Drug-induced nephrotoxicity

Overview

•Type IV (delayed) hypersensitivity reaction - drug or metabolite acts as hapten, triggering T-lymphocyte and eosinophil infiltration of the renal interstitium

•Onset typically 7-10 days after first exposure (shorter on re-exposure)

•Most common cause: penicillins (especially amoxicillin); PPIs are an increasingly recognised cause with more insidious onset

•Classic triad: fever + rash + arthralgia - present in only ~30% of cases

•More consistently found: eosinophilia, sterile pyuria, (eosinophiluria)

•Hyperkalaemia is the most common electrolyte abnormality - impaired tubular potassium excretion

🎯
Any unexplained AKI within 10 days of starting a new drug - especially a penicillin or PPI - should prompt consideration of AIN, even without the full triad.

Investigations

🥇 First-line

•U&E (creatinine, eGFR, hyperkalaemia), FBC (eosinophilia), urine dipstick/microscopy (sterile pyuria, eosinophiluria in AIN; muddy brown casts in ATN)

•If nephrogenic DI suspected: serum and urine osmolality; water deprivation test then desmopressin - nephrogenic DI shows no rise in urine osmolality after desmopressin

•Drug levels: lithium and aminoglycoside levels - essential for monitoring toxicity

🏆 Gold standard

•renal biopsy - confirms AIN (interstitial oedema, tubulitis, eosinophil/T-lymphocyte infiltration); reserved for diagnostic uncertainty or failure to recover

Lithium-induced Nephrogenic Diabetes Insipidus

•Lithium enters collecting duct cells via sodium channels and desensitises the renal response to ADH - interferes with V2 receptor signalling and downregulates aquaporin-2 water channels

•Result: inability to concentrate urine regardless of ADH levels

•Presents with polyuria (>3 L/day) and polydipsia; raised serum osmolality, low urine osmolality

•No response to *desmopressin - distinguishes nephrogenic DI from central DI (which does respond) and psychogenic polydipsia (urine concentrates after water deprivation alone)

Other Key Drug-Kidney Mechanisms

Drug-induced nephrotoxicity patterns
Drug/classMechanismKey finding
NSAIDsBlock prostaglandin-mediated afferent vasodilation → ↓ intraglomerular pressure → ↓ GFR; especially dangerous in low-perfusion statesPre-renal AKI; bland urine
ACE inhibitors / ARBsBlock efferent arteriolar constriction → ↓ intraglomerular pressure; critical risk in bilateral renal artery stenosisPre-renal AKI; hyperkalaemia
Aminoglycosides (e.g. ***gentamicin***)Accumulate in proximal tubular cells via megalin receptors → reactive oxygen species → apoptosis (ATN)Muddy brown granular casts; monitor trough levels
***Cisplatin***Direct DNA cross-linking in proximal tubular cells + peritubular vasoconstriction → ATNMuddy brown casts; electrolyte wasting
***Amoxicillin*** / penicillinsType IV hypersensitivity → T-cell/eosinophil interstitial infiltration → AINFever, rash, arthralgia, eosinophilia, sterile pyuria
***Lithium***Desensitises ADH response; downregulates aquaporin-2 → nephrogenic DIPolyuria, polydipsia; no response to desmopressin

Drug/class	Mechanism	Key finding
NSAIDs	Block prostaglandin-mediated afferent vasodilation → ↓ intraglomerular pressure → ↓ GFR; especially dangerous in low-perfusion states	Pre-renal AKI; bland urine
ACE inhibitors / ARBs	Block efferent arteriolar constriction → ↓ intraglomerular pressure; critical risk in bilateral renal artery stenosis	Pre-renal AKI; hyperkalaemia
Aminoglycosides (e.g. *gentamicin*)	Accumulate in proximal tubular cells via megalin receptors → reactive oxygen species → apoptosis (ATN)	Muddy brown granular casts; monitor trough levels
*Cisplatin*	Direct DNA cross-linking in proximal tubular cells + peritubular vasoconstriction → ATN	Muddy brown casts; electrolyte wasting
*Amoxicillin* / penicillins	Type IV hypersensitivity → T-cell/eosinophil interstitial infiltration → AIN	Fever, rash, arthralgia, eosinophilia, sterile pyuria
*Lithium*	Desensitises ADH response; downregulates aquaporin-2 → nephrogenic DI	Polyuria, polydipsia; no response to desmopressin

Management and Prevention

•Cornerstone: stop the causative drug as early as possible

•AIN: stop culprit drug, ensure adequate hydration, monitor U&E; if creatinine fails to improve within 1-2 weeks consider oral prednisolone

•Aminoglycosides: use once-daily dosing regimens to minimise tubular accumulation; therapeutic drug monitoring

⚠️
The 'triple whammy' - ACE inhibitor/ARB + diuretic + NSAID - significantly elevates AKI risk and should be avoided, especially in older or volume-depleted patients. Withhold all three during intercurrent illness (sick day guidance).