1. Helmut Hopfer Basel, Switzerland
Drugs & Kidney
Helmut Hopfer
Basel, Switzerland

2. 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
- drug related renal pathology can affect all kidney compartments
- the tubulointerstitium is commonly involved, best known examples NSAID and antibiotics
- immunologically mediated vs. toxic/ischemic damage, dose is important for the latter
- drugs should be considered in all primary tubulointerstitial diseases
- glomeruli und vasculature is only infrequently affected (w/o CNI arteriolopathy), mimicks many primary renal diseases
- personal awareness

3. 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
CNI
Bisphosphonates
Penicillamine
Captopril
Propylthiouracil
Hydralazin
Rifampicin
Gemcitabine
Cisplatin
Bucillamine
Tamoxifen
Anti-VEGF
Lithium
Sirolimus
Interferon
Mitomycine C
ACE-I
Antibiotics
Diazepam
Thiazids
COX2-I
Barbiturates
Virostatics
OSPS
HES
Quinolones
Ifosfamide
Methotrexate
Ranitidin
Clopidogrel
Quinine
Phenytoin
Sulfasalazine
- multiple drugs have been implicated, this list is far from complete
- frequency is unknown

4. 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
- if you take out the common culprits NSAID, antibiotics, and CNI, even large centers have only few cases of suspected/established drug toxicity for a given drug
- once several case reports and one or two small case series have been published, new cases are usually not reported
- often, we have limited clinical data at the time of biopsy and clinical feedback is limited as well
- it is difficult to establish cause - effect relationships and the molecular basis of drug toxicity is unknown for most drugs due to the lack of experimental models; rechallenge is rarely done
- often a temporal association is the only hint
- unspecific patterns

5. 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
- bisphosphonates have been fairly well studied
- zoledronate is used in hypercalcemia of various causes; pamidronate is another example of an i.v. bisphosphonate, but in Europe it is not used as commonly as zoledronate
- renal toxicity has mainly been described in the context of multiple myeloma and bone metastasis
- after i.v. administration there is rapid binding to bone at sites of active remodelling; localized release by osteoclasts
- inhibition of farnesyl diphosphatate synthases resulting in post-translational modification of small GTPases, which inhibits cellular signaling and cell function

6. Renal Handling of Bisphosphonates
tubular secretion
glomerular filtration
- the remaining bisphosphonate is eliminated without modifications through the kidneys, partly by glomerular filtration and partly by tubular secretion
- susceptible cells are podocytes and tubular epithelial cells
- transporters involved have not been identified

7. Glomerular pathology in BPs FSGS, collapsing variant, also NOS
minimal change disease
Pamidronate
Zoledronate
Alendronate
- glomerular patterns described are FSGS and minimal changes
- mechanism unknown

8. Nach: Kino et al., Biopharm Drug Dispos 20: 193, 1999
- handling by tubules has been studied in more detail
- upper panel shows the situation, in which the cell is able to handle the drug
- lower panel: high dose reaching the kidney in a short time
- in this szenario the uptake is rate limiting and this szenario is true over a wide concentration range
Nach: Kino et al., Biopharm Drug Dispos 20: 193, 1999
T. Pfister, Roche

9. Nach: Kino et al., Biopharm Drug Dispos 20: 193, 1999
- second szenario: situation with a lower dose over a longer range of time
- here, the transport into the tubular lumen is rate limiting
Nach: Kino et al., Biopharm Drug Dispos 20: 193, 1999

10. - pathological findings: dilatation of tubuli, simplification of epithelial cells, beginning tubular atrophy, interstitial fibrosis

11. KI67 NaK-ATPase Markowitz et al., Kidney Int 64:281, 2003
- there is an increase number of cells positive for KI67 and a derangement of the NaK-ATPase
- regeneration of tubular cells and tubular dysfunction
Markowitz et al., Kidney Int 64:281, 2003

12. - I assume many of you will be familiar with this fish and will also know, what is going to happen
- the fish flies through the air, will hit an uninvolved bystander and then a figh will ensue
Goscinny and Uderzo, 1969

13. - if you throw, let's say, zoledronate at a multiple myeloma, it will hit the kidneys, but will cause renal deterioration in only 8-17%, and a severe increase in serum creatinine in only 2%
- why is this so?

14. Renal Zoledronate Toxicity
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
ATN
- there are other risk factors contibuting to kidney injury
- this study found the following factors to be independent
- in general, preexisting renal damage or loss of nephron mass as well as the use of other nephrotoxic drugs seem to be very important

15. time (h) bisphosphonate tubular damage regeneration signal
proliferation
renal recovery
proliferation blocked
abortive regeneration
- I want to show a final example that timing of drug exposure may be a relevant factor
back leak syndrome
renal insufficiency
cisplatin

16. 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

17. Drugs & Kidney: Literature
Perazella MA, Markowitz GS: Bisphosphonate nephrotoxicity. Kidney Int 74: , 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: , 2009