Drug-Induced Nephrotoxicity

ACE Inhibitors

ACE inhibitors are frequently associated with proteinuria and renal insufficiency. The prevalence of proteinuria in captopril-treated patients is estimated at 1%. The risks of renal insufficiency are greater with long-acting ACE inhibitors such as enalapril or lisinopril than with captopril.

Nonsteroidal Anti-inflammatory Drugs NSAIDs

including COX-2 inhibitors, can reduce Clcr and produce renal insufficiency as a result of renal circulatory changes caused by inhibition of prostaglandin synthesis. These effects tend to be relatively minor and usually reversible. The prevalence is usually low (0.5–1% of patients), but some patients are at increased risk; predisposing factors are advanced age, pre-existing renal impairment, and states of renal hypoperfusion (eg, sodium depletion, hypotension, diuretic use, hepatic cirrhosis, and CHF). Reversible acute interstitial nephritis and necrosis occur occasionally. It is not possible at this time to accurately categorize the prevalence associated with each NSAID. Fenoprofen is the NSAID most commonly associated with interstitial nephritis and nephrotic syndrome

Acyclovir

Acyclovir is concentrated in the urine, and its precipitation in the collecting tubules with subsequent obstructive nephropathy frequently accompanies high-dose (500 mg/m2) IV use; oral therapy is apparently free from this problem.

Aldesleukin

Almost all patients receiving aldesleukin develop acute renal impairment marked by decreased Clcr, oliguria or anuria, and fluid retention. Most patients recover within 1 week after drug discontinuation, but some require ≥1 month.

Acetazolamide

Glaucoma therapy with acetazolamide is associated with a 10-fold increase in the risk of renal stone formation. Calcium phosphate and calcium oxalate stones have been identified.

Allopurinol

Glomerulonephritis, interstitial nephritis, and interstitial fibrosis occur rarely in allopurinol-treated patients. Most cases are associated with generalized hypersensitivity reactions to allopurinol (allopurinol hypersensitivity syndrome).

Amphotericin B

Mild or moderate renal impairment occurs in 50% of patients treated with conventional amphotericin B, with severe renal impairment in 8%. The drug causes a reduction in renal plasma flow as well as glomerular and tubular damage.

Aminoglycosides

Proximal tubular necrosis occurs in up to 30% of patients treated with aminoglycosides for >7 days. Because of slow clearance of these drugs from renal tissue, they still can be present in high concentrations in the kidney after serum levels are undetectable, but there does not appear to be a good correlation between renal tissue concentrations of individual .

aminoglycosides

Aminoglycoside-induced acute renal failure is usually nonoliguric, which can delay its recognition. It is often first detected as an asymptomatic increase in Crs. Detectable changes in GFR usually occur at least 5 days after initiation of therapy and can progress after drug discontinuation. Aminoglycoside-induced renal damage is related to total dosage and duration of treatment. Administration of single daily doses does not markedly affect the frequency of nephrotoxicity. Recovery of some to all lost renal function can occur over several weeks after drug discontinuation.

Analgesics

Analgesic nephropathy is a syndrome of papillary necrosis, interstitial nephritis, and progressive renal medullary impairment that occurs in persons with long-term consumption of large quantities of oral analgesic products, especially combination products.

Analgesic nephropathy has been clearly associated with products containing phenacetin, but the removal of phenacetin from nonprescription analgesic products has not been consistently associated with a decline in analgesic nephropathy mortality.

Acetaminophen or salicylates taken alone or in combination do not seem to cause analgesic nephropathy.

Azacitidine

Proximal and distal tubular dysfunction, polyuria, glucosuria, and decreases in serum bicarbonate occur occasionally during azacitidine therapy.

Carboplatin

Although apparently less nephrotoxic than cisplatin, carboplatin therapy is frequently associated with reductions in GFR and increased electrolyte losses (especially calcium and magnesium). Patients with pre-existing renal impairment and those who receive inadequate hydration during drug administration are at greatest risk.

Cephalosporins

The cephalosporin (and cephamycin) antibiotics are capable of producing rare interstitial nephritis similar to the penicillins. Increases in BUN and Crs occur occasionally. The nephrotoxicity of the newer cephalosporins is minimal compared with older drugs such as cephalothin.

Cidofovir

Proteinuria occurs frequently during cidofovir therapy. Probenecid decreases the prevalence and magnitude of proteinuria and must be given with cidofovir.

Cisplatin

Dosage-related proximal tubular impairment is the major limiting factor in cisplatin therapy and can occur in 50–75% of patients.

The greatest damage occurs in the first month of therapy, and it appears to be more likely when the drug is administered repetitively at close intervals.

Contrast Media, Radiopaque

Increased Crs occurs frequently in patients receiving iodine-containing contrast media. In unselected patients, the prevalence of Crs >0.5 mg/dL or >50% above pretreatment is 2–7%. Renal lesions include medullary necrosis and proximal tubular vacuolation and necrosis as well as the deposition of urate and oxalate crystals.

The most common pattern is acute oliguric renal failure developing within 24 hr after the administration of the contrast agent and lasting 2–5 days;

Cyclosporine

Dose-related nephrotoxicity occurs in 30–50% of cyclosporine-treated patients and frequently limits the usefulness of the drug.

Cyclosporine causes vasoconstriction in preglomerular arterioles, which can lead to chronic arteriopathy and tubular atrophy if the dosage is not reduced.

Cyclosporine nephrotoxicity is usually reversible during the first 6 months of therapy, but the risk of permanent renal impairment increases with time.

Calcium-channel blockers

appear to reduce the prevalence of cyclosporine-induced nephrotoxicity in renal transplant patients.

Demeclocycline

This drug can produce nephrogenic diabetes insipidus, which is usually, but not always, dosage related. For this reason, it has been used in the management of the syndrome of inappropriate antidiuretic hormone secretion.

Diuretics

Thiazide Occasional cases of interstitial nephritis have been reported, which might be the result of hypersensitivity reactions. Long-term use of diuretics might increase the risk of renal cell carcinoma, especially in women.

Fluoroquinolones

Acute interstitial nephritis is associated with fluoroquinolone antibiotics; a hypersensitivity mechanism is suspected but remains to be confirmed. Most reported patients are >50 yr old.

Furosemide

Use of high-dose furosemide (5–10 mg/kg/day) in adults with refractory CHF is associated with a 40% decrease in Clcr. Nephrocalcinosis and nephrolithiasis occur in up to 64% of low-birthweight infants treated with furosemide. These effects usually resolve after drug discontinuation.

Gallium Nitrate

Nephrotoxicity is the most frequent adverse effect of gallium, and elevations in BUN and Crs can occur after only 1 ddos

Oral auranofin

appears to be less nephrotoxic than parenteral gold products.

Ifosamide

Reversible, subclinical nephrotoxicity occurs in almost all ifosamide-treated patients, with clinically important nephrotoxicity in many.

Immune Globulin Intravenous

administration of immune globulin can produce reversible acute renal failure after the first or repeated exposures. The origin of the acute renal failure is not the immune globulin but rather the large amount of sucrose used in some immune globulin products to reduce the formation of immunoglobulin aggregates.

Maltose- and dextrose-stabilized products

might have the same capacity, but there are no case reports in the literature.

Indinavir

Crystalluria occurs in most indinavir-treated patients; many develop nephrolithiasis, back pain, or flank pain.

Lithium

Lithium frequently produces nephrogenic diabetes insipidus, which is, at least in part, dosage related. This typically mild effect is usually reversible with drug withdrawal.

Mannitol

High doses (>200 g/day or >400 g/2 days) are associated with acute oliguric renal failure. Although low doses act as renal vasodilators, high doses produce renal vasoconstriction.

Methotrexate

This drug is directly toxic to the kidney in large doses, causing acute tubular necrosis. Acute renal impairment occurs in 30–50% of patients treated with high-dose methotrexate and leucovorin rescue.

Fluoride

causes distal tubular dysfunction by inhibiting sodium and chloride transport in the ascending loop of Henle and reducing the response to antidiuretic hormone.

Omeprazole

Interstitial nephritis occurs rarely during omeprazole therapy. At least 13 cases have been published, 10 with positive biopsies; 5 cases were rechallenged with recurrence of interstitial nephritis in all. Onset is usually after 2 weeks to 6 months of omeprazole therapy.

Penicillamine

Slight to moderate proteinuria occurs in 7–30% of patients on long-term (≥6 months) therapy with penicillamine for rheumatoid arthritis.

Penicillins

Interstitial nephritis has been reported with most penicillins. Methicillin was by far the most frequently implicated penicillin (frequency 10–16%); the reason for its dominance in unknown. Penicillin-induced interstitial nephritis is an immune reaction that most commonly occurs during a long course of therapy. The reaction is usually accompanied by other signs of hypersensitivity such as fever, rash, and eosinophilia; hematuria also can occur. The reduction of renal function might not be oliguric, so urine volume is not a reliable parameter to monitor. Recovery usually occurs within weeks to months after drug discontinuation.

Pentamidine

Prospective trials of IV pentamidine for the treatment of Pneumocystis carinii pneumonia show nephrotoxicity in 4–66% of patients.

Polymyxins

Adverse reactions involving the kidney occur in about 20% of patients receiving colistimethate parenterally. Tubular necrosis is the most frequently described lesion, but interstitial nephritis is also reported. High dosage, long duration of therapy, and renal impairment are predisposing factors.

Rifampin

There are at least 49 published cases of rifampin-induced acute renal failure. Acute tubular necrosis is the most common lesion. This appears to be a hypersensitivity reaction and most often occurs with intermittent or interrupted dosage regimens but has accompanied continuous therapy.

Streptozocin

Nephrotoxicity is the most common dosage-limiting side effect. The prevalence increases with prolonged administration until virtually all patients demonstrate renal impairment.

Sulfonamides,

Antibacterial Early sulfonamides were poorly soluble, and urinary crystallization was a common problem.

Triamterene

Triamterene therapy is associated with an increase in urinary sediment, and the drug can be incorporated into existing renal calculi.

Vancomycin

Nephrotoxicity from vancomycin was commonly reported early in its history. Currently, the prevalence of vancomycin-induced renal impairment (usually mild) is 5–17%. It is usually reversible after discontinuation of the drug. Concomitant administration of aminoglycosides results in at least additive nephrotoxicity.

Tacrolimus

Acute nephrotoxicity occurs with a prevalence similar to that of cyclosporine. Progressive nephrotoxicity is reported with long-term (>1 yr) therapy.

Tetracyclines

Fanconi syndrome, characterized by tubular damage with proteinuria, glycosuria, aminoaciduria, and electrolyte disturbances, was associated with the use of outdated tetracycline products. Because of changes in the manufacturing process, this syndrome is now unlikely to occur.

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