Tubulointerstitium: New Drugs - New Lesions

1
TubulointerstitiumNew Drugs - New Lesions
Helmut Hopfer Institute for Pathology Basel
2
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
3
Agenda

• Zoledronate
• (bisphosphonate)
• Tenofovir
• (nucleotide reverse transcriptase inhibitor)
• Foscarnet
• (viral DNA polymerase inhibitor)

4
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

5
(No Transcript)
6
KI67
NaK-ATPase
Markowitz et al., Kidney Int 64281, 2003
7
Renal Handling of Bisphosphonates
glomerular filtration
8
Nach Kino et al., Biopharm Drug Dispos 20 193,
1999 T. Pfister, Roche
9
Nach Kino et al., Biopharm Drug Dispos 20 193,
1999
10
Goscinny and Uderzo, 1969
11
(No Transcript)
12
Renal Zoledronate Toxicity

• 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 4524, 2006

13
time (h)
bisphosphonate
tubular damage
regeneration signal
renal recovery
proliferation
proliferation blocked
abortive regeneration
back leak syndrome
renal insufficiency
cisplatin
14

• Glomerular pathology in BPs
• FSGS, collapsing variant
• minimal change disease
• Mainly Pamidronate

15
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

16
(No Transcript)
17
KI67
18
Proposed Mechanism

• 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 89513, 2009

19
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)

20
A. Gaspert, Pathology, USZ
21
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

22
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
23
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