• Acute renal failure occurs in 4.9% of hospitalized patients with renal insufficiency.
  
• Fifty percent of patients experience nonoliguric acute renal failure.
  
• Antibiotics, analgesics, nonsteroidal anti-inflammatory drugs, contrast media, and angiotensin-converting enzyme inhibitors are the most common causes of acute renal failure.
  
• Impaired renal function, decreased volume status, exposure to contrast media, and aminoglycosides account for 79% of all cases of renal failure.

Although most therapeutic agents infrequently cause community-acquired renal failure, a number of diagnostic and therapeutic agents can produce renal injury and renal failure among hospitalized patients. These renal injuries may be caused either directly or indirectly by drugs or metabolites of these agents in critically ill patients. Recent data suggest that renal adverse effects caused by pharmaceutical agents may contribute to approximately 30% of acute renal failure (ARF) incidents in hospitalized patients. Antibiotics, analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), contrast media, and angiotensin-converting enzyme (ACE) inhibitors were the most commonly reported causes of ARF (see Figure 9–2).

A number of factors make the kidneys more susceptible to drug toxicity. First, the kidneys receive a high fraction (20–25%) of cardiac output relative to their weight, so drugs transit to the kidneys in large amounts. The kidneys represent only 0.4% of the body weight but receive 25% of resting cardiac output; therefore kidneys are exposed to a significant concentration of therapeutic agents. Second, blood flow to the kidneys is rich in oxygen, and the kidneys are very sensitive to reduction in blood perfusion and oxygen deprivation. Third, the renal countercurrent concentrating mechanism for water also concentrates drugs and chemicals within the filtered tubular fluid. Thus, local concentrations of these substances in contact with renal epithelia may exceed that in peripheral blood. Finally, most drug-induced renal failure occurs in patients with subclinical preexisting renal dysfunction.

Renal failure associated with drug-induced nephropathy can be classified into six categories based on pathophysiologic injuries. These injuries include prerenal failure, acute tubular necrosis (ATN), acute tubulointerstitial disease (ATID), tubular obstruction (crystal-induced ARF), hypersensitivity (glomerulonephritis), and thrombotic microangiopathy. A list of common therapeutic agents associated with each of these injuries is provided in Table 14–1.

Histologically, acute interstitial nephritis (AIN), most commonly known as tubulointerstitial disease, is differentiated from other injuries by infiltration and proliferation of inflammatory cells within the interstitium. The most frequent etiologies of AIN include drug-induced AIN, infection, and autoimmune hypersensitivity reactions. Patients with drug-induced AIN usually present with nonspecific symptoms. A sudden oliguria, increase in serum creatinine, and decrease in renal function are usually present. Nausea and vomiting, malaise, and/or anorexia should be expected over 5–10 days of exposure to nephrotoxins. However, patients with NSAID-induced AIN usually present with renal dysfunction 8–12 months following exposure. In addition, decreased inflammation and tubulitis may be present.

The clinical features of AIN include a low grade fever, rash, and eosinophilia. In AIN, the reduction of renal function appears as a result of infiltration of inflammatory cells within the renal interstitium. Accumulation of proteins and fibronectin is thought to be the major cause of reduced renal function. Although fibrosis is not very common initially, patchy fibrotic lesions will ultimately develop in the renal cortex and medullocortical sections. The most common causes of drug-induced AIN include NSAIDs, penicillins and cephalosporins, rifampin, sulfonamides (including medications that include sulfa moieties such as furosemide, bumetanide, and thiazide-type diuretics), cimetidine, allopurinol, ciprofloxacin, 5-aminosalicylates (eg, mesalamine), and, to a lesser degree, other quinolone antibiotics. There is strong evidence that suggests hypersensitivity and immunologically mediated mechanisms play an important role in the etiology of drug-induced AIN. The presence of cytotoxic T cells, helper T cells, T cell-mediated cell injury, and B cell involvement suggests activation of an immune cascade following exposure to an offending agent. Clinically, these histopathologic reactions are often accompanied by fever, skin rash, eosinophilia, and arthralgia. Supportive care, withdrawal of nephrotoxins, and discontinuation of any suspected offending agents are the initial steps in the treatment of AIN. Drug-induced AIN is often reversible and patients usually improve without any long-term sequalae. In more serious cases, systemic corticosteroid therapy leads to rapid improvement.

Crystal nephropathy defines a prototype of renal injury associated with crystal deposition and tubular obstruction in the kidneys. Drugs that may cause crystal nephropathy include acyclovir, sulfonamides, methotrexate, and indinavir. Risk factors for drug-induced crystal nephropathy include age, renal impairment, volume depletion from nausea and vomiting, liver failure, and decreased effective circulating volume. The patient’s risk factors influence renal blood flow and ultimately drug tubular flow. Many cases of drug-induced crystal nephropathy have occurred after prolonged administration of causative agents or large doses without adjustment of the dose for impaired renal function. Certain drugs (methotrexate, sulfonamides, and triamterene) are eliminated more readily in an alkaline environment and lowering of the urine pH may place these patients at a higher risk of crystal nephropathy. In contrast, the severity of crystal nephropathy by indinavir is influenced by alkaline urine.

The mechanism of drug-induced glomerulonephritis involves several different pathways. In most cases, the exact pathway is unknown but several theories have been proposed. Drugs that have been reported to cause drug-induced glomerular disease are listed in Table 14–1. Drugs that induce glomerular disease can be classified according to the immunologic reaction they induce or by acting as a hepatan and activating antigen–antibody complex formation. Some agents have a dose-dependent effect on glomerular structures. Although the signs and symptoms of drug-induced glomerular disease are highly variable, most patients with glomerular disease usually present with sudden loss of GFR and proteinuria.

Aminoglycosides

Incidence & Risk Factors

Aminoglycosides have important antibacterial properties for the treatment of gram-negative infections in clinically unstable patients. These agents have shown a concentration-dependent bactericidal property against most gram-negative bacteria. The major dose and duration-limiting factors related to toxicity of aminoglycosides are nephrotoxicity and ototoxicity. Although a single large dose may cause reversible renal dysfunction, most studies correlate nephrotoxicity with prolonged use in patients at risk for aminoglycoside toxicities. According to a number of studies, the incidence of aminoglycoside-induced nephrotoxicity is in the range of 5–15%. Patients over 70 years of age and patients with preexisting renal impairment, intravascular volume depletion, hepatorenal syndrome, and septic patients have a higher incidence of renal dysfunction following exposure to aminoglycosides. Even with aggressive monitoring and when peak and trough serum concentrations are kept within the desired therapeutic range, aminoglycoside-induced renal dysfunction is still a possibility in high-risk populations. Various risk factors that predispose to the development of aminoglycoside nephrotoxicity have been identified.

Aminoglycoside-induced nephrotoxicity manifestations have varied from asymptomatic, to a mild and reversible increase in blood urea nitrogen (BUN) and serum creatinine, to serious but infrequent end-stage renal disease (ESRD) requiring life-long dialysis. The onset of aminoglycosideinduced nephrotoxicity is usually after 7–10 days of therapy. However, a rapid onset of nephrotoxicity after even one dose of aminoglycosides has been reported. In most patients, serum creatinine and BUN return to normal levels 2–3 weeks after discontinuation of aminoglycosides. Nonoliguric renal insufficiency is the most common manifestation of aminoglycoside nephrotoxicity. Less common manifestations include various isolated tubular syndromes, eg, nephrogenic diabetes insipidus, Fanconi syndrome, and renal potassium or magnesium wasting. Fortunately, severe oliguric renal failure requiring dialysis is rare from aminoglycosides alone. A drug-induced concentrating defect characterized by polyuria and secondary thirst stimulation precedes the detectable rise in BUN and serum creatinine and occurs in as many as 30% of hospitalized patients given >5–7 days of aminoglycoside treatment. Granular casts and mild proteinuria occur frequently but are not of diagnostic assistance. In addition, in patients who satisfy the clinical criteria for aminoglycoside nephrotoxicity, cellular autophagocytosis has been observed with electron microscopy.

Loading doses should be sufficient to achieve high peak levels to maximize bacterial killing. Because the elimination half-life of aminoglycosides, is markedly prolonged as renal function falls, maintenance-dose intervals should be carefully adjusted in patients with existing renal dysfunction when aminoglycosides are required. Extending the interval between doses is safer than reducing the size of individual doses in patients with renal insufficiency. Correctable risk factors should be minimized. Among the clinically available aminoglycosides, the spectrum of nephrotoxicity is gentamicin > tobramycin > amikacin > netilmicin. Monitoring of peak serum levels will ensure efficacy, whereas elevation of the trough level, showing drug accumulation, will often precede a rise in the less-sensitive serum creatinine measurements. Once-daily aminoglycoside dosing may be less nephrotoxic for a given total daily dose.

Pathogenesis

A number of mechanisms have been proposed for nephrotoxicity of aminoglycosides. Most data suggest that aminoglycosides accumulate in the renal cortex. These findings have been reported in animal and human studies. Megalin is an endocytotic receptor expressed and located at the brush-border membrane. Following binding to this receptor, aminoglycosides are taken up into the proximal tubular cells. The concentration of aminoglycosides in the proximal tubule is approximately 10- to 100-fold higher than the plasma concentration. At this concentration, aminoglycosides may interfere with protein synthesis in proximal tubular cells and lead to ATN.

Once-a-day gentamicin dosing or once every 36-hour dosing has become common in recent years. This method is particularly common when patients are at risk of nephrotoxicity or ototoxicity. A number of meta-analyses of randomized clinical trials and single-center reports with the use of a once-a-day dosing schedule suggest a reduced incidence of aminoglycoside nephrotoxicity. Compared to conventional three times a day administration, once-daily dosing may result in a 10–50% lower incidence of serious adverse reactions. This paradoxic finding can be explained in part by the saturable nature of aminoglycoside transport across the brush-border membrane of proximal tubular cells. During once-daily dosing, only a limited quantity (15 mg/dL) of aminoglycosides can cross during the initial high plasma concentration. This method of administration allows for a prolonged exposure to a low plasma concentration of aminoglycosides below the saturable threshold.

Prevention & Treatment

Therapeutic drug monitoring plays an important role in the treatment of serious infections with aminoglycosides. Several studies have demonstrated that therapeutic drug monitoring with appropriately applied pharmacokinetic principles reduces the nephrotoxicity and other adverse drug reactions related to usage of aminoglycosides. Table 14–2 provides dosing recommendations for the use of aminoglycosides in the treatment of various infections.

Aminoglycoside nephrotoxicity may occur despite therapeutic drug monitoring, use of once-daily dosing, and/or short-term treatment. Progression of nephrotoxicity can occur after discontinuation of the last dose. Most patients recover but it may take several months before recovery is complete. Renal dysfunction may be prolonged and require up to a year for function to return to normal. Permanent renal impairment requiring dialysis may occur.

Vancomycin

Incidence & Risk Factors

Vancomycin is a commonly used antibiotic for the treatment of gram-positive bacterial infections resistant to penicillin and cephalosporines. The reported incidence of vancomycin-induced nephrotoxicity varies widely depending on the criteria used to define nephrotoxicity and generally ranges between 0 and 35%.

The relationship between therapeutic plasma monitoring (trough) of vancomycin and nephrotoxicity is uncertain. Since vancomycin is excreted mainly through the kidneys, renal dysfunction would predispose patients to elevated serum vancomycin concentrations. It is not clear whether high serum vancomycin levels and nephrotoxicity are linked.

Pathogenesis

Most histologic examinations of the kidneys indicate that vancomycin might cause marked destruction of proximal tubules. The hallmark of vancomycin-induced renal dysfunction is destruction of glomeruli and necrosis of proximal tubules. It has been suggested that oxidative stress is the underlying pathogenesis of vancomycin-induced nephrotoxicity.

Prevention & Treatment

Vancomycin-induced nephrotoxicity is a largely unpredictable event. However, if patients are at risk for renal dysfunction, a number of measures can be taken to prevent overt renal failure. When treating a serious bacterial infection, all therapeutic options should be considered. Vancomycin should be utilized only when medically necessary. In patients who require vancomycin treatment consideration should be given to volume status, renal function, prolonged treatment course (over 10 days), concomitant use of aminoglycosides and/or other nephrotoxic agents, and advanced age. Frequent monitoring of renal function is highly recommended, particularly in patients with preexisting renal dysfunction. If renal toxicity is observed, the vancomycin dose should be adjusted according to renal function (Table 14–3). A doubling of the baseline serum creatinine is indicative of serious nephrotoxicity.