1/31 Drug-Induced Nephrotox - Pilch Flashcards
overview of renal drug excretion
implication for kidneys
three partitioning events
-
glomerular filtration
- only free (non-protein-bound) drug is filtered
- drug pH and lipophilicity has no effect!
- unfiltered drug continues through → contributes to conc gradient in cortex
-
tubular secretion
- drug moves from blood to lumen via active transport mech
- separate carrier-mediated systems: acids (anions) and bases (cations)
- saturable carriers having little specificity for drug structure
- protein-free and protein-bound drugs can both be secreted
-
tubular reabs
- at distal tubule, intraluminal drug conc is HIGH (bc water has been reabs) → drug diffuses passively back out of nephron lumen into blood
- only free, unionized drug diffuses back (pH partitioning occurs)
*as drug moves through nephron, drug concentration gets higher and higher → distal tubule is subjected to v high conc of drugs
risk factors for drug-induced nephropathy
3 broad categories
specifics
1. patient specific factors
- age
- volume depletion
- underlying disease
- pharmacogenetics
2. kidney specific factors
- high blood delivery rate
- high toxin conc
- renal metab
3. drug specific factors
- direct nephrotox
- prolonged exposure
- multiple toxin exposure
- solubility
pathogenesis of drug-induced nephrotox
6 common mechs
- altered intraglom hemodynamics
- tubular cell toxicity
- inflammation
- crystal nephropathy
- rhabdomyolysis
- thrombotic microangiopathy (TMA)
altered intraglomerular hemodyamics
disrupted autoregulation of intraglom pressure and GFR
- NSAIDs
- ACE inhibitors
- calcineurin inhibitors
- antiVEGF agents
tubular cell toxicity
occurs via
- impaired mitochondrial function
- disrupted tubular transport
- increased oxidative stress
- formation of free radicals
- aminoglycosides
- antiretrovirals
- cisplatin
- zoledronate
inflammation
infl changes in the glomerulus, tubular cells, and interstitium → fibrosis and renal scarring
- NSAIDs
- INFalpha
- lithium
- pamidronate
- proton pump inhibitors
- phenytoin
- herbals with aristolochic acid
crystal nephropathy
production of crystals that are insoluble in urine → obstruct urine flow
- ampicillin
- ciprofloxacin
- sulfonamides
- methotrexate
- triamterene
rhabdomyolysis
lysis of skeletal muscle myocytes → myoglobin release into plasma →
- renal toxicity
- tubular obstruction
- altered GFR
- statins
- heroin
- cocaine
- alcohol
thombotic microangiopathy (TMA)
platelet thrombi in microcirc → renal injury via immune mediated rxns or direct endothelial tox
- clopidogrel
- cyclosporine
- mitomycin C
- antiVEGF agents
- quinine
clinical features of aminoglycoside nephrotoxicity
manifests 5-7d post tx initiation
- usually non-oliguric
- may be assoc with other fluid and electrolyte abnormalities resulting from tubular damage
- loss of urine concentrating ability
- Mg-uria → hypoMg-emia
- PO4uria → hypoPO4emia
recovery usually after 2-3wk of stopping tx
risk factors for aminoglycoside nephrotox
AG-induced nephrotox
highly polar bactericidal agents (sugar + amine)
eliminated (unchanged) by kidney → drug clearance directly proportional to creatinine clearance
pathophysio
- cant cross membranes, but are anionic → can form pockets with their anionic parts to disrupt membrane integrity
- also hijack anionic transporters of tubular cells to enter cells
- once inside, disrupt lots of stuff, esp MITO
drugs reach high conc in renal cortex → directly toxic to prox tubular cells
AG-induced nephrotox2
effect on glom
most nephrotoxic AGs
tubular cell toxicity is coupled with glom effects → reduction in GFR →→ clinical AKI
neomycin, gentamicin, tobramycin are the most nephrotoxic AGs
- appears in 10-25% of AG courses
- effects reversible upon discontinuation of tx
prevention of AG-induced nephrotox
avoid concurrent use of nephrotox agents
adequate hydration
assess baseline renal fx
- adults: MDRD or Cockroft-Gault formua
- kids: Schwartz formula
consolidated aminoglycoside dosing
4-7mg/kg every 24h (adjusted for level of renal dysfx)
peak levels ~20 mcg/mL, trough levels <1 mcg/dL
- exploits post-antibiotic effect of AGs on Gram- bacteria
- inhibitory or cidal effect that persists after AG is cleared by metabolism and elimination
- higher peak concs maximizes postential for concentration-dependent killing while avoiding elevated trough concs → helps avoid toxicity
at higher doses, more AG excreted without reabs → doesnt accumulate and injure renal tubular cells
healthy glom filtration barrier
renal effects of antiVEGF tx
- hypertension
-
theory: bevacizumab causes downreg of enzyme involved in producing NO
- systemic vasoconst → HTN
- antiVEGF HTN is often transient, typically resolves on drug discont
- also, HTN is usually easily controlled w/ standard HTN regimen
- proteinuria
- common, but not usually in nephrotic range
-
theory: affects fx and localization of VEGF and VEGFR
- inhibition of VEGF signaling in endothelial glomerular cells alters fenestration formation →disrupts glom filtration barrier → proteinuria
- usually temporarly, resolves with drug discont, not gen assoc with renal dysfx
- AKI: acute kidney injury
- v rare: proteinuria in nephrotic range → clinical AKI
- mesangiolysis, swelling of glom endothelial cells, loss of endothelial fenestrae, efacement of podocyte foot processes
- acute TMA is most common histopathologic lesion
- most cases, renal fx stabilizes after drug discont
herbal remedies containing aristolochic acid
AA nephropathy
many ingredients used in traditional medicine in China, Japan, India contain aristolochic acid
AAN is a progressive form of interstitial nephritis → can lead to ESRD, urothelial malignancy
pathogenesis of AAN
phase I metabolites can be toxic if REACTIVE
ex. aristolactam nitrenium ion (ANI) - reactive nephrotoxic metabolite
