Drugs & Kidney

Helmut Hopfer

Basel, Switzerland

Patterns of Drug-induced Lesions

Tubulointerstitium

Acute tubular injury

- Osmotic nephrosis

- Nephrocalcinosis

- Chrystal NP

Acute interstitial nephritis

Chronic tubulointer-stitial nephropathy

Glomeruli

Minimal change disease

Focal segmental glomerulosclerosis

Membranous GN

Crescentic GN

Thrombotic micro-angiopathy

Blood vessels

Hyalinosis

Thrombotic micro-angiopathy

Vasculitis

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

Problems

• Case reports or small case series

• Incomplete clinical data at time of biopsy

• Difficulty establishing cause - effect relationships

• Patterns are usually not specific for a certain drug

• Some drugs may cause various patterns

Example: Zoledronate

• Intravenous 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

Renal Handling of Bisphosphonates

glomerular filtration

tubular secretion

Glomerular pathology in BPs

• FSGS, collapsing variant, also NOS

• minimal change disease

PamidronateZoledronateAlendronate

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

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

KI67 NaK-ATPase

Markowitz et al., Kidney Int 64:281, 2003

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

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

• Alertness and awareness of the renal patho-logist are a key prerequisite for identification

Drugs & Kidney: Literature

• Perazella MA, Markowitz GS: Bisphosphonate nephrotoxicity. Kidney Int 74:1385-1393, 2008

• Markowitz GS, Perazella MA: Drug-induced renal failure: a focus on tubulo-intestitial disease. Clin Chim Acta 351:31-47, 2005

• John R, Herzenberg AM: Renal toxicity of therapeutic drugs. J Clin Pathol 62:505-515, 2009