Tubulointerstitium: New Drugs - New Lesions

1. Tubulointerstitium:New Drugs - New Lesions Helmut Hopfer Institute for Pathology Basel

2. Virostatics Quinolones Bisphosphonates Bisphosphonates Propylthiouracil Propylthiouracil Methotrexate Bucillamine Anti-VEGF Anti-VEGF Tamoxifen Ifosfamide Phenytoin Interferon Sirolimus Cisplatin Cisplatin Quinine NSAID OSPS HES Thiazids COX2-I Lithium Lithium Captopril Mitomycine C Mitomycine C Penicillamine Penicillamine Sulfasalazine Gemcitabine Barbiturates Clopidogrel Hydralazin Rifampicin Ranitidin ACE-I NSAID CNI CNI CNI CNI Antibiotics Diazepam 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. 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 Zoledronate

6. KI67 NaK-ATPase Markowitz et al., Kidney Int 64:281, 2003

7. tubular secretion 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

12. ATN 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 4:524, 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

17. KI67

18. MRP2 OAT1 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 89:513, 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