Step 2 CK · Internal Medicine · Nephrology

Drug-Induced Nephrotoxicity & Renal Drug Dosing

Name: Drug-Induced Nephrotoxicity & Renal Drug Dosing
Creator: Veli Bakalov, MD

Name the culprit, prevent the injury, dose for the GFR

Nephrology·Acute Kidney Injury & Renal Diagnostics·5 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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NSAIDs constrict the afferent arteriole and ACE inhibitors/ARBs dilate the efferent arteriole; add a diuretic and volume loss and GFR collapses (the triple whammy).
Calcineurin inhibitors cause afferent vasoconstriction (reversible AKI), chronic striped fibrosis, hyperkalemia, hypomagnesemia, and hypertension; CYP3A4 inhibitors raise their levels.
Aminoglycosides cause nonoliguric ATN after 5–10 days with potassium and magnesium wasting; use once-daily dosing and monitor troughs.
Amphotericin B causes distal (type 1) RTA with hypokalemia and hypomagnesemia; prevent with saline loading and lipid formulations.
Tenofovir disoproxil fumarate causes Fanconi syndrome (glycosuria with normal glucose, phosphaturia, type 2 RTA); switch to tenofovir alafenamide.
IV acyclovir, sulfadiazine, indinavir, and methotrexate cause crystal nephropathy; high-dose methotrexate also needs urine alkalinization, leucovorin, and glucarpidase for toxic levels with AKI.
Sucrose-containing IVIG and mannitol cause osmotic nephrosis; oral sodium phosphate bowel preps cause acute phosphate nephropathy.
Metformin is contraindicated at eGFR below 30 and should not be started at 30–45; at eGFR below 30, AKI, or dialysis, use a group II (macrocyclic) gadolinium agent at the lowest dose and avoid group I agents (nephrogenic systemic fibrosis).
In severe CKD, use unfractionated heparin instead of full-dose enoxaparin, fentanyl or hydromorphone instead of morphine or meperidine, and avoid nitrofurantoin and magnesium- or phosphate-containing laxatives.

Hemodynamic injury

Who is at risk. Drug nephrotoxicity is most likely in older adults and in patients with CKD, diabetes, heart failure, cirrhosis, or volume depletion. Risk also rises when several nephrotoxins are combined. Drugs injure the kidney by altering glomerular hemodynamics, poisoning tubular cells, forming crystals or osmotic vacuoles, or provoking an immune interstitial nephritis. Allergic interstitial nephritis from β-lactams, PPIs, and NSAIDs is covered with AKI.

The triple whammy. Glomerular pressure is held up by prostaglandins that dilate the afferent arteriole and by angiotensin II, which constricts the efferent arteriole. NSAIDs remove the first and constrict the afferent arteriole; ACE inhibitors and ARBs remove the second and dilate the efferent arteriole. A diuretic adds volume depletion. The three together collapse GFR, typically in an older patient who then develops vomiting or diarrhea. The urine is bland and the FENa low. Treatment is stopping the drugs and restoring volume.

After an ACE inhibitor or ARB is started, a creatinine rise of up to about 30% reflects the intended fall in glomerular pressure and is acceptable. A larger rise suggests volume depletion or bilateral renal artery stenosis. During a dehydrating illness, patients should pause ACE inhibitors or ARBs, diuretics, NSAIDs, metformin, and SGLT2 inhibitors ("sick-day rules").

Calcineurin inhibitors. Cyclosporine and tacrolimus cause dose-dependent afferent vasoconstriction, producing an acute AKI that reverses when the dose is lowered. Over years they cause chronic nephrotoxicity with striped interstitial fibrosis and arteriolar hyalinosis. Other renal effects are hyperkalemia, hypomagnesemia, hypertension, and thrombotic microangiopathy. Trough levels guide dosing. CYP3A4 inhibitors (azoles, clarithromycin, diltiazem, grapefruit) raise levels and cause toxicity. CYP3A4 inducers (rifampin, phenytoin, St John's wort) lower levels and risk rejection.

Direct tubular toxins

Aminoglycosides. Proximal tubular cells take up aminoglycosides through the megalin receptor, and the drug accumulates in lysosomes until the cells die. The typical result is nonoliguric ATN after 5–10 days of therapy with potassium and magnesium wasting. Uptake is saturable, so one large daily dose delivers less drug to the tubule than divided doses while keeping concentration-dependent killing. Monitor troughs and keep courses short. Ototoxicity (cochlear and vestibular) is often permanent and is worsened by loop diuretics.

Tubular toxins

Drug	Injury and clues	Prevention or response
Aminoglycosides	Nonoliguric ATN at days 5–10; low K and Mg	Once-daily dosing, troughs, short courses
Amphotericin B	Membrane pores → distal (type 1) RTA, low K and Mg, polyuria; afferent vasoconstriction	Saline loading before each dose; lipid formulation
Cisplatin	Proximal tubular AKI; persistent Mg wasting	Vigorous saline hydration, Mg replacement
Foscarnet	ATN, nephrogenic DI; chelates Ca and Mg (seizures)	Pre-hydration; monitor electrolytes
Vancomycin	Dose-related tubular injury; more AKI with piperacillin-tazobactam than with cefepime or meropenem	AUC-guided dosing (400–600), shortest course, de-escalate
Tenofovir (TDF)	Proximal tubulopathy: Fanconi syndrome, type 2 RTA	Switch to tenofovir alafenamide (TAF)
Ifosfamide	Fanconi syndrome; hemorrhagic cystitis	Mesna protects the bladder

Fanconi syndrome. Generalized proximal tubular failure causes several findings together:

glycosuria with a normal blood glucose
phosphaturia, leading to hypophosphatemia and osteomalacia
aminoaciduria and low-grade tubular proteinuria
bicarbonate wasting, a proximal (type 2) RTA

TDF causes it by concentrating in proximal cells and injuring their mitochondria. TAF gives far lower plasma tenofovir levels and spares the tubule.

Trimethoprim and cimetidine raise serum creatinine by blocking its tubular secretion without lowering true GFR. Trimethoprim also causes hyperkalemia by blocking ENaC, as amiloride does.

Crystal, osmotic, and phosphate injury

Crystal nephropathy. Drugs that dissolve poorly in urine precipitate in the tubules when given rapidly, at high dose, or to a volume-depleted patient.

IV acyclovir forms needle-shaped birefringent crystals and causes AKI within 24–48 hours.
Sulfadiazine, used for toxoplasmosis, forms sheaf-of-wheat crystals that are favored by acidic urine.
Indinavir forms crystals and stones; indinavir stones are not visible on CT.

Prevent crystals with vigorous IV hydration, slow infusion, and renal dose adjustment. If AKI occurs, hydrate and reduce or stop the drug.

High-dose methotrexate. Methotrexate precipitates in acidic tubular fluid. The AKI it causes slows its own clearance, which magnifies marrow and mucosal toxicity.

Before the doseHydrate; alkalinize urine with IV bicarbonate to pH ≥7; stop NSAIDs, PPIs, TMP-SMX, and penicillins, which slow clearance
After the doseLeucovorin rescue guided by serial methotrexate levels
Toxic level with AKIGlucarpidase (carboxypeptidase G2) cleaves circulating methotrexate

Osmotic nephrosis. Osmotic agents that are filtered but not metabolized are taken up by proximal tubular cells, which swell with vacuoles. AKI follows within days. Culprits are sucrose-stabilized IVIG, mannitol, and hydroxyethyl starch. Use sucrose-free IVIG infused slowly, limit cumulative mannitol while watching the osmolal gap, and avoid hydroxyethyl starch in critical illness.

Acute phosphate nephropathy. Oral sodium phosphate bowel preparation delivers a large phosphate load, and calcium phosphate deposits in distal tubules and collecting ducts. The injury is subacute, often discovered weeks to months later, and frequently irreversible. Risk factors are CKD, older age, hypovolemia, ACE inhibitors or ARBs, diuretics, and NSAIDs. Polyethylene glycol preparations avoid it.

Dosing in chronic kidney disease

Principles. Many drug labels base renal dosing on creatinine clearance (Cockcroft-Gault). Loading doses are usually unchanged. Maintenance doses are reduced or dosing intervals lengthened for renally cleared drugs.

Common renal dosing decisions

Drug	Risk in CKD	Action
Metformin	Lactic acidosis	Contraindicated at eGFR <30; do not start at 30–45 and reassess the dose if already taking it; hold around iodinated contrast if eGFR 30–60 or AKI, recheck at 48 h
Gadolinium	Nephrogenic systemic fibrosis	At eGFR <30, AKI, or dialysis: avoid group I agents; group II (macrocyclic) agents carry very low risk and should not be withheld when indicated, so use the lowest diagnostic dose, then prompt hemodialysis in dialysis patients
Enoxaparin	Accumulation, bleeding	CrCl <30: 1 mg/kg once daily with anti-Xa levels, or switch to unfractionated heparin
DOACs	Accumulation	Renal dose adjustment; dabigatran is most renally cleared (~80%), apixaban least
Morphine, meperidine, codeine	Active metabolites: sedation, respiratory depression, myoclonus, seizures	Fentanyl or cautiously dosed hydromorphone
Nitrofurantoin	Too little reaches the urine; systemic toxicity	Avoid at CrCl <30
Magnesium or phosphate laxatives and enemas	Hypermagnesemia; hyperphosphatemia	Use PEG or senna

Gadolinium and NSF. Nephrogenic systemic fibrosis appears weeks to months after exposure, with thickened, woody skin of the limbs and trunk, joint contractures, and sometimes visceral fibrosis. It has no reliable treatment, so prevention is everything.

Heparins. Unfractionated heparin is cleared by nonrenal mechanisms, has a short half-life, and is fully reversed by protamine. That makes it the usual choice in severe kidney failure or when a procedure is likely. Protamine only partly reverses enoxaparin, and fondaparinux is contraindicated at CrCl <30.