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Tubulointerstitium: New Drugs - New Lesions Helmut Hopfer Institute for Pathology Basel Patterns of Drug-induced Lesions Tubulointerstitium Antibiotics Acute interstitial NSAID nephritis ACE-I Diazepam Lithium tubulointerChronic Thiazids stitial nephropathy CNI COX2-I Acute Virostatics tubular injury Barbiturates - Osmotic nephrosis HES Bisphosphonates - Nephrocalcinosis Cisplatin OSPS - Chrystal NP Ifosfamide Methotrexate Quinolones Ranitidin Glomeruli Minimal NSAID change Lithium disease Sirolimus Interferon Focal segmental Bucillamine glomerulosclerosis Bisphosphonates Captopril Penicillamine Membranous GN Hydralazin Rifampicin Crescentic GN Propylthiouracil Cisplatin Thrombotic microMitomycine C Tamoxifen angiopathy Anti-VEGF CNI Gemcitabine Blood vessels Hyalinosis CNI Clopidogrel Thrombotic microCNI angiopathy Anti-VEGF Quinine Vasculitis Mitomycine C Phenytoin Propylthiouracil Penicillamine 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 diphosphatate 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, 1999 T. 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) bisphosphonate tubular damage regeneration signal renal recovery proliferation proliferation blocked abortive regeneration back leak syndrome cisplatin renal insufficiency 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 • Potentially inhibits mammalian DNA polymerases, including mtDNA polymerase oxidative stress MRP2 • HIV-1 transgenic mice treated with tenofovir mitochondrial damage depletion of mtDNA in proximal tubules OAT1 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 Glomeruli Acute interstitial nephritis Minimal change disease Chronic tubulointerstitial nephropathy Focal segmental glomerulosclerosis Acute tubular injury - Osmotic nephrosis - Nephrocalcinosis - Chrystal NP Membranous GN Crescentic GN Thrombotic microangiopathy Blood vessels Hyalinosis Thrombotic microangiopathy 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