Mechanisms and clinically important examples of drug induced nephrotoxicity

1. Drug-induced nephrotoxicity
The third most common cause of AKD (Acute Kidney Disease)
15-25% of AKI cases → drug-related toxicity
20% of drug-induced AKD cases → require renal replacement therapy
Up to 20% of drugs in clinical practice → nephrotoxic
Nehal M. Ramadan

2. Definition
Drug-induced nephrotoxicity ⇒ the
presence of any kidney injury caused
directly or indirectly by medications.

3. For Diagnosis of drug-induced nephrotoxicity → Some criteria are proposed →
● Exposure to the nephrotoxic agent for at least 24 hours.
● Injury mechanism related to the drug is similar to the condition presented.
● CP & Investigations are not completely compatible with other causes of
nephropathy.
● Risk factors of nephrotoxicity.
1. ↓ renal functional reserve (↓ glomeruli → can not increase the filtration
rate) → chronic kidney disease, older patients & other systemic
conditions as cardiac diseases, hypotension, DM & obesity
2. A larger concentration of drugs on the tubules → high dose,
hypoalbuminemia & genetic polymorphisms
3. Synergistic injury mechanisms → (cisplatin + aminoglycoside) →
cisplatin competes for the transporter responsible for tubular secretion
of aminoglycoside → ↑ cytoplasmic conc. Of aminoglycosides

4. Risk factors of drug-induced nephrotoxicity
Inherent nephrotoxic
potential of the drug
● Antimicrobial agents
● Anticancer drugs
● Analgesics
● immunosuppressive agents
Dose dependant
Vancomycin
Aminoglycosides
Cisplatin
Methotrexate
NSAIDs
ttt → Minimize duration &
conc. of the drug
Idiosyncratic
Proton pump inhibitors
Beta-lactams antibiotics
Calcineurin inhibitors
(cyclosporine&
tacrolimus)
ttt → avoid use of the
drug

5. Drugs causing AKI

6. NSAIDs
If used > 14 days
Susceptible populations
Ptns with sepsis,
decompensated CHF, cirrhosis,
dehydration, or using drugs that
act on renal hemodynamics
(cyclosporine, iodinated
contrast, RAAS inhibitors).
ttt
● Choose other options for
analgesia in patients with
risk of AKI
● Use for the minimum
duration
● Correct hypovolemia

7. Vancomycin
● Oral vancomycin → NO
● Dose (> 4g/d) & duration
(>14 days)-dependant
● Due to oxidative stress &
obstructive tubular cast
formation (vancomycin-
uromodulin caste)
● Renal injury → reversible
● Piperacillin-tazobactam +
vancomycin → a synergistic
nephrotoxicity
● ttt → change to linezolid or
daptomycin.
○ Teicoplanin might have
a better safety profile
○ In cases you can not
stop vanco → monitor
serum levels.
Aminoglycosides
Dose- & duration- (> 10 days) dependant & with
multiple daily doses.
Irreversible
High-risk patients →
● Ptns with hypokalemia and
hypomagnesemia
● Ptns with concomitant renal ischemia
Ttt →
● Change to
another drug
● Correct
hypokalemia &
hypomagnesemia
● Short time of
use
● Avoid use in
hypovolemic
patients
● Dosage
once/day,
● Adjust dose
according to the
serum level.

8. Methotrexate
Dose-dependant
Mech →
Formation of crystals in the
distal tubule + formation of
oxygen free radicals → local
inflammation and necrosis
Drug interactions →
methotrexate +
sulfas/beta-lactams
presence of ascites or
pleural effusion
High dose folinic acid
IV HCO3
Enzymatic cleavage of
methotrexate

9. Drugs causing tubular
damage

10. Amphotericin B
Direct tubular injury (↑ cellular membrane
permeability to cations) + ischemia caused by VC
of the afferent arteriole
CP→ hypokalemia, hypomagnesemia, diluted
urine, metabolic acidosis & ↓GFR → one week of
medication use.
Reversible
Ttt →
● Change to less toxic formulations (the lipid/liposomal
formulations are less toxic) or different antifungal
agent
● In cases there is no alternative to the use of
amphotericin deoxycholate →
○ Increase time of infusion
○ Hydration pre-infusion (500 to 1000 mL)
○ Monitor electrolytes
○ Use amiloride and spironolactone → prevent of
hypokalemia.

11. Drugs causing CKD
CALCINEURIN INHIBITORS
(cyclosporine & tacrolimus)
Main mechanisms →
● VC of the afferent arteriole.
● HTN
● Thrombotic microangiopathy
● Tubule-interstitial fibrosis and
atrophy
AKI → reversible
CKD → irreversible
Ttt → monitor serum levels

12. Mech of
drug-related
renal toxicity

13. Summary