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

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

6. KI67NaK-ATPase Markowitz et al., Kidney Int 64:281, 2003

7. Renal Handling of Bisphosphonates glomerular filtration tubular secretion

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. 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

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

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. 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

19. Foscarnet Pyrophosphate analogue, binds to viral DNA polymerase and halts DNA chain elongation 2 nd 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