Tubulointerstitium:New Drugs - New LesionsHelmut HopferInstitute for Pathology Basel

Patterns of Drug-induced LesionsTubulointerstitiumAcute interstitial nephritisChronic tubulointer-stitial nephropathyAcute tubular injury - Osmotic nephrosis- Nephrocalcinosis- Chrystal NPGlomeruliMinimal change diseaseFocal segmental glomerulosclerosisMembranous GNCrescentic GNThrombotic micro-angiopathyBlood vesselsHyalinosisThrombotic micro-angiopathyVasculitis

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

ZoledronateNitrogen-containing BPHypercalcemia, esp. multiple myeloma and bone metastasis in solid tumorsBinding to bone, osteoclast inhibition after localized releaseInhibition of farnesyl diphospha-tate synthase inhibition of small GTPases involved in cell signaling

KI67NaK-ATPaseMarkowitz et al., Kidney Int 64:281, 2003

Renal Handling of Bisphosphonatesglomerular filtration

Nach: Kino et al., Biopharm Drug Dispos 20: 193, 1999T. Pfister, Roche

Nach: Kino et al., Biopharm Drug Dispos 20: 193, 1999

Goscinny and Uderzo, 1969

Renal Zoledronate ToxicityRisk factors for kidney injury:Multiple myeloma or RCC vs. other basic diseasesIncreased ageNumber of dosesCurrent use of NSAIDCurrent or prior use of cisplatin

McDermott et al., J Support Oncol 4:524, 2006

time (h)tubular damagebisphosphonateregeneration signalcisplatinproliferationproliferation blockedabortive regenerationback leak syndromerenal insufficiencyrenal recovery

Glomerular pathology in BPsFSGS, collapsing variantminimal change disease

Mainly Pamidronate

TenofovirAcyclic nucleoside phosphonate, nucleotide reverse transcriptase inhibitorManagement of HIV infections, chronic hepatitis B virusRenal elimination (70-80%) by glomerular filtration and tubular secretionSevere nephrotoxicity is rare

KI67

Proposed MechanismPotentially inhibits mammalian DNA polymerases, including mtDNA polymerase oxidative stressHIV-1 transgenic mice treated with tenofovirmitochondrial damagedepletion of mtDNA in proximal tubules

Kohler et al., Lab Invest 89:513, 2009

FoscarnetPyrophosphate analogue, binds to viral DNA polymerase and halts DNA chain elongation2nd line therapy for CMV and HSV infections, esp. AIDS and transplant patientsNot metabolized, excreted by kidneys (glomerular filtration and tubular secretion)Decrease in creatinine clearance (12%), acute renal failure (1-5%)

A. Gaspert, Pathology, USZ

SummaryMultiple drugs cause common patterns of renal pathologyTubules are most frequently affected due to tubular secretionImportant risk factors are preexisting renal diseases and concomitant use of other potentially nephrotoxic drugs

Patterns of Drug-induced LesionsTubulointerstitiumAcute interstitial nephritisChronic tubulointer-stitial nephropathyAcute tubular injury - Osmotic nephrosis- Nephrocalcinosis- Chrystal NPGlomeruliMinimal change diseaseFocal segmental glomerulosclerosisMembranous GNCrescentic GNThrombotic micro-angiopathyBlood vesselsHyalinosisThrombotic micro-angiopathyVasculitis

SummaryMultiple drugs cause common patterns of renal pathologyTubules are most frequently affected due to tubular secretionImportant risk factors are preexisting renal diseases and concomitant use of other potentially nephrotoxic drugs