tubulointerstitium: new drugs - new lesions helmut hopfer institute for pathology basel
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Tubulointerstitium:New Drugs - New Lesions
Helmut HopferInstitute for Pathology Basel
Patterns of Drug-induced Lesions
Tubulointerstitium
Acute interstitial nephritis
Chronic tubulointer-stitial nephropathy
Acute tubular injury
- Osmotic nephrosis
- Nephrocalcinosis
- Chrystal NP
Glomeruli
Minimal change disease
Focal segmental glomerulosclerosis
Membranous GN
Crescentic GN
Thrombotic micro-angiopathy
Blood vessels
Hyalinosis
Thrombotic micro-angiopathy
Vasculitis
NSAID CNINSAID
Bisphosphonates
PenicillamineCaptopril
Propylthiouracil
Hydralazin
Rifampicin
Gemcitabine
Cisplatin
Bucillamine
Tamoxifen
Anti-VEGF
Lithium
Sirolimus
Interferon
CNI
Mitomycine C
ACE-I
Antibiotics
DiazepamLithium
Thiazids
CNI COX2-I
BarbituratesVirostatics
OSPS
Bisphosphonates
HES
Cisplatin
Quinolones
IfosfamideMethotrexate
Ranitidin
ClopidogrelCNIAnti-VEGF
Quinine Mitomycine C
PhenytoinPropylthiouracilPenicillamine
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 diphospha-tate 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, 1999T. 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)
tubular damage
bisphosphonate
regeneration signal
cisplatin
proliferation
proliferation blocked
abortive regeneration
back leak syndrome renal insufficiency
renal recovery
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
OAT1
MRP2• Potentially inhibits mammalian
DNA polymerases, including mtDNA polymerase oxidative stress
• HIV-1 transgenic mice treated with tenofovir mitochondrial damage depletion of mtDNA in
proximal tubules
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
Acute interstitial nephritis
Chronic tubulointer-stitial nephropathy
Acute tubular injury
- Osmotic nephrosis
- Nephrocalcinosis
- Chrystal NP
Glomeruli
Minimal change disease
Focal segmental glomerulosclerosis
Membranous GN
Crescentic GN
Thrombotic micro-angiopathy
Blood vessels
Hyalinosis
Thrombotic micro-angiopathy
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