ACUTE AND CHRONIC INTERSTITIAL NEPHRITIS (PPT / 14536.5

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ACUTE AND CHRONIC
INTERSTITIAL NEPHRITIS
PROF. Dr . MARLEEN PRAET,
MD, PHD
University Hospital Ghent Belgium
Interferences with the
interstitium: broad spectrum
• Infection:
– direct (BK virus, TBC, acute pyelonephritis),
– indirect( βStreptococci)
• Immunologic
– Allergic: drug – induced
– Auto-immune: Sjögren syndrome
– Alloimmune: acute cellular allograft rejection
– Unknown: IgG4- associated acute interstitial nephritis
• Toxic: Pb poisoning, cadmium poisoning, Balkan endemic
nephropathy
• Metabolic: oxalosis secondary to malabsorbtion , gout
• Obstruction: ureteral- pelvic junction stenosis:
• Radiation: radiation interstitial nephritis
• Idiopathic: sarcoidosis
What is the program:
• Morphology of the interstitium
• Importance
• Different entities of interstitial disease
– Appearances are often similar despite varied
mechanisms
– Search for etiologic agent, distinctive features:
granuloma, eosinophils, crystals, viral
inclusions
Morphology of the interstitium
• Composed of a loosely organized matrix
consisting of the collagen types I and III,
proteoglycans containing the “interstitial
cells”:
–
–
–
–
matrix producing fibroblasts
macrophages
dendritic reticulum cells
endothelial cells
Morphology of the interstitium
• Fibrosis develops after infiltration by
mononuclear cells (lymphocytes) which is
accompanied by deposition of fibronectin,
collagen type I, III, VI and IV.
• There is a physiological balance between
ongoing matrix formation and - degradation.
Importance of interstitial cells
• Interstitial fibroblasts:
– Fibrogenesis
– Production of erythropoietine (they lose this function
during the process of fibrogenesis)
– Can transform into myofibroblasts (expression of SMA)
– Changes in the interstitial area play an important negative
predictive value on the long term follow up of the primary
kidney disease. Important and determining factors are
interstitial volume (=fibrosis) and inflammation
Different entities of interstitial disease
•
•
•
•
•
•
•
•
•
•
•
•
Acute interstitial nephritis
Chronic interstitial nephritis
Acute pyelonephritis
Chronic pyelonephritis (reflux related)
Xanthogranulomatous pyelonephritis
Malakoplakie
Myeloma kidney
IgG4 interstitial nephritis
Lead induced interstitial nephritis
Urate nephropathy
TX related Polyoma induced interstitial nephritis
Balkan interstitial nephritis
Acute interstitial nephritis
• Most common etiologies are:
– a) those related to the use of medications: 85%
– b) those related to infectious agents: 10%
– c) those associated to systemic disease or
glomerular diseases: 1%
– d) idiopathic disease: 4%
Acute interstitial nephritis: drugs
• Etiology: AB (penicillins and cephalosporins, methicillin),
diuretics, NSAID’s, chinese herbs, lithium
• Pathogenesis:
T cell mediated allergic - immune reaction on drug or drug-self
protein conjugate (hapten) later followed by accumulation of
lymphocytes, plasmocytes and histiocytes
• Histology:
– Early signs: oedema, lymphocytes focally
– Later: eosinophils, lymphocytes, plasmocytes and histiocytes with
granuloma formation(with giant cells) in 30 %, especially after AB
– Tubulitis (distal tubules): with breaks of TBM, necrosis of tubular
cells and atrophy and loss of tubules.
– Tamm Horsfall may find its way to the interstitium (DD
obstruction of nephron).
Acute
drug
induced
interstitial
Oedema and focal inflammation
nephritis
Granuloma
EOS
Granuloma
Acute drug induced interstitial
nephritis
• Normally are the glomeruli not afflicted.
• One exception: use of NSAID’s: can
combine ARF with Nephrotic Syndrome
(effect of cell- mediated lymphokine
directed reaction) inducing Minimal
Lesions (effacement of foot processes of
podocytes)
Acute interstitial nephritis:
clinics
Acute Renal Failure and
reduced glomerular
filtration rate:
-
-
depends on the severity of
inflammation
interstitial oedema causes
elevated intratubular pressure
intratubular obstruction through
intra luminal cells
tubular backleak
vasoconstriction
tubuloglomerular feedback
Outcome of drug- induced
interstitial nephritis
• Recovery?
– Drug withdrawal: 6090% in 1 to 12 mths
– Irreversible with
analgesics, NSAIDs,
longterm use
• Adverse prognostic
features
– Marked interstitial
inflammation
– Granuloma (50%
irreversible)
– Tubular atrophy
– Fibrosis
Acute interstitial infectious
nephritis
• Infectious:direct invasion or remote infections
bacteria (ß hemolytic streptococci), parasites
(Leishmania) and viruses (EBV, measles)
• Pathogenesis: immunological hypersensitivity
reaction to the infectious agent, effect of
chemokines produced by the kidney in response
• Histology:
– Early signs: invasion by lymphocytes, eosinophils around the veins
– In casu there is tubular destruction: histiocytes accumulate
– Tubulitis with disappearance of the brush border in proximal
tubules
ACUTE INTERSTITIAL INFECTIOUS NEPHRITIS
Acute interstitial nephritis:
systemic
• Association with: Goodpasture syndrome,
lupus nephritis, mixed cryoglobulinemia,
membranoproliferative glomerulonephritis
Chronic interstitial nephritis
• Etiology: chronic drug intake (analgesics,
lithium), urinary obstruction, chronic reflux,
• Pathogenesis: persistence of damageing factor:
ischemia, chronic immune reaction
• Histology: fibrosis + diffuse infiltration by
lympho’s, plasmo’s, histiocytes (with granuloma).
Tubular changes (atrophy, compensatory
hypertrophy with microcystic changes)
• Beware of:
– Papillary necrosis, - sclerosis and- calcification: due to sclerosis of
the capillaries under the urothelial epithelium
– Tumor development: papillary tumors, multifocal
Chronic interstitial nephritis
Papillary sclerosis
CIN
Interstitium in transplants
• Calcineurin inhibitors:
– Heart, liver, pancreas, kidney transplants in
different doses
– Different levels of interstitial damage
– Most structural nephrotoxic effects in arterioles
and glomeruli are manifestations of Thrombotic
MicroAngiopathy(TMA) with different patterns
of severity. The interstitial fibrosis has an
uncertain pathogenesis but is probably vascular.
Toxicity of calcineurin inhibitors
Cellular rejection in kidney Tx
• Histology:
– Very early: eosinophils
– Followed by T lymphocytes
– Later: Plasmocytes IgG+ if IgM+ : be aware of
polyoma infection
– In peritubular capillaries (PTC):
lymphocytes++
Cellular rejection
Tubulitis
CD3
Acute pyelonephritis
• Etiology: ascending infection from the pyelon
• Pathogenesis: microbial release of degradative
enzymes and toxic molecules, direct contact or
penetration of the host cell by the infectious agent
and the inflammatory response mediated by
antibodies, T cells
• Histology:
– Tubules are damaged by neutrophils (Congored)
Acute pyelonephritis
Chronic pyelonephritis
• Etiology: reflux
• Histology:
- wedge shaped interstitial fibrosis(follows the
traject of the papillae and ascending tubules)
accompanied by tubular atrophy, vascular
atheromatosis, glomerular sclerosis, inflammation
- outside the wedges: normal parenchyma but
with secondary changes in the glomeruli:
glomerular hypertrophy, FSGS
Chronic pyelonephritis
Chronic pyelonephritis
Tamm Horsfall protein
Xanthogranulomatous
pyelonephritis
• Etiology: chronic ascending infection: lithiasis,
pyelal or ureteral tumors, ureter stenosis. The
infective organisms are E. Coli, Proteus sp,
Klebsiella, Pseudomonas, Enterococcus
• Histology:
– accumulation of histiocytes in the interstitum
containing PAS/Diastase resistant granules in the
cytoplasm
– fibrosis
– chronic inflammatory cells
Malakoplakia
• Etiology: accumulation of phagolysosomes in the
cytoplasm of macrophages containing bacteria in
various stages of breakdown.
• Histology: identical to xanthogranulomatous
pyelonephritis but with presence of Michaelis
Gutman bodies: these are PAS +, von Kossa
positive (calcium+), Perls + round lamellar
structures measuring 4 tot 10 µ
MALAKOPLAKIA
Granulomatous interstitial
nephritis
– Sarcoidosis: naked granulomas in cortex with
Langhans giant cells: 29 %
– Drug induced interstitial nephritis (AB):45%
– Infection: TBC, fungal infections
– Gout: urate granuloma
– Cholesterol granuloma
URATE GRANULOMA
Myeloma kidney or CAST
nephropathy
• Differentiate from other light chain entities:
excretion of light chains due to plasma cell
dysfunctions (MGUS, myeloma, Waldenström
lymphoma) can be accompanied by deposits of
light chain in the kidney: where?
• Glomeruli: LCDD
• Tubules: Cast nephropathy or myeloma kidney
• TBM: atypical LCDD with deposition of monotypic kappa
light chain deposits
• Interstitium: secondary inflammation
• Vessels: LCDD
How to differentiate?
• Good lightmicroscopy
• Immunohistochemistry/Immunofluorescence
• Electronmicroscopy
Distinctive patterns
Cast
nephropathy
Glomeruli :
no deposits
Tubules:
Interstitium: Vessels: no
intraluminal inflammation deposits
casts +
tubulitis
LCDD
Glomeruli Tubules:
: nodular TBM
thickened
LM- IF
Atypical
LCDD
Glomeruli :
no deposits
Tubules:
tubulitis
IF- EM
Interstitium:
fibrotic
Vessels:
in 40%
thickened
by
deposits
Interstitium: Vessels: no
inflammation deposits
CASTNEPHROPATHY
• TUBULES
Intraluminal casts:
LM: hard casts,
birefringent, dual
colored, giant cells
IF: Kappa 60%, Lambda
40%
EM
• INTERSTITIUM
Inflammation
CAST NEPHROPATHY
Polyoma Nephropathy
• Reactivation of a latent endogenous virus in
immune incompetent patients
• Nephropathy usually presents during the
first year after transplantation
Polyoma Nephropathy
• Histology:
– Viral replication produces nuclear inclusions and cell
necrosis (urothelium, tubular epithelium)
– T and B lymphocytes, plasmocytes, histiocytes
accompany the necrosis with plasma cell tubulitis
– Starts in the medulla
– Progression is marked by tubular atrophy, interstitial
fibrosis and graft loss
Polyoma
Pb interstitial nephritis
Balkan endemic nephropathy
• Where?: Croatia, Bosnia, Serbia, Bulgaria,
Romania with prevalence between 2% and
10%
• Pathogenesis: unknown: genetic
predisposition, role played by coronavirus,
heavy metals, ochratoxin, mycotoxins
Chinese Herbs Nephropathy
• 1992 and 1993: slimming regimen
containing Chinese Herbs: Stephania
tetrandra.
• Role played by aristolochic acid forming
premutagenic adducts with DNA in the
kidney and urothelium:patients developed
renal failure and TCC 5 months later
Chinese Herbs Nephropathy
Cosyns JP. Drug Safety 2003, 26 : 33-48
Stephania
Added value of
immunofluorescence?
• With Ig G deposits
– Lupus
– IgG4- related systemic
disease
• Without IgG deposits
– Drug- induced acute
interstitial nephritis
– Tubulointerstitial
nephritis with uveitis
– Sjögren syndrome
– Systemic reaction to
certain infections
Diagnosis of interstitial nephritis
• Careful pathological analysis
• Careful clinical history
• Communication between clinician and
pathologist
Tubular disease
• Acute tubular damage:
– Ischemia: vasoconstriction with endothelial activation
will determinate the extent of the tubular cell loss:
cellular, geographic, focal
– Toxins:
•
•
•
•
Myoglobinuria
Heavy metal exposure (Pb, Cd)
Oxalate crystal deposits: ethylene glycol toxicity
Calcineurin inhibitors: megamitochondria, isometric
vacuolisation
Tubular damage
GHENT
Thank you
THANK YOU !
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