Nephrotoxic drugs

Tom Hewlett, MD

Many pharmaceutical agents can have nephrotoxic side effects. It would be impossible for
general practitioners to remember them all. There are, however, a few drug classes used daily in
general practice that have such serious adverse effects it is worthwhile remembering which ones
they are.

Antibiotics

Antibiotics can cause renal failure through a variety of mechanisms, including direct toxicity to
the renal tubules, allergic interstitial nephritis, and crystallization of the drug within the renal
tubules.

Aminoglycosides can be nephrotoxic, and doses must be adjusted for patients with renal
impairment. Even so, proper dose adjustment is no guarantee of safety.1 Aminoglycosides are
excreted solely in the urine and are directly toxic to proximal tubular cells. Once-daily dosing
with aminoglycosides is convenient and could be less toxic for people with normal renal
function,2 but no data support once-daily dosing for patients with impaired renal function even if
dosage is adjusted. Family physicians should avoid aminoglycosides completely for patients with
renal insufficiency. If no suitable alternative is available for patients suspected of having life-
threatening Gram-negative bacteremia, a single 1.5-mg/kg dose of an aminoglycoside would be
considered safe and would allow time to consult with an infectious disease expert (level V
evidence).

Allergic interstitial nephritis, an idiosyncratic reaction, can be a side effect of many drugs.
Antibiotics are by far the most common culprits. You cannot prevent interstitial nephritis; you
can only recognize the syndrome promptly and discontinue the offending agent. Ongoing fever,
rash, progressive renal failure, and eosinophilia during prolonged antibiotic therapy should
suggest interstitial nephritis, which can be confirmed by renal biopsy. Although penicillins and
cephalosporins are well recognized causative agents, almost any antibiotic can be the cause. The
fluoroquinolone ciprofloxacin is now a well recognized cause of allergic interstitial nephritis
(level III evidence).3

Crystallization of antibiotics in the renal tubules can lead to acute oliguric renal failure and has
been reported with sulfa drugs, acyclovir, and indinavir (used to treat HIV infection). Although
adequate hydration can prevent it, risk is increased substantially in the low glomerular filtration
rate state of chronic renal insufficiency.4 Adjusting the dose of sulfa drugs for patients with renal
insufficiency is recommended, but does not guarantee safety. Although renal function can be
restored after discontinuation of sulfa, patients are sometimes rendered permanently dependent
on dialysis. It is best to avoid sulfa drugs for patients with renal insufficiency. Trimethoprim
alone is as effective as combination therapy with trimethoprim-sulfamethoxazole for
uncomplicated urinary tract infections (level I evidence).5

Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors

These two classes of drugs have similar safety profiles for patients with renal insufficiency (level
III evidence). Both can cause edema, hypertension, congestive heart failure (CHF), and acute or
chronic renal failure.6 Effects are dose dependent and usually reversible, although patients with
advanced renal failure can become permanently dependent on dialysis. Suitable alternatives
should be sought wherever practical. Acetaminophen is by far the safest analgesic for patients
with renal failure (level V evidence).

In the past, combinations of acetaminophen and other analgesics were thought to be responsible
for analgesic nephropathy, but acetaminophen alone in recommended doses is rarely nephrotoxic
(except when combined with alcohol).7 Colchicine (dose adjusted for renal impairment), joint
injection, and brief courses of systemic corticosteroids are better tolerated than nonsteroidal anti-
inflammatory drugs (NSAIDs) for episodic gout in renal insufficiency.8 If an NSAID is
absolutely required, use the lowest dose necessary for controlling inflammation for the shortest
period possible and monitor patients closely for edema, hypertension, CHF, and renal function
(level IV evidence).

Angiotensin-converting enzyme inhibitors and adrenergic receptor binders

These classes of drugs have been immensely successful for managing cardiovascular disease,
hypertension, and chronic nephropathy. Large clinical trials of stable outpatients showed the
drugs were extremely well tolerated, but none of these trials included patients with advanced
renal failure (creatinine levels >300 mol/L).9 Initiation of angiotensin-converting enzyme
inhibitors and adrenergic receptor binders (ACE/ARB) in patients with advanced renal failure
can precipitate uremia, hyperkalemia, and dialysis dependence. Physicians are advised to refer
these patients to nephrologists before initiating ACE/ARB therapy (level IV evidence).

Previously stable patients taking chronic ACE/ARB therapy can become dehydrated and develop
profound renal failure that requires temporary dialysis. Volume depletion often mandates
withdrawing ACE/ARB therapy; it can be reintroduced successfully once euvolia is established.
Although bilateral renal artery stenosis has been considered a contraindication to ACE inhibitors
in the past, renovascular disease is often associated with severe hypertension that responds well
to blockage of the renin-angiotensin system.10 In high-risk patients, blood pressure, creatinine,
and potassium should be carefully monitored when initiating or increasing the dose of these
drugs. Some mild elevation in serum creatinine is acceptable to get the benefits of ACE/ARB.
Some authors have argued creatinine levels could be allowed to rise 30%, as long as they
stabilize and patients have no symptoms of uremia11 (level IV evidence).

Lithium

Lithium therapy for bipolar affective disorder has long been associated with a variety of renal
abnormalities, including nephrogenic diabetes insipidus, chronic interstitial nephritis, and
minimal change glomerulonephropathy.12 By far the most worrying is progressive renal failure
in association with interstitial nephritis. Whether lithium is the causal agent is unclear; the
relationship might simply be an association since patients with chronic psychotic disorders not
treated with lithium are also at higher risk of chronic interstitial nephritis13 (level III evidence).
Withdrawing lithium therapy can have disastrous consequences and should be done only under
the supervision of physicians experienced in managing bipolar affective disorder.

Intravenous contrast dye

High-molecular-weight or ionic contrast dye can cause severe vasospasm in the afferent arteriole
and acute renal failure in susceptible patients. Risk factors include diabetes, myeloma, chronic
renal failure, dehydration, diuretic therapy, and CHF.14 Vasospasm is less common with newer
lower-molecular-weight or nonionic contrast dye (level I evidence).15 Hydration with
intravenous saline is the simplest way to reduce contrast nephrotoxicity (level I evidence),16 and
use of prophylactic acetylcysteine can also reduce it (level II evidence).17 It remains unclear
whether these measures can prevent acute tubular necrosis in extremely high-risk patients with
advanced renal failure. The best way to prevent vasospasm is to avoid contrast dye altogether by
using ultrasound, magnetic resonance imaging (gadolinium enhancement is not nephrotoxic),18
or unenhanced computed tomography scans for high-risk patients (level III evidence).

Conclusion

If physicians avoided NSAIDS, cyclooxygenase-2 inhibitors, sulfa drugs, aminoglycosides, and

intravenous contrast dye in patients with renal insufficiency, they would rarely see cases of drug-
induced renal failure, except for dehydration associated with ACE/ARB therapy.

References

1. Smith CR, Lipsky JJ, Laskin OL, Hellmann DB, Mellits ED, Longstreth J, et al. Double-blind
comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin. N Engl J
Med 1980;302(20):1106-9.
2. Barza M, Ioannidis JP, Cappelleri JC, Lau J. Single or multiple daily doses of
aminoglycosides: a meta-analysis. BMJ 1996;312(7027):338-45.
3. Allon M, Lopez EJ, Min KW. Acute renal failure due to ciprofloxacin. Arch Intern Med
1990;150(10):2187-9.
4. Schwartz A, Perez-Canto A. Nephrotoxicity of antiinfective drugs. Int J Clin Pharmacol Ther
1998;38(3):164-7.
5. Trimethoprim Study Group. Comparison of trimethoprim at three dosage levels with co-
trimoxazole in the treatment of acute symptomatic urinary tract infection in general practice. J
Antimicrob Chemother 1981;7:179-83.
6. Perazella MA, Eras J. Are selective COX-2 inhibitors nephrotoxic? Am J Kidney Dis
2000;35(5):937-40.
7. Kaysen GA, Pond SM, Roper MH, Menke DJ, Marrama MA. Combined hepatic and renal
injury in alcoholics during therapeutic use of acetaminophen. Arch Intern Med
1985;145(11):2019-23.
8. Clive DM. Renal transplant-associated hyperuricemia and gout. J Am Soc Nephrol
2000;11:974-9.
9. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration
rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN
Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet 1997;349(9069):1857-
63.
10. Hollenberg NK. The treatment of renovascular hypertension: surgery, angioplasty, and
medical therapy with converting-enzyme inhibitors. Am J Kidney Dis 1987;10(1 Suppl 1):52-60.
11. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitorassociated elevations in
serum creatinine: is this a cause for concern? Arch Intern Med 2000;160:685-93.
12. Boton R, Gaviria M, Batlle DC. Prevalence, pathogenesis, and treatment of renal dysfunction
associated with chronic lithium therapy. Am J Kidney Dis 1987;10(5):329-45.
13. Walker RG. Lithium nephrotoxicity. Kidney Int Suppl 1993;42(Suppl 1):S93-8.
14. Barrett BJ. Contrast nephrotoxicity. J Am Soc Nephrol 1994;5(2):125-37.
15. Rudnick MR, Goldfarb S, Wexler L, Ludbrook PA, Murphy MJ, Halpern EF, et al.
Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial. The
Iohexol Cooperative Study. Kidney Int 1995;47(1):254-61.
16. Solomon R, Werner C, Mann D, DElia J, Silva P. Effects of saline, mannitol, and furosemide
to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med
1994;331(21):1416-20.
17. Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of
radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J
Med 2000;343(3):180-4.
18. Townsend RR, Cohen DL, Katholi R, Swan SK, Davies BE, Bensel K, et al. Safety of
intravenous gadolinium (Gd-BOPTA) infusion in patients with renal insufficiency. Am J Kidney
Dis 2000;36(6):1207-12.

Just the Berries for Family Physicians originated at St Marthas Regional Hospital in 1991 as a
newsletter for members of the Department of Family Medicine. Its purpose was to provide
useful, practical, and current information to busy family physicians. It is now distributed by the
Medical Society of Nova Scotia to all family physicians in Nova Scotia. Topics discussed are
suggested by family physicians, and in many cases, articles are researched and written by family
physicians.

Just the Berries has been available on the Internet for several years. You can find it at
www.theberries.ns.ca. Visit the site and browse the Archives and the Berries of the Week. We are
always looking for articles on topics of interest to family physicians. If you are interested in
contributing an article, contact us through the site. Articles should be short (350 to 1200 words),
must be referenced, and must include levels of evidence and the resources searched for the data.
All articles will be peer reviewed before publication.

Dr Hewlett is a staff nephrologist at the Cape Breton Regional Hospital in Sydney, NS.
 Drug Prescribing in Renal Impairment
Post your experience

Renal impairment may be the result of a variety of renal or systemic diseases, such as diabetic
nephropathy or systemic lupus erythematosus. Normal ageing results in a decline in renal
function due to loss of nephrons. Elderly patients should therefore be assumed to have some
degree of renal impairment when prescribing. If even mild renal impairment is considered likely,
renal function should be checked before prescribing any drug which requires dose modification.
Reasons for problems with medications in renal failure include:

Failure to excrete a drug or its metabolites.

Many side-effects are tolerated poorly by patients in renal failure.

Some drugs cease to be effective when renal function is reduced.

Assessment of renal function1

See separate article - Assessing Kidney Function - and separate calculator for estimating eGFR .

Normal glomerular filtration rate is approximately 100 ml/min/1.73 m2.

Since April 2006 in the UK, most local laboratories calculate estimated glomerular
filtration rate (eGFR) on all samples sent for creatinine measurement.

Prescribing in renal impairment

Drugs that are renally excreted may need to have their doses reduced in patients with
renal insufficiency or end-stage renal disease:
o For prescribing purposes renal impairment is usually divided into 3 grades:

Mild: GFR 20-50 ml/minute; serum creatinine approximately 150-300

micromol/l.
Moderate: GFR 10-20 ml/minute; serum creatinine approximately 300-
700 micromol/l.
Severe: GFR less than 10 ml/minute; serum creatinine > 700 micromol/l.

Patients with a GFR above 50 ml/min do not usually require any dosage
adjustment.
Nephrotoxic drugs should, if possible, be avoided in patients with renal
disease because the consequences of nephrotoxicity are likely to be more
serious when the renal reserve is already reduced.
 o The situation may change if a patient begins dialysis, since some drugs will be
removed by the dialysis. Dialysis may lead to the loss of therapeutic effect for
some drugs.
o Drugs to which particular attention must be given include many antibiotics, H2
blockers, digoxin, anticonvulsants and non-steroidal anti-inflammatory drugs.
For many drugs with only minor or no dose-related side-effects very precise modification
of the dose regimen is unnecessary and a simple scheme for dose reduction is sufficient.
For more toxic drugs with a small safety margin dose regimens based on glomerular
filtration rate should be used.
The total daily maintenance dose of a drug can be reduced either by reducing the size of
the individual doses or by increasing the interval between doses. For some drugs, if the
size of the maintenance dose is reduced it will be important to give a loading dose if an
immediate effect is required. The loading dose should usually be the same size as the
initial dose for a patient with normal renal function.

Drugs causing biochemical changes

Prescribing any drug that increases potassium levels is potentially very dangerous, e.g.
potassium supplements and potassium-sparing diuretics. Other products that contain
potassium include ispaghula husk laxatives.
Products with a high sodium content, e.g. some antacids, may cause sodium and water
retention in patients with renal impairment.
Excessive vitamin D replacement therapy can cause hypercalcaemia that may precipitate
or exacerbate renal impairment. Many patients with chronic renal failure are prescribed
alfacalcidol, and therapy should therefore be closely monitored.

Nephrotoxic drugs

Drugs causing prerenal damage

Drugs that cause excessive gastrointestinal losses, either through diarrhoea or vomiting,
also cause volume depletion and may precipitate acute renal failure.
NSAIDs, even in short courses, can cause acute renal failure as a result of renal
underperfusion.
ACE inhibitors can also cause a deterioration in renal function. However, this is a
problem only in patients with compromised renal perfusion, particularly those with renal
artery stenosis.
Care should be taken when an ACE inhibitor and NSAID are prescribed together as this
combination may precipitate an acute deterioration in renal function.

Drugs causing intrarenal damage

 Intrarenal damage may result a direct toxic effect on the kidneys or hypersensitivity
reactions.
Most drugs that cause damage within the kidneys do so as a result of hypersensitivity
reactions, which involve either glomerular or interstitial damage.
Drugs that have been reported to cause glomerulonephritis include penicillamine, gold,
captopril, phenytoin and some antibiotics, including penicillins, sulphonamides and
rifampicin.
Drugs that may cause interstitial nephritis include penicillins, cephalosporins,
sulphonamides, thiazide diuretics, furosemide, NSAIDs and rifampicin.
There are a number of drugs that cause direct toxicity to the renal tubules (acute tubular
necrosis), e.g. aminoglycosides, amphotericin and ciclosporin.

Drugs causing postrenal damage (urinary tract obstruction)

High-dose sulphonamides, acetazolamide or methotrexate may cause crystalluria and

could therefore cause obstruction.
Anticholinergics, e.g. tricyclic antidepressants, and alcohol may cause urinary tract
obstruction due to retention of urine in the bladder.

Other nephrotoxic drugs

Cephalosporins: cephaloridine, one of the first cephalosporins introduced, has been

associated with direct renal toxicity and is no longer in clinical use. Other cephalosporins
are much less likely to produce renal damage but third generation cephalosporins, e.g.
cefixime, have very rarely been reported to cause nephrotoxicity.
Analgesics:

o NSAIDs may cause acute renal failure due to hypoperfusion and interstitial
nephritis, as well as analgesic nephropathy (chronic interstitial nephritis and
papillary necrosis).
o Analgesic nephropathy has been most commonly seen with combination analgesic
products that contain aspirin and/or paracetamol.
o Analgesic nephropathy is one of the few preventable causes of chronic renal
failure. Discontinuation of the abused drugs often results in stabilisation or even
improvement in renal function but continued abuse leads to further renal damage.
Lithium: serum levels of lithium consistently above the therapeutic range have been
associated with development of a nephrogenic diabetes insipidus.

Use of a dosage table

Dose recommendations are based on the severity of renal impairment. This is expressed in terms
of glomerular filtration rate. The serum creatinine concentration is sometimes used instead as a
measure of renal function but is only a rough guide even when corrected for age, weight, and
sex. Nomograms should be used where accuracy is important.

Document references
1. The Renal Association; UK CKD Guidelines; eGFR

Internet and further reading

Chronic kidney disease, NICE Clinical Guideline (September 2008); Early identification
and management of chronic kidney disease in adults in primary and secondary care
Consensus statement on management of early chronic kidney disease, Renal Association
(2007)
The Renal Association