Transcript Drugs - Pathology

Tubulointerstitium:
New Drugs - New Lesions
Helmut Hopfer
Institute for Pathology Basel
Patterns of Drug-induced Lesions
Tubulointerstitium
Antibiotics
Acute
interstitial
NSAID
nephritis
ACE-I
Diazepam
Lithium tubulointerChronic
Thiazids
stitial nephropathy
CNI
COX2-I
Acute Virostatics
tubular injury
Barbiturates
- Osmotic nephrosis
HES
Bisphosphonates
- Nephrocalcinosis
Cisplatin
OSPS
- Chrystal NP
Ifosfamide
Methotrexate
Quinolones
Ranitidin
Glomeruli
Minimal
NSAID change
Lithium
disease
Sirolimus
Interferon
Focal segmental
Bucillamine
glomerulosclerosis
Bisphosphonates
Captopril
Penicillamine
Membranous
GN
Hydralazin
Rifampicin
Crescentic GN
Propylthiouracil
Cisplatin
Thrombotic microMitomycine C
Tamoxifen
angiopathy
Anti-VEGF
CNI
Gemcitabine
Blood vessels
Hyalinosis
CNI
Clopidogrel
Thrombotic
microCNI
angiopathy
Anti-VEGF
Quinine
Vasculitis
Mitomycine C
Phenytoin
Propylthiouracil
Penicillamine
Sulfasalazine
Agenda
• Zoledronate
(bisphosphonate)
• Tenofovir
(nucleotide reverse transcriptase inhibitor)
• Foscarnet
(viral DNA polymerase inhibitor)
Zoledronate
• Nitrogen-containing BP
• Hypercalcemia, esp. multiple
myeloma and bone metastasis
in solid tumors
• Binding to bone, osteoclast
inhibition after localized release
• Inhibition of farnesyl diphosphatate synthase  inhibition of
small GTPases involved in cell
signaling
KI67
NaK-ATPase
Markowitz et al., Kidney Int 64:281, 2003
Renal Handling of Bisphosphonates
glomerular filtration
tubular secretion
Nach: Kino et al., Biopharm
Drug Dispos 20: 193, 1999
T. Pfister, Roche
Nach: Kino et al., Biopharm
Drug Dispos 20: 193, 1999
Goscinny and Uderzo, 1969
Renal Zoledronate Toxicity
ATN
Risk factors for kidney injury:
• Multiple myeloma or RCC
vs. other basic diseases
• Increased age
• Number of doses
• Current use of NSAID
• Current or prior use of
cisplatin
McDermott et al., J Support Oncol 4:524, 2006
time (h)
bisphosphonate
tubular damage
regeneration signal
renal recovery
proliferation
proliferation blocked
abortive regeneration
back leak syndrome
cisplatin
renal insufficiency
Glomerular pathology in BPs
• FSGS, collapsing variant
• minimal change disease
Mainly Pamidronate
Tenofovir
• Acyclic nucleoside
phosphonate, nucleotide
reverse transcriptase inhibitor
• Management of HIV infections,
chronic hepatitis B virus
• Renal elimination (70-80%) by
glomerular filtration and tubular
secretion
• Severe nephrotoxicity is rare
KI67
Proposed Mechanism
• Potentially inhibits mammalian
DNA polymerases, including
mtDNA polymerase  
oxidative stress
MRP2
• HIV-1 transgenic mice treated
with tenofovir
 mitochondrial damage
 depletion of mtDNA in
proximal tubules
OAT1
Kohler et al., Lab Invest 89:513, 2009
Foscarnet
• Pyrophosphate analogue, binds
to viral DNA polymerase and
halts DNA chain elongation
• 2nd line therapy for CMV and
HSV infections, esp. AIDS and
transplant patients
• Not metabolized, excreted by
kidneys (glomerular filtration and
tubular secretion)
• Decrease in creatinine clearance
(12%), acute renal failure (1-5%)
A. Gaspert, Pathology, USZ
Summary
• Multiple drugs cause common patterns of
renal pathology
• Tubules are most frequently affected due
to tubular secretion
• Important risk factors are preexisting renal
diseases and concomitant use of other
potentially nephrotoxic drugs
Patterns of Drug-induced Lesions
Tubulointerstitium
Glomeruli
Acute interstitial
nephritis
Minimal change
disease
Chronic tubulointerstitial nephropathy
Focal segmental
glomerulosclerosis
Acute tubular injury
- Osmotic nephrosis
- Nephrocalcinosis
- Chrystal NP
Membranous GN
Crescentic GN
Thrombotic microangiopathy
Blood vessels
Hyalinosis
Thrombotic microangiopathy
Vasculitis
Summary
• Multiple drugs cause common patterns of
renal pathology
• Tubules are most frequently affected due
to tubular secretion
• Important risk factors are preexisting renal
diseases and concomitant use of other
potentially nephrotoxic drugs