Drug-related nephrotoxicity
Description
- ~20% of hospital-acquired AKI is drug-related and most is preventable
- Classify by site and mechanism - that is what determines the urine findings and the treatment
| Site | Lesion | Urine |
|---|---|---|
| Pre-glomerular | Haemodynamic (afferent/efferent tone) | Bland, low FENa |
| Glomerulus | MCD, FSGS, membranous, TMA | Proteinuria +/- haematuria |
| Tubule | ATN, crystal, osmotic, tubulopathy | Muddy brown casts, crystals, glycosuria |
| Interstitium | AIN, chronic interstitial nephritis | Sterile pyuria, WCC casts |
| Post-renal | Crystal obstruction, retroperitoneal fibrosis | Obstruction on US |
- *Always ask: is this a real fall in GFR, or an interference?*
Epidemiology
- Nephrotoxic drugs implicated in 14-26% of AKI in adults; higher in ICU and oncology
- Aminoglycoside ATN in 10-20% of courses
- Contrast-associated AKI incidence has fallen substantially with iso/low-osmolar agents - the causal contribution is now thought to be much smaller than historically believed
- Risk multiplied by: age, pre-existing CKD, volume depletion, sepsis, heart failure, cirrhosis, the triple whammy (ACEi/ARB + diuretic + NSAID)
Aetiopathogenesis
A. Haemodynamic - reversible, no structural damage
- NSAIDs - block prostaglandin-mediated afferent vasodilatation -> dec GFR
- Dangerous exactly when prostaglandins matter: hypovolaemia, cirrhosis, heart failure, CKD
- ACEi/ARB - block angiotensin II-mediated efferent constriction -> dec filtration pressure
- A rise up to 30% is expected and acceptable; more suggests bilateral renal artery stenosis
- Calcineurin inhibitors - afferent vasoconstriction (acute) and arteriolar hyalinosis with striped fibrosis (chronic)
- SGLT2i - a small early haemodynamic dip; not nephrotoxicity
B. Direct tubular toxicity (ATN)
- Aminoglycosides - freely filtered, taken up via megalin into proximal tubular cells -> lysosomal phospholipidosis
- Non-oliguric AKI at day 5-10, hypomagnesaemia, hypokalaemia; once-daily dosing reduces uptake (saturable transport)
- Amphotericin B - membrane pore formation -> type 1 RTA, K+ and Mg2+ wasting, nephrogenic DI; liposomal is less toxic
- Cisplatin - proximal tubular necrosis, profound magnesium wasting, salt wasting
- Vancomycin - *drug-uromodulin interaction -> intratubular cast formation*; synergistic with piperacillin-tazobactam
- Tenofovir disoproxil, adefovir, cidofovir, indinavir, zoledronate - proximal tubular toxicity, Fanconi syndrome
- Radiocontrast - direct toxicity + medullary vasoconstriction
C. Crystal nephropathy
- Aciclovir (IV bolus, dehydrated), sulfonamides, methotrexate, indinavir, atazanavir, triamterene, high-dose vitamin C
- Prevented by volume expansion +/- urinary alkalinisation (methotrexate)
D. Interstitial nephritis - see AIN
- PPIs, NSAIDs, beta-lactams, checkpoint inhibitors, allopurinol, 5-ASA, rifampicin
E. Glomerular
- NSAIDs -> minimal change; pamidronate/interferon/anabolic steroids -> FSGS (collapsing)
- Gold, penicillamine, NSAIDs, anti-TNF -> membranous
- Hydralazine, propylthiouracil, levamisole-adulterated cocaine -> drug-induced lupus / ANCA vasculitis with glomerular involvement
- VEGF inhibitors (bevacizumab, TKIs) -> TMA + proteinuria + HTN
F. Thrombotic microangiopathy
- Calcineurin inhibitors, gemcitabine, mitomycin C, quinine, ticlopidine, VEGF inhibitors, interferon
G. Interference - creatinine rises, GFR does not
- Trimethoprim - *inhibits distal tubular secretion of creatinine (and K+) -> apparent creatinine rise + hyperkalaemia with an unchanged true GFR*
- Cimetidine, cobicistat, dolutegravir, ritonavir - same mechanism
- Flucytosine, cefoxitin - assay interference (Jaffe method)
- Cystatin C-based eGFR is unaffected - use it when the question matters
H. Osmotic nephrosis
- IVIG (sucrose-containing), mannitol, hydroxyethyl starch, high-dose IV immunoglobulin
Calcineurin inhibitor toxicity - the full list
- Nephrotoxicity; HTN (ciclosporin > tacrolimus); dyslipidaemia (ciclosporin > tacrolimus); neurotoxicity (tacrolimus > ciclosporin); diabetes (tacrolimus > ciclosporin)
- Hypomagnesaemia, hypophosphataemia, hyperkalaemia (type 4 RTA)
- GI and hepatic toxicity, avascular necrosis, HUS/TMA
- Ciclosporin only: gum hypertrophy, hirsutism
Diagnosis
- Timeline is the diagnosis: chart every drug against the creatinine curve, including OTC and complementary medicines
| Clue | Points to |
|---|---|
| Muddy brown granular casts, FENa >2% | ATN |
| Sterile pyuria, WCC casts, eosinophilia, rash | AIN |
| Crystals on microscopy | Crystal nephropathy |
| Glycosuria with normal glucose, hypophosphataemia, hypouricaemia | Proximal tubulopathy / Fanconi |
| Bland urine, FENa <1%, rapid reversal on stopping | Haemodynamic |
| Thrombocytopenia, schistocytes, LDH inc | TMA |
| Rising creatinine, normal cystatin C, hyperkalaemia | Trimethoprim-type interference |
- Drug levels where available (vancomycin, aminoglycoside, CNI, lithium, methotrexate)
- Biopsy if the diagnosis or the decision to continue the drug is unclear
Management
Prevention - where most of the benefit is
- Identify high-risk patients before prescribing: eGFR <60, age >65, volume depletion, sepsis, heart failure, cirrhosis, myeloma, diabetes
- Dose by absolute CrCl (Cockcroft-Gault) for narrow-therapeutic-index drugs, not BSA-normalised eGFR
- Avoid the triple whammy: ACEi/ARB + diuretic + NSAID
- Volume expansion before contrast, cisplatin, aciclovir, methotrexate
- Contrast: isotonic saline in high-risk patients (eGFR <30); *N-acetylcysteine and bicarbonate are NOT effective (PRESERVE)*
- Aminoglycosides: once-daily dosing, shortest possible course, trough monitoring, avoid with vancomycin or loop diuretics
- Vancomycin: AUC-guided dosing (AUC/MIC 400-600) rather than trough-only - reduces nephrotoxicity
- Methotrexate: alkalinise urine to pH >7, high-dose leucovorin, glucarpidase for delayed clearance
- Sick-day plan: withhold ACEi/ARB, diuretics, metformin, SGLT2i, NSAIDs during acute illness
Once injury has occurred
- Stop or substitute the drug - the definitive treatment for most mechanisms
- Restore volume, treat sepsis, relieve obstruction
- Lesion-specific
- AIN -> corticosteroids if not improving after withdrawal
- Crystal -> volume, alkalinisation, stop the drug
- Lithium toxicity -> haemodialysis (small Vd, dialysable)
- Methotrexate -> glucarpidase, alkalinisation; not dialysable in a useful way
- TMA -> stop the drug; plasma exchange rarely helps drug-induced TMA (unlike TTP)
- VEGF inhibitor -> BP control, ACEi/ARB, drug hold
- Document as an adverse drug reaction in the record and communicate to the GP
Associations
- Volume depletion, sepsis, heart failure, cirrhosis - the setting that turns a tolerated drug into a nephrotoxin
- Pre-existing CKD, age >65, diabetes, myeloma
- Polypharmacy; NSAID and PPI use
- Contrast, cardiac surgery, ICU admission
- Analgesic nephropathy -> papillary necrosis and transitional cell carcinoma
- Chinese herbal / aristolochic acid nephropathy -> interstitial fibrosis + urothelial malignancy
- Lithium -> nephrogenic DI, chronic interstitial nephritis, microcysts
Natural history & complications
- Haemodynamic and interference effects reverse in days
- ATN recovers over 1-3 weeks if the insult stops - non-oliguric recovers better than oliguric
- AIN: ~50-60% complete recovery, 30-40% residual CKD
- Chronic interstitial nephritis (lithium, CNI, analgesics, aristolochic acid) is progressive and irreversible
- Cisplatin magnesium wasting can persist for years; aminoglycoside vestibular/auditory toxicity is permanent
- Every AKI episode raises long-term CKD, cardiovascular and mortality risk - arrange follow-up creatinine and UACR at 3 months
- The commonest error is failing to review the medication list at discharge and restarting the culprit
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