Drugs

1
Drugs Kidney

• Helmut Hopfer
• Basel, Switzerland

2
Patterns of Drug-induced Lesions

• Tubulointerstitium
• Acute tubular injury
• - Osmotic nephrosis
• - Nephrocalcinosis
• - Chrystal NP
• Acute interstitial nephritis
• Chronic tubulointer- stitial nephropathy

Glomeruli Minimal change disease Focal
segmental glomerulosclerosis Membranous
GN Crescentic GN Thrombotic micro- angiopathy
Blood vessels Hyalinosis Thrombotic
micro- angiopathy Vasculitis
3
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
4
Problems

• Case reports or small case series
• Incomplete clinical data at time of biopsy
• Difficulty establishing cause - effect
  relationships
• Patterns are usually not specific for a certain
  drug
• Some drugs may cause various patterns

5
Example Zoledronate

• Intravenous 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

6
Renal Handling of Bisphosphonates
glomerular filtration
7

• Glomerular pathology in BPs
• FSGS, collapsing variant, also NOS
• minimal change disease
• Pamidronate
• Zoledronate
• Alendronate

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
(No Transcript)
11
KI67
NaK-ATPase
Markowitz et al., Kidney Int 64281, 2003
12
Goscinny and Uderzo, 1969
13
(No Transcript)
14
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

15
time (h)
bisphosphonate
tubular damage
regeneration signal
renal recovery
proliferation
proliferation blocked
abortive regeneration
back leak syndrome
renal insufficiency
cisplatin
16
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
• Alertness and awareness of the renal patho-logist
  are a key prerequisite for identification

17
Drugs Kidney Literature

• Perazella MA, Markowitz GS Bisphosphonate
  nephrotoxicity. Kidney Int 741385-1393, 2008
• Markowitz GS, Perazella MA Drug-induced renal
  failure a focus on tubulo-intestitial disease.
  Clin Chim Acta 35131-47, 2005
• John R, Herzenberg AM Renal toxicity of
  therapeutic drugs. J Clin Pathol 62505-515, 2009