Unipen

Most physicians are aware of the potential nephrotoxic effects of certain antibiotics. Aminoglycosides and amphotericin B (Fungizone) are examples of drugs that can cause acute renal failure due to acute tubular necrosis. Fortunately, many less nephrotoxic agents are available. However, certain antibiotics have more subtle renal and electrolyte effects that require early recognition and correction to prevent serious consequences. These effects include allergic acute interstitial nephritis, vasculitis, electrolyte disturbances and renal tubular acidosis.

Allergic Acute Interstitial Nephritis

Allergic acute interstitial nephritis can be subtle or overt and may mimic acute tubular necrosis. This condition is characterized by inflammation in the renal interstitium with edema resulting in tubular dysfunction and renal failure.[1] Acute interstitial nephritis can result from infections and immunologic disorders but, more frequently, is associated with an allergic reaction to a drug. This condition is the cause of 3 to 16 percent of cases of acute renal failure,[2] although the actual prevalence may be underestimated. Commonly prescribed drugs that cause acute interstitial nephritis include nonsteroidal anti-inflammatory drugs (NSAIDs) and antibiotics.

Although penicillins, cephalosporins and sulfonamides have the highest reported incidence of allergic acute interstitial nephritis, almost any antibiotic can be implicated. Table 1 shows antibiotics that have been associated with allergic acute interstitial nephritis. The triad of fever, rash and arthralgias associated with acute interstitial nephritis has been reported to occur in only 10 to 40 percent of patients.[2] These symptoms may be accompanied by eosinophilia or eosinophiluria. Urinalysis may show low-grade proteinuria, white blood cells or hematuria. No specific or sensitive noninvasive tests are available to identify patients with allergic acute interstitial nephritis. Definitive diagnosis requires a kidney biopsy. Therefore, the diagnosis usually relies on the clinical judgment of the physician. Complications of acute interstitial nephritis include papillary necrosis and type IV renal tubular acidosis.[1,2]

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Antibiotic-Induced Vasculitis

Hypersensitivity vasculitis and allergic granulomatous disorders have been associated with antibiotic use.[3,4] The clinical picture of vasculitis involving the kidney is similar to that of allergic acute interstitial nephritis, with features including rash, fever, eosinophilia, arthralgias, myalgias and lymphadenopathy.[5] Hypersensitivity vasculitis may result in significant dermatologic findings, such as palpable purpura. Skin biopsy in such cases reveals leukocytoclastic angiitis. The clinical manifestations of vasculitis depend on the size of the blood vessel and the organ involved and may result in liver function abnormalities, gastrointestinal bleeding, cerebritis, uveitis and pulmonary hemorrhage. When multiple sites are involved, consideration should be given to the possibility of vasculitis.

Hypersensitivity vasculitis has been reported with use of many antibiotics (Table 1). Beta-lactam antibiotics and sulfa-containing agents most commonly cause vasculitis, but the pathophysiologic mechanism is not well established. Part of the reason that the etiology is unclear may be that many infectious diseases are also associated with vasculitis, including meningococcemia, Rocky Mountain spotted fever, invasive aspergillosis and several viral entities. It may be difficult to decide between continuing treatment of those infections or stopping antibiotic therapy if renal dysfunction is present. Collaboration with an infectious disease consultant may be important in these situations to determine if alternative antibiotic therapy is possible. Treatment may require not only withdrawal of all suspect drugs, but also initiation of corticosteroid therapy, even during active treatment of a preexisting infection.

Fluid and Electrolyte Imbalance

Fluid and electrolyte imbalance can be a serious problem related to antibiotic therapy. Table 2 outlines treatments for various electrolyte abnormalities.

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SODIUM AND VOLUME OVERLOAD

Certain antibiotics are administered as sodium or potassium salts, which may contribute to hypernatremic or hyperkalemic states. The sodium content of some antibiotics can be very high (Table 3), and administration of these agents should be avoided in patients who are already hypernatremic or subject to fluid overload (such as elderly persons with congestive heart failure). In particular, older carboxypenicillins (e.g., ticarcillin [Ticar]) have a high sodium content and may be replaced by the newer ureidopenicillins (e.g., mezlocillin [Mezlin]), which also have an expanded antibiotic spectrum but with a lower salt load. Rarely, hypernatremia can be precipitated directly by use of high doses of sodium-containing antibiotics.[6]

TABLE 3

Sodium Content of Selected Antibiotics

* - Sodium content expressed in mg of sodium per day based on standard intravenous dosing,

Derived from Physicians' desk reference. 48th ed. Oradell, N.J.: Medical Economics Co., 1994 and Drug facts & comparisons. St. Louis: Facts and Comparisons, 1993.

ALTERED WATER METABOLISM

Demeclocycline (Declomycin) can induce diabetes insipidus and has been used clinically to treat the syndrome of inappropriate antidiuretic hormone (SIADH). Other antibiotics also have the potential to depress renal response to antidiuretic hormone, causing nephrogenic diabetes insipidus, including amphotericin B, gentamicin (Garamycin) and methicillin (Staphcillin).[7]

POTASSIUM DISORDERS

Hypokalemia can result from antibiotic therapy through several mechanisms. Amphotericin B appears to alter tubular membrane permeability, leading to magnesium wasting.[8] Hypomagnesemia can lead to renal potassium wasting with resulting refractory hypokalemia. High doses of certain beta-lactam antibiotics, such as nafcillin (Unipen), carbenicillin (Geocillin) or ticarcillin, act as nonreabsorbable anions that "drag" potassium out of tubules.[9] Aminoglycosides also have been shown to cause renal potassium wasting, probably through direct toxic effects on tubular function.[10]

Hyperkalemia has been associated with high doses of trimethoprim-sulfamethoxazole (Bactrim, Septra) in patients with acquired immunodeficiency syndrome. Recently, this problem has also been described in elderly patients who were treated with standard doses.[11] High doses of penicillin G potassium, which contains 1.7 mEq of potassium per 1 million units, can potentially precipitate hyperkalemia, particularly in patients with renal impairment. Penicillin G sodium is an appropriate alternative in those patients.

MISCELLANEOUS ELECTROLYTE DISORDERS

As stated earlier, magnesium wasting has been observed with the use of amphotericin B but can also occur with the aminoglycosides.[12] Hypophosphatemia has been reported to occur with tetracyclines[13] and with foscarnet (Foscavir), the anticytomegalovirus drug. Full biochemistry profiles that include serum phosphate and magnesium levels should be performed when antibiotic therapy extends beyond two weeks. Serum magnesium levels, however, can be normal despite total body deficiency. A trial of magnesium replacement may be considered if refractory hypokalemia or unexpected cardiac arrhythmias develop.

Renal Tubular Acidosis

Fanconi's syndrome is manifested by a combination of phosphaturia, aminoaciduria, glycosuria and for uricosuria. It is associated with a proximal tubular defect in bicarbonate recovery resulting in a non-anion gap acidosis. This syndrome, a form of proximal renal tubular acidosis, has been found to occur with the use of outdated tetracyclines[14] Aminoglycosides have also been associated with a Fanconi-like syndrome, although this is rare.[15] Amphotericin B appears to affect the distal rather than proximal tubules by altering tubular permeability and either directly or indirectly disturbing the hydrogen ion gradient, leading to a form of distal renal tubular acidosis.[12]

Antibiotics and AIDs

Patients with AIDS often require treatment with various toxic antibiotics and experience many of the renal and electrolyte disorders described previously. Amphotericin B is used to treat cryptococcal meningitis and other complicated mycoses. This drug is commonly associated with renal failure, which can be prevented in some instances by maintaining adequate volume expansion with saline.[8] Other drugs, such as foscarnet and acyclovir, have also been associated with a high incidence of acute renal failure.[16,17]

Patients with AIDs are prone to develop electrolyte disturbances, which may be due in part to malnutrition, adrenal insufficiency, therapy with multiple drugs, and drug-induced or infectious diarrhea. Antibiotics can also contribute to these disturbances (Table 4). Hyperkalemia may occur in association with use of pentamidine (Pentam, Nebupent)[18] and high-dose trimethoprim-sulfamethoxazole,[19] which are used in the prophylaxis and treatment of Pneumocystis carinii pneumonia. Both pentamidine and trimethoprim appear to have a potassium-sparing effect, similiar to that of amiloride (Midamor), which blocks sodium channels in the distal nephron and blunts potassium excretion. Foscarnet, used in the treatment of cytomegalovirus retinitis and colitis, may induce a variety of electrolyte disturbances, including hypocalcemia, hypophosphatemia, hyperphosphatemia, hypomagnesemia and hypokalemia.[20]

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Laboratory Errors

Tetracyclines have been associated with elevation of blood urea nitrogen (BUN) without a similar increase in creatinine. This has been thought to be associated with the anti-anabolic effects of the drug.[21] Chloramphenicol (Chloromycetin) can also elevate BUN by interfering with the assay.[21,22] Cephalosporins can interfere with the assay for creatinine, while trimethoprim-sulfamethoxazole can interfere with tubular secretion of creatinine, leading to increases of the measured serum creatinine.[21,22] Although antibiotics can cause overt proteinuria, false elevations of urinary protein can also occur through mechanisms that are not well understood.[22]

Antibiotics and Renal Impairment

Dosage adjustments should always be made in patients with renal impairment since drug accumulation can lead to increased nonrenal and renal toxicity.[23] Doses of aminoglycosides and vancomycin (Vancocin, Lyphocin) are adjusted for renal clearance to reduce nephrotoxicity. Nitrofurantoin (Furadantin) is contraindicated in patients with significant renal insufficiency because the risk of neurologic toxicity is increased.[22] In fact, even drugs that are not primarily excreted through the kidney (penicillins, cephalosporins and quinolones) frequently require adjustment of dosage for patients with renal impairment. Renal failure or insufficiency affects the pharmacokinetics of many drugs by decreasing protein binding and directly affecting nonrenal clearance mechanisms. Referral to a pharmacology reference or antibiotic dosage guide is often helpful.

Table 5 outlines an approach to the evaluation of patients who experience rising BUN and creatinine levels while receiving antibiotic therapy.

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The Authors

RICHARD KASAMA, M.D. is assistant professor of clinical medicine in the Department of Medicine in the Nephrology Division at the University of Medicine and Dentistry of New Jersey School of Osteopathic Medicine, Stratford. He received his medical degree from Hahnemann University School of Medicine, Philadelphia. Dr. Kasama completed a fellowship in nephrology at the Hospital of the University of Pennsylvania, Philadelphia, and served a residency at Graduate Hospital, Philadelphia.

ALFRED SORBELLO, D.O. is clinical associate professor of medicine in the Department of Medicine in the Division of Infectious Diseases at the University of Medicine and Dentistry of New Jersey School of Osteopathic Medicine and chief of service in the Department of Medicine at Kennedy Memorial Hospital/University Medical Center, Cherry Hill (N.J.) Division. He received his degree from the University of Medicine and Dentistry of New Jersey-Stratford and completed a fellowship in infectious diseases at Albany (N.Y.) Medical College and Medical Center Hospital.

REFERENCES

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[3.] Adler SG, Cohen AH, Border WA. Hypersensitivity phenomena and the kidney: role of drugs and environmental agents. Am J Kidney Dis 1985;5:75-96.

[4.] Somer T, Finegold SM. Vasculitides associated with infections, immunization and antimicrobial drugs. Clin Infect Dis 1995;20:1010-36.

[5.] Jennette JC, Falk RJ. The pathology of vasculitis involving the kidney. Am J Kidney Dis 1994;24:130-41.

[6.] Brunner FP, Frick PG. Hypokalaemia, metabolic alkalosis, and hypernatraemia due to "massive" sodium penicillin therapy. Br J Med 1968;4:550-2.

[7.] Levi M, Berl T. Water metabolism. In: Gonick HC. Current nephrology. Vol. 5. New York: Wiley, 1982;5;1-56.

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[9.] Lipner HI, Ruzany F, Dasgupta M, Lief PD, Bank N. The behavior of carbenicillin as a nonreabsorbable anion. J Lab Clin Med 1975;86:183-94.

[10.] Smith P, Guntupalli J, Eby B, Lau K. Evidence that gentamicin produces tubular wastage of K and Mg independent of reduced GFR and aldosterone [abstract]. Clin Res 1981;29;475A.

[11.] Modest GA, Price B, Mascoli N. Hyperkalemia in elderly patients receiving standard doses of trimethoprim-sulfamethoxazole [Letter]. Ann Intern Med 1994;120:437.

[12.] Porter GA, Bennett WM. Nephrotoxic acute renal failure due to common drugs. Am J Physiol 1981;241:1-8.

[13.] Decaux G. Tetracycline-induced renal hypophosphatemia in a patient with a syndrome of inappropriate secretion of antidiuretic hormone. Nephron 1988;48:40-2.

[14.] Fulop M, Drapkin A. Potassium-depletion syndrome secondary to nephropathy apparently caused by "outdated tetracycline." N Engl J Med 1965;272:986-9.

[15.] Melnick JZ, Baum M, Thompson JR. Aminoglycoside-induced Fanconi's syndrome. Am J Kidney Dis 1994;23:118-22.

[16.] Deray G, Martinez F, Katlama C, Levaltier B, Beaufils H, Darlis M, et al. Foscamet nephrotoxicity: mechanism, incidence and prevention. Am J Nephrol 1989;9:316-21.

[17.] Becker BN, Fall P, Hall C, Milam D, Leonard J, Glick A, et al. Rapidly progressive acute renal failure due to acyclovir: case report and review of the literature. Am J Kidney Dis 1993;22:611-5.

[18.] Kleyman TR, Roberts C, Ling BN. A mechanism for pentamidine-induced hyperkalemia: inhibition of distal nephron sodium transport. Ann Intern Med 1995;122:103-6.

[19.] Choi MJ, Fernandez PC, Patnaik A, Coupaye-Gerard B, D'Andrea D, Szerlip H, et al. Brief report: trimethoprim-induced hyperkalemia in a patient with AIDS. N Engl J Med 1993;328:703-6.

[20.] Jacobson MA, Gambertoglio JG, Aweeka FT, Causey DM, Portale AA. Foscarnet-induced hypocalcemia and effects of foscarnet on calcium metabolism. J Clin Endocrinol Metab 1991;72:1130-5.

[21.] Anderson HL Jr, Feinfield DA. Mechanisms of drug-induced renal failure. Hosp Physician. November 1987:27,31-3,36-7,40.

[22.] Aronoff GR, Abel SR. Practical guidelines for drug dosing in patients with renal impairment. In: Schrier RW, ed. Manual of nephrology. Boston: Little, Brown, 1990:189-201.

[23.] Manian FA, Stone WJ, Alford RH. Adverse antibiotic effects associated with renal insufficiency. Rev Infect Dis 1990;12:236-49.

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