Tubulointerstitium:New Drugs - New Lesions

Helmut HopferInstitute for Pathology Basel

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

NSAID CNINSAID

Bisphosphonates

PenicillamineCaptopril

Propylthiouracil

Hydralazin

Rifampicin

Gemcitabine

Cisplatin

Bucillamine

Tamoxifen

Anti-VEGF

Lithium

Sirolimus

Interferon

CNI

Mitomycine C

ACE-I

Antibiotics

DiazepamLithium

Thiazids

CNI COX2-I

BarbituratesVirostatics

OSPS

Bisphosphonates

HES

Cisplatin

Quinolones

IfosfamideMethotrexate

Ranitidin

ClopidogrelCNIAnti-VEGF

Quinine Mitomycine C

PhenytoinPropylthiouracilPenicillamine

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 diphospha-tate 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, 1999T. 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)

tubular damage

bisphosphonate

regeneration signal

cisplatin

proliferation

proliferation blocked

abortive regeneration

back leak syndrome renal insufficiency

renal recovery

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

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

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

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

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