Nephrotoxic Drugs in
General Practice

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 antibiotic within the renal tubules.

Aminoglycosides are well known for there nephrotoxic potential. Dose adjusting in renal impairment is well accepted. Regardless, proper dose adjustment is no guarantee of safety, and nephrotoxicity of aminoglycosides at therapeutic levels is well established.¹ Aminoglycosides are excreted solely in the urine and are directly toxic to proximal tubular cells. Once daily dosing of aminoglycosides is convenient, and may be less nephrotoxic in humans with normal renal function.² Regardless, there is no data in humans with impaired renal function to support the concept of safety of once daily aminoglycoside therapy, even if adjustment of the dosage and dosing interval are performed. The bottom line for the GP is to avoid aminoglycosides in renal insufficiency completely. If no suitable alternative is available in a patient suspected as having life threatening gram negative bacteremia, administration of a single 1.5mg/kg dose would be considered safe, and allow for time to consult with an infectious disease expert (Level 5 Evidence).

Allergic interstitial nephritis is an idiosyncratic reaction but reported as a possible side effect of a myriad of drugs. Antibiotics are by far the most common culprits. There is no way to prevent this side effect; one can only promptly recognize the syndrome and discontinue the offending agent. Essentially a renal biopsy diagnosis, the constellation of ongoing fever, rash, progressive renal failure, and eosinophilia during prolonged antibiotic therapy should raise suspicion of the diagnosis. Although penicillins and cephalosporins are well-recognized culprits, almost any antibiotic can cause it occasionally. The fluoroquinolone ciprofloxacin is now a well-recognized cause of allergic interstitial nephritis (Level 3 Evidence).³

Crystallization of antibiotics in the renal tubules can lead to acute oliguric renal failure and has been reported with sulfa, acyclovir, and indinavir (used to treat HIV infection). Although adequate hydration may prevent it, the risk is increased substantially in the low GFR state of chronic renal insufficiency.⁴ Although dosing adjustment of sulfa in renal insufficiency is recommended (the recommended dose of SEPTRA is one DS tablet daily), it does not guarantee safety. Although restoration of renal function after discontinuation of sulfa can occur, it is not universal and patients may be rendered permanently dialysis dependent. Thus, as with aminoglycosides, it is best for the GP to avoid sulfa in renal insufficiency. Therapy with trimethoprim alone is as effective as combination therapy with trimethoprim-sulfamethoxazole in uncomplicated UTI (Level 1 Evidence).³

NSAIDS/COX - 2 inhibitors

There is no difference in the safety profile of these two drug classes in renal insufficiency (Level 3 evidence). Both classes can lead to edema, hypertension, CHF, and acute on chronic renal failure, sometimes leading to need for dialytic support.⁶ The effect is dose dependent and usually reversible, although permanent dialysis dependence can occur in patients with advanced renal failure. Suitable alternatives should be sought wherever practical. Acetaminophen is by far the safest analgesic in renal failure (Level 5 Evidence). Although in the past combinations of acetaminophen with other analgesics were felt to be responsible for analgesic nephropathy, acetaminophen alone in recommended doses is rarely nephrotoxic (the exception being when combined with alcohol).⁷ Colchicine (dose adjusted for renal impairment), joint injection, or a brief course of systemic corticosteroids is better tolerated than NSAIDs for episodic gout in renal insufficiency.⁸ If an antinflammatory drug is absolutely required, use the lowest dose necessary for the control of inflammation, for the shortest time period possible, while closely monitoring the patient (edema, hypertension, CHF) and renal function (Level 4 Evidence).

ACE inhibitors/ARBs

These drug classes have been immensely successful for the management of cardiovascular disease, hypertension, and chronic nephropathy. In large clinical trials of stable outpatients they are extremely well tolerated. None of the large clinical trials included patients with advanced renal failure (Cr >300 µmol/l).⁹ Initiation of ACE/ARB in this patient population is difficult as it can precipitate uremia, hyperkalemia and dialysis dependence. Referral of patients with Cr >300 umol/l to a nephrologists is advised prior to initiating therapy with ACE/ARB(Level 4 Evidence). Another issue is the previously stable patient on chronic ACE/ARB therapy who develops dehydration. Profound renal failure can result and may require temporary dialysis therapy. Volume depletion often mandates withdrawing of ACE/ARB, which can be reintroduced successfully once euvolemia is established. Although bilateral renal artery stenosis has been considered a contraindication to ACEI in the past, renovascular disease is often associated with significant hypertension which responds well to blockade of the renin angiotensin system.¹⁰ In high risk patients, careful monitoring of BP, creatinine, and potassium should be undertaken when initiating or dose escalating these drugs. Some mild elevation in the serum creatinine is acceptable in order to get the benefits of ACE/ARB. Some authors have argued that one could let the creatinine rise 30%, as long as it stabilizes and the patient is free of uremic symptoms. (Level 4 evidence)

Lithium

Lithium therapy for bipolar affective illness 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 concerning has been progressive renal failure in association with interstitial nephritis. There remains uncertainty whether in fact lithium is the causal agent as the relationship may simply be an association, as patients with chronic psychotic disorders not treated with lithium also have an increased risk of chronic interstitial nephritis.¹³ (Level 3 evidence) Withdrawal of lithium therapy can be associated with disastrous consequences, and should only be done under the supervision of a physician experienced in management of bipolar affective disorder.

IV contrast dye

High molecular weight/ionic contrast dye can cause severe vasospasm in the afferent arteriole and acute renal failure in susceptible individuals. Risk factors include diabetes, myeloma, chronic renal failure, dehydration, diuretic therapy, and CHF.¹⁴ It is less common with newer lower molecular weight/nonionic contrast dye (Level 1 evidence).¹⁵ Hydration with I.V. saline is the simplest way to reduce contrast nephrotoxicity (Level 1 evidence).¹⁶ There is also evidence that use of prophylactic mucomyst can reduce the nephrotoxicity of IV contrast (Level 2 evidence).¹⁷ However, it remains uncertain whether low molecular weight/non ionic contrast and mucomyst can eliminate severe ATN in extremely high-risk patients with advanced renal failure, which can lead to need for temporary dialysis therapy. The best way to prevent it is to avoid contrast altogether, by utilizing ultrasound, MRI (gadolinium enhancement is not nephrotoxic)¹⁸, or unenhanced CT scanning in high risk patients (Level 3 evidence).

Summary:
If physicians avoided NSAIDS/Cox-2, sulfas, aminoglycosides, and IV contrast dye in patients with renal insufficiency, they would rarely see a case of drug induced renal failure, except for dehydration on ACE/ARB.

- Tom Hewlett

Thanks to Dr. Paul Sohi, nephrologist at Atlantic Health Sciences Corporation (and assistant professor of medicine Dalhousie University) in Saint John, New Brunswick, for reviewing the draft copy of this article.

References:

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2. Single or multiple daily doses of aminoglycosides: a meta-analysis. Barza M; Ioannidis JP; Cappelleri JC; Lau J. BMJ 1996 Feb 10;312(7027):338-45
    
3. Acute renal failure due to ciprofloxacin. Allon M; Lopez EJ; Min KW. Arch Intern Med 1990 Oct;150(10):2187-9
    
4. Crystal Induced Renal Failure. Burton D Rose, MD. UpToDate in Medicine
    
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
    
6. Are selective COX-2 inhibitors nephrotoxic?. Perazella MA; Eras J. Am J Kidney Dis 2000 May;35(5):937-40
    
7. Combined hepatic and renal injury in alcoholics during therapeutic use of acetaminophen. Kaysen GA; Pond SM; Roper MH; Menke DJ; Marrama MA. Arch Intern Med 1985 Nov;145(11):2019-23
    
8. Renal Transplant-Associated Hyperuricemia and Gout. David M. Clive. J Am Soc Nephrol 11:974-979, 2000
    
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. The Lancet Vol 349 • June 28, 1997, p 1858.
    
10. The treatment of renovascular hypertension: surgery, angioplasty, and medical therapy with converting-enzyme inhibitors. Hollenberg NK. Am J Kidney Dis 1987 Jul;10(1 Suppl 1):52-60
     
11. Angiotensin-Converting Enzyme InhibitorŠAssociated Elevations in Serum Creatinine: Is This a Cause for Concern? George L. Bakris, MD; Matthew R. Weir, MD. Arch Intern Med/Vol 160, Mar 13, 2000
     
12. Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy.. Boton R; Gaviria M; Batlle DC. Am J Kidney Dis 1987 Nov;10(5):329-45
     
13. Lithium nephrotoxicity. Walker RG. Kidney Int Suppl 1993 Jul;42:S93-8
     
14. Contrast nephrotoxicity. Barrett BJ. J Am Soc Nephrol 1994 Aug;5(2):125-37
     
15. Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial. The Iohexol Cooperative Study. Rudnick MR; Goldfarb S; Wexler L; Ludbrook PA; Murphy MJ; Halpern EF; Hill JA; Winniford M; Cohen MB; Van Fossen DB. Kidney Int 1995 Jan;47(1):254-61
     
16. Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. Solomon R; Werner C; Mann D; D'Elia J; Silva P. N Engl J Med 1994 Nov 24;331(21):1416-20
     
17. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. Tepel M; van der Giet M; Schwarzfeld C; Laufer U; Liermann D; Zidek W. N Engl J Med 2000 Jul 20;343(3):180-4
     
18. Safety of intravenous gadolinium (Gd-BOPTA) infusion in patients with renal insufficiency. Townsend RR; Cohen DL; Katholi R; Swan SK; Davies BE; Bensel K; Lambrecht L; Parker J. Am J Kidney Dis 2000 Dec;36(6):1207-12

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