2014
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YOU