Chapter 14. Acute Renal Failure from Therapeutic Agents

• 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.

Acyclovir

Incidence & Risk Factors

Over the past decade, there has been an increased usage of antiviral agents to treat local and severe systemic viral infections in immunocompromised patients. Most antiviral agents appear to be safe and do not cause nephrotoxicity. Acute renal failure is an important dose-limiting toxicity of acyclovir.

Acyclovir is primarily eliminated through the kidney with a small amount being metabolized in the liver. Many cases of acyclovir nephrotoxicity have been reported in the medical literature over the past 15 years. These reports have increased awareness and concern of acyclovir's nephrotoxic potential. Renal dysfunction most commonly occurs within the first few days of initiation of intravenous acyclovir therapy. Patients who receive high-dose bolus intravenous therapy, those who are volume depleted, and patients with preexisting renal insufficiency are at the greatest risk of developing renal injury. ARF has been reported in 5% of patients who receive high-dose bolus intravenous therapy but is rare in patients receiving oral therapy. The most common symptoms include nausea, vomiting, abdominal pain, and/or back pain. Patients may, however, be asymptomatic. A moderate rise (1–3 mg/dL) in serum creatinine from baseline should be expected while oliguria is uncommon. Urinalysis may show trace proteinuria, pyuria, and microscopic hematuria. Birefringent needle-shaped crystals may be seen free or within white blood cells in the urine sediment.

Pathogenesis

The pathogenesis of acyclovir-induced ARF is unclear and may involve an obstructive nephropathy from intratubular precipitation of acyclovir and/or immune hypersensitivity reaction. Acyclovir is moderately insoluble in the urine. The maximum solubility of acyclovir is 2.5 mg/mL. Low urine output and fast intravenous infusion of a large dose (500 mg/mm2) of acyclovir may lead to intratubular precipitation.

Prevention & Treatment

The most effective means of preventing acyclovir nephrotoxicity is to administer adequate intravenous fluid [normal saline (NS) 0.9%] to induce a urinary output of 100–150 mL/hour. Acyclovir-induced nephropathy may also be prevented by avoiding rapid bolus infusion. Acyclovir should be administered at a rate of 60 minutes for every 500-mg dose. Approaches to treatment of acyclovir-induced nephropathy are similar to those caused by other agents. Discontinuation of acyclovir therapy, increased hydration, or dose reduction/interval extension allows most patients to return to normal renal function within a few days to 2 weeks. Temporary dialysis is usually unnecessary, however, for severe complications of renal failure associated with acyclovir, hemodialysis could be utilized to remove 40–60% of plasma acyclovir.

Foscarnet

Incidence & Risk Factors

Foscarnet is a virostatic agent used in HIV-infected and other immunocompromised patients to prevent or treat serious cytomegalovirus (CMV) infections and acyclovir-resistant mucocutaneous herpes simplex infections. Foscarnet exhibits poor oral absorption necessitating intravenous therapy. As foscarnet is a phosphate analog, it can chelate calcium and be deposited in bone. Biotransformation does not occur and up to 28% is excreted unchanged in the urine. Foscarnet induces a rather unique form of renal failure in a majority of patients. Renal impairment occurs in varying degrees in the majority of patients. The exact incidence of foscarnet-induced nephropathy is not known. The rates of ARF from foscarnet vary in patients from 27% to 66%. Risks for renal failure have not been well defined but include impaired renal function, age, concomitant administration with other nephrotoxic agents, and dehydration.

Pathogenesis

The pathogenesis of foscarnet-induced renal failure remains speculative with a number of hypotheses being suggested. ARF appears to be caused by the formation of a foscarnet/ionized calcium complex that precipitates in renal glomeruli causing a crystalline glomerulonephritis. The salt crystals may also precipitate in renal tubules causing tubular necrosis. Fluid and electrolyte imbalances have been reported with foscarnet therapy. Polyuria, nephrogenic diabetes insipidus, hypokalemia, hypomagnesemia, hypophosphatemia or hyperphosphatemia, and hypocalcemia have been observed in patients treated with foscarnet. Hypocalcemia is the most frequently encountered and most serious imbalance. Although the total calcium levels remain unaffected, the ionized calcium decreases substantially. Patients with low ionized calcium levels may experience paresthesias, tingling, numbness, seizures, and death. Foscarnet therapy has been able to be resumed in some patients after restoration of electrolyte or mineral abnormalities. Ionized hypocalcemia may primarily be a result of foscarnet complexing with ionized calcium. However, renal dysfunction may also contribute to these electrolyte abnormalities.

Prevention & Treatment

Minimization of foscarnet-induced nephrotoxicity can be accomplished through vigorous hydration prior to therapy. Use of foscarnet with other nephrotoxins increases the likelihood of developing ARF. Intermittent infusion, as opposed to continuous infusion, may reduce foscarnet-induced nephrotoxicity. ARF is usually reversible, however, recovery may be gradual. Azotemia may worsen and last for several days before resolving. Continuation of foscarnet in patients who develop mild azotemia may be possible with reduced doses. Temporary dialysis may be necessary. Patients with preexisting renal insufficiency may require several months to recover full renal function following discontinuation of foscarnet.

Cidofovir, Adefovir, & Tenofovir

Incidence & Risk Factors

Cidofovir, adefovir, and tenofovir belong to a newer class of antiviral agents structurally described as acycylic nucleoside phosphonates. Cidofovir is an analog of the monophosphate of cytosine. When activated, these agents appear to interfere with synthesis and/or degradation of cellular membrane phospholipids. Cidofovir exhibits broad activity against the herpes viruses. It is primarily used to treat CMV retinitis in patients who have failed other treatments. Adefovir is an analog of adenine that interferes with a variety of ATPdependent processes once it undergoes phosphorylation within cells. It is used to treat active or chronic hepatitis B infections in patients intolerant to other antiviral therapies. Tenofovir, a newer nucleotide analog, is a reverse-transcriptase inhibitor approved to treat HIV infection. Nephrotoxicity is a major dose-dependent and dose-limiting toxicity of both cidofovir and adefovir. In clinical trials, approximately 25% or more of patients receiving intravenous cidofovir 3 mg/kg or more developed ARF related to renal proximal tubular injury. Associated abnormalities included proteinuria, increased serum creatinine, Fanconi syndrome with tubular proteinuria, and evidence of proximal tubular injury including glucosuria, hypophosphatemia, urinary bicarbonate wasting, and, rarely, chronic interstitial nephritis and nephrogenic diabetes insipidous. Upon discontinuation of cidofovir, renal function parameters return toward baseline. Proximal tubular injury was reported in 22–50% of HIV-positive patients infected with hepatitis B virus receiving doses of adefovir at greater than 30 mg/day for 72 weeks. The role of adefovir at doses of 10 mg/day inducing any renal or tubular dysfunction is rare and no case reports were found in a recent literature search. Toxicity appeared to be mild to moderate and accompanied by changes in serum potassium, bicarbonate and uric acid levels, proteinuria, and glucosuria. The incidence of these abnormalities appeared to be dose related.

Pathogenesis

Cidofovir and adefovir (>30 mg/day) have been noted to have significant nephrotoxicity. These potent drugs cause injury to proximal tubular epithelia. Proximal tubular cells express an organic anion transporter that actively takes up a variety of acyclic nucleotide analogs, including cidofovir and adefovir. These agents concentrate in tubular cells, interfere with various cell processes, and are then actively secreted into the tubular lumen. Renal clearance of these agents exceeds creatinine clearance suggesting that active tubular secretion contributes to renal clearance. Probenecid, an inhibitor of organic anion transport, decreases renal toxicity of these agents by reducing cellular uptake. A spectrum of injuries ranging from isolated proximal tubular defects (Fanconi-like syndrome) to severe ATN requiring renal replacement therapy has been observed with cidofovir and adefovir. Tenofovir, like cidofovir and adefovir, appears to accumulate in proximal tubular epithelial cells. However, based on clinical trials to date, tenofovir appears to have a low nephrotoxic potential. Only four case reports of renal dysfunction following exposure to tenofovir have been cited.

Prevention & Treatment

The following guidelines should be employed to reduce or avoid renal injury caused by cidofovir and adefovir. Pretreatment intravascular volume expansion with intravenous fluids, appropriate dosing for the level of renal function exhibited prior to therapy, avoidance in patients with significant renal dysfunction, avoidance of administration with recent use of any potentially nephrotoxic drug, and coadministration with probenecid.

Recent use of other nephrotoxic agents, preexisting renal impairment, and the development of proteinuria or other proximal tubular abnormalities during treatment may result in severe ARF. Renal failure may require dialysis. Despite drug discontinuation proximal tubular damage and resulting renal failure may be partially reversible or irreversible.

Indinavir

Incidence & Risk Factors

Several protease inhibitors have been approved by the U.S. Food and Drug Administration (FDA). Protease inhibitors share common adverse drug reaction profiles. Each agent, however, has its own unique toxicity. Compared with other protease inhibitors, a lower incidence of nausea, vomiting, abdominal discomfort, and taste disturbances have been reported with the use of indinavir. Indinavir is considered safe, although 4% of patients experienced flank pain with or without hematuria associated with nephrolithiasis during phase II/III clinical studies. However, it was not clear that indinavir or its metabolites were responsible for the formation of crystals in the urine. Nephrolithiasis or crystal precipitation has not been associated with other protease inhibitors.

Two distinct patterns of crystalluria have been reported in HIV-positive patients: Symptomatic and asymptomatic crystalluria. Asymptomatic crystalluria is more common than actual nephrolithiasis with symptomatic renal colic. In addition to nephrolithiasis, some patients develop crystalluria and dysuria with evidence of intrarenal sludge.

Several risk factors may influence the incidence of indinavir-induced urolithiasis. The incidence of first episode or recurrence of urolithiasis may increase during warmer temperatures. This finding may correlate with a higher incidence of dehydration or lack of compliance with fluid replacement during high environmental temperatures. HIV-positive patients with hepatitis C virus (HCV) coinfection and hemophilia or receiving trimethoprim-sulfamethoxazole (TMP/SMX) may incur greater risk of indinavir-associated urolithiasis.

Pathogenesis

Indinavir stones are considered radiolucent. These stones include calcium oxalate and calcium phosphate. Therefore, they may present as partly radiopaque. Renal biopsy documentation of acute indinavir-induced interstitial nephritis and obstructive ARF has been described in several HIV-positive patients. Renal biopsy showed evidence of interstitial nephritis/fibrosis and tubular atrophy. The medullary collecting tube was filled with crystals associated with histiocytes and giant cells. The exact mechanism of indinavir-induced ARF has not been elucidated. A high incidence of asymptomatic crystalluria or urolithiasis suggests the possibility of intrarenal obstruction due to precipitation of indinavir and/or its metabolites in the urinary collecting system.

Prevention & Management

Management and prevention in patients with indinavirinduced renal dysfunction may include discontinuation of indinavir, dose reduction, and hydration. Most patients can be treated for indinavir-associated nephrolithiasis with aggressive hydration and pain control. Patients should be advised to ingest at least 48 oz of fluid throughout the day. The urine output should be 1500 mL/day to limit indinavir urine concentrations less than 0.2–0.3 mg/mL. Patients with indinavir stones may be treated with hydration, but surgical intervention may be needed for the treatment of both obstruction and pain.

Intravenous Immunoglobulin & Hydroxyethylstarch

Incidence & Risk Factors

Intravenous immunoglobulin (IVIG) is used to treat a variety of autoimmune disorders. Since IVIG is prepared from pooled plasma from thousands of donors, it contains a range of antibodies. The majority of the antibodies are unmodified immunoglobulin (Ig)G (95%). The pharmacologic effect of IVIG includes blockade of macrophage Fc receptor, antiinflammation by inhibiting the generation of membrane attack complex, neutralization of autoantibody, inhibition of cell proliferation, and regulation of apotosis. The side effects of IVIG include infusion reaction (fever, chills, and facial flush), tachycardia, palpitation, anaphylaxis ARF, thrombosis, and aseptic meningitis. The FDA has received over 100 reports of adverse renal events related to IVIG use. Most of these serious adverse events have occurred in older patients with diabetes with previous renal impairment. Renal dysfunction usually occurs within 7 days of IVIG administration, with mean peak serum creatinine levels in the range of 6.2 mg/dL. Approximately 40% of patients required dialysis and 15% mortality was reported despite renal replacement therapy. The mean time to recover renal function in surviving patients is 10 days. Histologic evidence of extensive vacuolation of the proximal tubules has been reported in patients with IVIG-induced renal dysfunction. This histologic finding is consistent with osmotic nephrosis associated with administration of a high load of sucrose. Since 90% of the cases were reported in patients receiving sucrose-containing IVIG, sucrose was thought to be the culprit in IVIG-induced nephrotoxicity. Renal failure has been reported in a small number of patients exposed to hydroxyethylstarch following surgery. Osmotic nephrosis has been reported in these patients, however, a number of studies have refuted these findings.

Pathogenesis

IVIG-induced nephrotoxicity is largely related to the preparation of the product. Factors such as volume load, sugar, and sodium content, and osmolarity of the product should be considered. Sugar, such as sucrose, is often used as a stabilizer to prevent the aggregation of IgG. Sucrose is a disaccharide of glucose and fructose. It is reabsorbed in the proximal convoluted tubule (PCT) after being filtered. Unfortunately, the human kidney lacks the enzyme to hydrolyze sucrose. The accumulation of sucrose inside the PCT cells increases the osmolarity and draws the fluid into the cells. Renal failure occurs as a result of cell swelling, vacuolization, and tubular luminal occlusion from swollen tubular cells.

Different preparations contain varied amounts of sucrose. The incidence of ARF does not seem to correlate with the amount of sucrose, so it has been proposed that small amounts of sucrose may be sufficient to induce renal impairment or IVIG itself may be contributing to or causing renal failure.

Prevention & Management

Patients should be adequately hydrated prior to IVIG administration. The concurrent use of IVIG, NSAIDs, metformin, and radiocontrast agents should be avoided because of the synergistic effect on renal function. For sucrose-containing products, the infusion rate should not exceed 3-mg sucrose/kg/minute. Baseline serum creatinine, BUN, and urine output should be obtained and monitored closely during the course of IVIG therapy. In patients at an increased risk of ARF, use of non-sucrose-containing IVIG products is highly recommended.

Amphotericin B

Incidence & Risk Factors

Amphotericin B is a polyene antibiotic with activity against a broad spectrum of fungi. However, renal function becomes impaired in approximately 80% of patients given amphotericin B. This nephrotoxicity is dose related and probably inevitable when the cumulative dose exceeds 3 g in adults. Patients at high risk include elderly patients, particularly those with depleted extracellular volume.

Pathogenesis

The usual clinical presentation of amphotericin B nephrotoxicity is characterized by defects in renal tubular function. Occasionally, this condition will progress to nonoliguric renal failure. Modest proteinuria associated with a relatively normal urinary sediment is the initial finding. Frank azotemia is preceded by hypokalemia, renal tubular acidosis, and impaired urinary concentrating capacity. In addition, the presence of a magnesium-wasting syndrome is a prominent feature of amphotericin nephrotoxicity. Repetitive courses of amphotericin B may cause permanent impairment of renal function.

Histologic changes associated with the administration of amphotericin B are surprisingly minimal. These changes are seen in the glomerulus and renal tubule. Amphotericin B has been shown to cause acute renal vasoconstriction and damage to the distal tubular epithelium. Although the exact mechanism causing nephrotoxicity is unclear, amphotericin B may bind to membrane sterols in renal vasculature cells and renal tubular epithelial cells altering membrane permeability. This event may initiate a sequalae of other events that alter renal function. These events may include activation of second messengers, activation of renal homeostatic mechanisms, and/or release of mediators. Frequent monitoring of serum creatinine is recommended. If toxicity occurs, the amphotericin dosage can be reduced to the previous level, interrupted for 2 days, or a double dose can be given on alternate days. A doubling of the baseline serum creatinine is indicative of serious nephrotoxicity.

Prevention & Treatment

Sodium supplementation in the form of intravenous saline can be used as a safe and effective means of reducing the risk of amphotericin nephrotoxicity to approximately 10%. Sodium (150 mEq/day) can be administered as follows: 500 mL NS 30 minutes before amphotericin B administration and a second 500 mL given during the 30 minutes after completion of the amphotericin infusion. The goal is to achieve a urinary sodium excretion of 250–300 mmol/day. Liposomal amphotericin B may allow for larger doses to be administered with a higher therapeutic index. Several different lipid-based amphotericin B preparations have been introduced in the market recently. These formulations have a lower rate of nephrotoxicity when compared to the standard formulation of amphotericin B. Administration-associated adverse drug reactions (fever, chills) are significantly lower with lipid-based amphotericin B. Among all lipid-based amphotericin B formulations, liposomal amphotericin (AmBisome) is significantly less nephrotoxic. Fewer patients require a dose reduction/discontinuation with Ambisome for the treatment of invasive mycoses due to adverse drug reactions when compared to other lipid-based amphotericin B formulations (ABLC, Abelcet, and ABCD, Amphotec).

Patients should be premedicated with diphenhydramine 25 mg intravenously/orally and acetaminophen 650 mg orally before receiving amphotericin to minimize infusion-related reactions. To protect the kidneys, patients should be well hydrated and should receive sodium loading. This can easily be accomplished by administering an intravenous 250–500 mL 0.9% saline bolus before and after infusion of amphotericin.

Voriconazole is pharmacokinetically and therapeutically superior to amphotericin B in many respects and should be substituted for amphotericin for the treatment of disseminated Candida and invasive aspergillosis infections. It is a potent inhibitor of cytochrome P450-3A4 hepatic metabolism. Therefore, plasma concentrations of cyclosporine/tacrolimus should be monitored closely to avoid potential toxicities.

ACE Inhibitors & Angiotensin Receptor Blockers

Incidence & Risk Factors

ACE inhibitors and ARBs are frequently used in the treatment of hypertension. Emerging evidence suggests that treatment of hypertension and concomitant lowering of intraglomerular pressure has a renoprotective effect in patients with diabetes and non-diabetic nephropathy. ACE inhibitors have become the antihypertensive therapeutic class of choice when the first evidence of microalbuminuria is detected in patients with diabetes.

ACE inhibitors and ARBs selectively dilate the efferent arteriole affecting renal hemodynamics. Dilation of the efferent arteriole rarely compromises the glomerular filtration rate (GFR) in patients with normal renal perfusion. However, acute renal dysfunction can occur if atherosclerotic vascular disease is present in major renal arteries, when high-grade bilateral renal artery stenosis or stenosis in a single kidney (renal transplant recipients) exists, or in any condition or drug-induced condition in which renal hemodynamics maintained by the renin/angiotensin system is altered.

Pathogenesis

Several conditions including volume depletion from diuretic therapy, concomitant administration with agents that cause vasoconstriction (NSAIDs, cyclosporine), chronic renal insufficiency of any cause [eg, congestive heart failure (CHF), hypertension], or during development of illnesses that decrease circulatory volume (vomiting, diarrhea, worsening CHF) put patients at greater risk of renal impairment. These patients depend on efferent arteriolar vasoconstriction to maintain adequate glomerular filtration. Initiation of ACE inhibitors or ARBs may result in a rapid fall in the GFR and a rise in serum creatinine. This usually occurs within 2 weeks of initiation of these agents and can be more pronounced in patients with documented risk factors. Clinicians should ensure that patients are not hypovolemic and therapy should begin with a low dose that is slowly titrated. A chemistry panel should be obtained on all patients prior to and within 5–7 days of initiation of drug therapy. This is critical, especially in elderly patients and those with known preexisting risk factors. Patients at risk of developing ARF with initiation of ACE inhibitors or ARBs can be identified early in therapy if cautious monitoring occurs (Figure 14–1).

Prevention & Treatment

ARF caused by ACE inhibitors is usually reversible. If renal dysfunction occurs, dosage reduction or reduction in the dosage of any concomitantly administered diuretic usually results in improved renal hemodynamics. Restoration of fluid and electrolyte balance, withdrawal of any interacting drugs, and, if necessary, temporary dialysis may be indicated. Substitution with an ARB almost always elicits the same effect and should be avoided.

Hyperkalemia is often present with ACE inhibitor-induced ARF, especially in elderly patients with chronic renal disease or patients receiving selective aldosterone inhibitors. The rise in plasma potassium concentration is usually modest. Often, ACE inhibitors offset hypokalemia, which occurs with many diuretics. Concomitant administration with potassium-sparing diuretics or potassium supplements increases the risk of developing hyperkalemia. If potassium levels above 6 mEq/L do not decline upon restoration of fluid balance, treatment with sodium polystyrene sulfonate may be indicated. Substitution with an ARB may reduce the incidence of hyperkalemia if potassium is less than 5.5 mEq/L.

Mortality secondary to ACE inhibitor or ARB therapy is low. Upon discontinuation of ACE inhibitors/ARBs renal function usually improves within a few days provided tubular damage has not occurred. Correction of risk factors for developing ACE inhibitor/ARB-induced ARF may allow continuation of therapy unless renal vascular disease or chronic renal insufficiency is the cause of ACE inhibitor/ARB-associated ARF. In patients with chronic renal insufficiency, up to a 20% rise in serum creatinine can be anticipated. This rise indicates that the drug is exerting its desired effect, reversing glomerular hyperfiltration. If the rise in serum creatinine does not exceed 20%, the ACE inhibitor or ARB should be continued. As surviving nephrons adapt, stabilization of serum creatinine usually ensues. A 50% dosage reduction can be attempted when serum creatinine rises above 30%. If the rise in serum creatinine does not stabilize within 4 weeks the ACE inhibitor or ARB should be discontinued (Figure 14–3).

Cisplatin and Carboplatin

Incidence & Risk Factors

Cisplatin and carboplatin are among the most widely used antineoplastic agents. Both agents exhibit a dose-related effect against a variety of solid tumor types. Cisplatin inhibits DNA synthesis through formation of DNA intrastrand cross-links, denatures the double helix, binds covalently to DNA bases, and disrupts DNA function. It also binds to RNA and proteins. Nephrotoxicity is the primary dose-limiting toxicity of cisplatin. Carboplatin was subsequently developed to avoid the nephrotoxicity of cisplatin while maintaining the antitumor effect. Carboplatin has since been shown to possess nephrotoxicity comparable to cisplatin. The epidemiology of nephrotoxicity varies between different cancer treatment regimens. Loss of 30–50% of GFR is a common reported adverse reaction with the use of platins. Use of other nephrotoxic agents, volume depletion, larger doses, coadministration with other nephrotoxic agents, and/or diuretics increased the risk of nephrotoxicity following exposure to platin analogs.

Pathogenesis

The majority of cisplatin is excreted largely unchanged in the urine. Platinum binds extensively to plasma proteins. Unbound cisplatin is freely filtered at glomeruli and may be secreted. Excreted platinum is mutagenic and may be responsible for second malignancies that arise after cisplatin therapy. Cisplatin accumulates in renal tubular cells via transport or binding to components of the organic base transport system. Autoradiographic studies have shown that radiolabeled cisplatin accumulated primarily in the S3 segment of proximal tubules, which is also the site of cisplatin-induced renal cell toxicity. The pathogenesis of cisplatin-induced cytotoxicity has been studied. Several suspected intracellular targets have been identified, including those involved in renal tubule energy production and DNA synthesis. Upon entry into renal cells, cisplatin undergoes biotransformation. Cisplatin binds cell macromolecules while a large portion of total cell platinum exists in a form with a molecular weight below 500 Da and exhibits a different chromatographic behavior than cisplatin.

Polyuria, reduced glomerular filtration, and electrolyte disturbances are frequently observed in cisplatin-treated patients. Polyuria occurs in two phases. During the first 24–48 hours after administration, urine osmolality falls while the GFR remains unchanged. Early polyuria often improves spontaneously. A second phase of polyuria occurs between 72 and 96 hours following cisplatin administration. This phase is accompanied by a disruption of glomerular filtration. A 20–40% sustained reduction in the GFR is common. Cisplatin-induced alteration of cellular respiration may lead to an incomplete distal tubule acidosis causing disturbances in magnesium, potassium, hydrogen, and calcium balance. Hypomagnesemia is a frequent complication of treatment with cisplatin. Repletion of serum magnesium levels and magnesium supplementation reduce the risk of adverse effects from hypomagnesemia. ATN and AIN have been reported with cisplatin treatment.

Prevention & Management

Several strategies have been employed to reduce cisplatin-induced nephrotoxicity. Prehydration with hypertonic salts may reduce cisplatin-induced ARF. A high urinary chloride concentration following saline-based hydration may reduce conversion of cisplatin to toxic aquated metabolites. Diuretics (furosemide) have also been utilized to decrease cisplatin transit time thorough renal tubules and to maintain adequate urinary output during vigorous hydration therapy. Although diuresis is commonly used, several clinical studies have shown it to be of no clinical benefit. Administering cisplatin as a continuous infusion or divided daily dose over 3–5 days is as effective therapeutically as a bolus dose. Avoidance of a large bolus dose decreases the intensity of renal drug exposure and may reduce cisplatin-induced nephrotoxicity. Coadministration with mannitol is thought to confer a protective effect by dilution of cisplatin within renal tubules due to urine volume expansion. Coadministration with nephrotoxic drugs such as aminoglycosides, NSAIDs, or iodinated contrast media should be avoided. Cisplatin and carboplatin should be used with caution in patients at risk for renal dysfunction.

Lithium

Incidence & Risk Factors

Lithium was discovered in 1817 and has been used since 1949 for the treatment of bipolar disorder. Following oral administration, lithium is absorbed completely from the gastrointestinal (GI) tract. Lithium is not protein bound and distributes in all human tissues. It is eliminated largely unchanged through renal excretion without any metabolism. A higher lithium half-life has been reported in bipolar patients compared to others. The most common side effects reported with lithium are renal toxicities, thyroid toxicosis, weight gain, somnolence, and cardiovascular abnormalities. Lithium-induced nephropathy is slow but progressive and is characterized by chronic interstitial nephritis including fibrosis, tubular atrophy, cystic tubular lesions, and glomerular sclerosis.

The true incidence of lithium-induced nephropathy is largely unknown. Renal dysfunction secondary to exposure to lithium occurs in up to 20% of the patients receiving lithium for any psychiatric disorder. The reported incidence ranged from 1% to 30%. Renal biopsy information obtained from psychiatric patients without exposure to lithium have shown similar renal injuries and histologic patterns. This finding suggests that renal injury can be from other etiologic processes independent of exposure to lithium. The prevalence, incidence, and severity of lithium-induced renal failure depend on the plasma concentration as well as the patient's renal function.

Pathogenesis

Lithium toxicities appear to be dose and concentration dependent. Serum concentrations between 1 and 1.5 mEq/L will most likely cause impaired concentration, lethargy, irritability, muscle weakness, tremor, slurred speech, and nausea. Plasma concenterations greater than 2.5 mEq/L have been associated with renal failure. At therapeutic plasma concentrations lithium impairs the acidification ability of distal collecting tubules, which leads to renal tubular acidosis but not systemic metabolic acidosis. In the collecting tubule, lithium inhibits production of cyclic AMP (cAMP), downregulates the aquaporin-2 channel, decreases antidiuretic hormone (ADH) receptor density, and leads to ADH resistance and impairment of collecting duct concentrating capacity, which leads to polyuria, polydipsia, and nephrogenic diabetes insipidus. Because of the need for long-term lithium therapy in bipolar patients, chronic renal disease manifesting as chronic tubulointerstitial nephropathy (CTIN) is often seen. Renal biopsy reveals tubular atrophy and interstitial fibrosis either associated with cortical and medullary tubular cysts and dilation. CTIN is predominantly found in the distal and collecting tubule. Lithium also directly affects the glomerulus. Focal segmental glomerulosclerosis and global glomerulosclerosis are also seen, and tend to parallel in severity the underlying tubulointerstitial disease. This finding explains the reduced GFR and proteinuria in patients with chronic lithium therapy. Despite the discontinuation of the lithium, many patients who had serum creatinine >2.5 mg/dL progressed to ESRD.

Prevention & Management

Bipolar patients usually require long-term lithium treatment. Lithium has a narrow therapeutic range (1–1.5 mEq/L during acute episode therapy and 0.6–1.2 mEq/L during maintenance therapy). Chronic and acute poisoning can occur in patients whose lithium dosage has been increased or in those with a decreased effective circulating volume. Therefore, close monitoring of serum levels is important to prevent acute and chronic renal failure. Patients should be instructed to drink 8–12 glasses of liquid every day during lithium therapy. Because low sodium intake could promote lithium reaborption, patients should maintain a regular non-low-salt diet. To avoid dehydration, prolonged exposure to the sun is discouraged and physicians should be contacted immediately if fever, diarrhea, or vomiting develops. Diuretics, especially thiazides, should be avoided with lithium concomitantly if possible. Thiazide diuretics contract extracelluar volume; therefore, lithium reabsorption is increased in the proximal tubule. In addition, medications that potentially increase serum lithium levels such as cyclosporine and NSAIDs (except low dose aspirin) or drugs with nephrotoxic properties such as aminoglycosides should be avoided (Table 14–4).

Fluid restoration is essential to manage lithium-induced nephrotoxicity. Acute renal insufficiency usually occurs in association with severe dehydration, and adequate fluid replacement rapidly restores kidney function. Loop diuretics can acutely abolish the lithium reabsorption process in the loop of Henle and increase lithium excretion; hence, furosemide (up to 40 mg/hour) can be used in case of lithium toxicity. However, such treatment cannot take place unless a large volume of fluids will be used to replace the loss of sodium and water induced by furosemide. In addition, lithium retention can occur following the discontinuation of furosemide due to its short duration of action and the reestablishment of intra- and extracellular lithium equilibrium. Acetazolamide combined with sodium bicarbonate can also be used instead of furosemide because acetazolamide inhibits the reabsorption of lithium by the proximal tubules.

Electrolyte supplements, especially sodium and potassium, should be given at the same time as management of lithium-induced nephrotoxicity because hyponatremia and hypokalemia are often seen in these patients. When patients cannot be managed medically or when renal function is severely impaired, hemodialysis is the most efficient way to decrease lithium levels because lithium is entirely dialyzable. Lithium leaves the cells rather slowly and serum levels can rebound if hemodialysis stops too soon. Therefore, hemodialysis should take place for a longer period or at frequent intervals (Table 14–5).

Nonsteroidal Anti-Inflammatory Drugs

Incidence & Risk Factors

NSAIDs are frequently used to treat chronic inflammatory conditions and for amelioration of acute and chronic pain. Widespread access and over-the-counter availability of these agents lead to the frequent impression that these drugs are safe and relatively devoid of toxicity. Unfortunately, NSAIDs or even aspirin use can pose a substantal risk to a large number of patients, especially when used chronically. Renal toxicity of the NSAIDs is discussed in Chapter 15.