Helmut Hopfer Basel, Switzerland 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 - 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

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

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

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

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

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

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

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

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

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

- 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

- 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?

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

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

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