Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

31. Drug-Induced Kidney Disease

Thomas D. Nolin


 Images The initial diagnosis of drug-induced kidney disease (DIKD) typically involves detection of elevated serum creatinine and blood urea nitrogen, for which there is a temporal relationship between the toxicity and use of a potentially nephrotoxic drug.

 Images DIKD is best prevented by avoiding the use of potentially nephrotoxic agents for patients at increased risk for toxicity. However, when exposure to these drugs cannot be avoided, recognition of risk factors and specific techniques, such as hydration, may be used to reduce potential nephrotoxicity.

 Images Acute tubular necrosis is the most common presentation of DIKD in hospitalized patients. The primary agents implicated are aminoglycosides, radiocontrast media, cisplatin, amphotericin B, and osmotically active agents.

 Images Angiotensin-converting enzyme inhibitors and nonsteroidal antiinflammatory drugs are associated with hemodynamically mediated kidney injury, the pathogenesis of which is a decrease in glomerular capillary hydrostatic pressure.

 Images Acute allergic interstitial nephritis is observed in up to 27% of kidney biopsies performed for hospitalized patients with unexplained acute kidney injury. Clinical manifestations of AIN typically present approximately 14 days after initiation of therapy and include fever, maculopapular rash, eosinophilia, arthralgia, often with pyuria, hematuria, proteinuria, and oliguria.


Numerous diagnostic and therapeutic agents have been associated with the development of drug-induced kidney disease (DIKD) or nephrotoxicity. It is a relatively common complication with variable presentations depending on the drug and clinical setting, inpatient or outpatient. Manifestations of DIKD include acid–base abnormalities, electrolyte imbalances, urine sediment abnormalities, proteinuria, pyuria, and/or hematuria. However, the most common manifestation of DIKD is a decline in the glomerular filtration rate (GFR), which results in a rise in serum creatinine (Scr) and blood urea nitrogen (BUN) and several other indicators of acute and chronic kidney injury (see eChap. 18 and Chap. 28).1 Initial diagnosis of DIKD is often delayed as it typically is based on the detection of elevated Scr and BUN, for which there is a temporal relationship between the kidney injury and exposure to the potentially nephrotoxic drug. This is consistent with classic qualitative definitions of acute renal failure, which have relied on either an abrupt increase in Scr or an abrupt decline in urine output (see eChap. 18 and Chap. 28). Historically, the clinical use of numerous definitions of acute renal failure and nephrotoxicity based on quantitative changes in the Scr concentration and other clinical end points made it extraordinarily difficult to ascertain their true incidence.2During the last decade however, standard terminology (e.g., acute kidney injury, AKI) and diagnostic criteria based on a combination of physiologic measurements (e.g., Scr and urine output) have been adopted and are now routinely used in clinical practice and research.3,4This will likely lead to new epidemiologic data about DIKD that are more accurate.

Nephrotoxicity is often reversible if one discontinues the use of the offending agent, but in some cases there may still be an AKI and progression to stage 5 chronic kidney disease (CKD), which includes end-stage renal disease (ESRD). Currently, many different mechanisms are responsible for the pathogenesis of DIKD, and the introduction of new drugs with novel mechanisms of action provides the potential for the identification of new presentations of AKI and CKD. This chapter reviews the epidemiology, pathophysiology, risk factors, and basic principles of prevention of DIKD. Detailed discussions of these issues plus management strategies are presented for the most commonly used agents that have been associated with a moderate to high likelihood of DIKD.


The incidence and characteristics of outpatient or community-acquired DIKD are not well understood since mild toxicity is often unrecognized in this setting. However, the acquisition of data regarding the pharmacoepidemiology of these effects has become more important as care increasingly shifts to the outpatient setting. The incidence of community-based AKI that required dialysis was recently reported to be 29.5 per 100,000 person years and 522.4 per 100,000 person years for patients not requiring dialysis.5 Although the incidence of drug-induced AKI was not specifically reported, earlier studies have implicated community-acquired DIKD in up to 20% of hospital admissions due to AKI.6 Conversely, AKI has been reported in up to 7% of hospitalized patients,7 and as many as 20% to 30% of critically ill patients may experience AKI during their hospitalization.8,9 Drug-induced causes have been implicated in up to 60% of all cases of in-hospital AKI and as such are a recognized source of significant morbidity and mortality. Although the incidence of in-hospital antibiotic-induced AKI alone has been reported to be as high as 36%, it appears to be declining, while cases of in-hospital AKI due to nonselective nonsteroidal antiinflammatory drugs (NSAIDs), angiotensin-converting enzyme inhibitors (ACEIs), chemotherapeutic agents, and antiviral drugs are increasing.1

CLINICAL PRESENTATION Drug-Induced Kidney Disease


    • The most common manifestation is a decline in GFR leading to a rise in Scr and BUN

    • Alterations in renal tubular function without loss of glomerular filtration may be evident


    • Patients may complain of malaise, anorexia, vomiting, shortness of breath, or edema, particularly in the outpatient setting


    • Decreased urine output may be an early sign of toxicity, particularly with radiographic contrast media, NSAIDs, and ACEIs, with progression to volume overload and hypertension

    • Proximal tubular injury: Metabolic acidosis with bicarbonaturia; glycosuria in the absence of hyperglycemia; and reductions in serum phosphate, uric acid, potassium, and magnesium due to increased urinary losses

    • Distal tubular injury: Polyuria from failure to maximally concentrate urine, metabolic acidosis from impaired urinary acidification, and hyperkalemia from impaired potassium excretion

Laboratory Tests

    • An abrupt (within 48 hours) reduction in kidney function defined as an absolute increase in Scr of ≥ 0.3 mg/dL (27 μmol/L), a percentage increase in Scr of ≥50% (1.5-fold from baseline), or a reduction in urine output (documented oliguria of less than 0.5 mL/kg per hour for more than 6 hours),13 when correlated temporally with the initiation of drug therapy may indicate drug-induced AKI

Other Diagnostic Tests

    • Urinary excretion of N-acetyl-β-D-glucosaminidase, γ-glutamyl transpeptidase, glutathione S-transferase, and interleukin (IL)-18 are markers of proximal tubular injury and have been used for the early detection of AKI in critically ill patients

    • Kidney injury molecule-1 (KIM-1) is expressed in the proximal tubule and is upregulated for patients with ischemic acute tubular necrosis, appearing in the urine within 12 hours after the ischemic insult

    • Neutrophil gelatinase-associated lipocalin (NGAL) protein may be detected in the urine within 3 hours of ischemic injury

Images Because the most common manifestation of DIKD is a decline in GFR leading to a rise in Scr and BUN, the onset of toxicity in hospitalized, acutely ill patients is most often recognized by routine laboratory monitoring. Decreased urine output may also be an early sign of toxicity, particularly with radiographic contrast media, NSAIDs, and ACEIs. In the outpatient setting, nephrotoxicity is often recognized by the development of symptoms such as malaise, anorexia, vomiting, volume overload (shortness of breath or edema), and hypertension. Scr or BUN concentrations and urine collection for creatinine clearance may subsequently be measured to quantify the degree of decline in GFR. Marked intrasubject between-day variability of Scr values have been noted (±20% for values within the normal range; see eChap. 18). Furthermore, they may be altered as the result of dietary changes and initiation of drug therapy, which may interfere with the assay procedure. Thus changes in Scr or urine output consistent with the diagnostic criteria for AKI (see Chap. 28),10 when correlated temporally with the initiation of drug therapy, are a common threshold for the identification of DIKD.

Nephrotoxicity may also be evidenced by primary alterations in renal tubular function without a corresponding loss of glomerular filtration. In this setting, urinary enzymes and low-molecular-weight proteins may be used as earlier and more specific biomarkers of nephrotoxicity compared with Scr and BUN, which are relatively insensitive markers of kidney injury.11,12 Scr and BUN are used as surrogates of kidney function, not injury per se, and typically significant kidney injury must have occurred days before a rise in either is evident. Urinary excretion of kidney injury molecule-1 (KIM-1), N-acetyl-β-glucosaminidase, γ-glutamyl transpeptidase, glutathione S-transferase, neutrophil gelatinase-associated lipocalin (NGAL), and interleukin-18 are markers of proximal tubular injury and have been used for the early detection of acute kidney damage in several patient populations.1114 For example, the transmembrane protein KIM-1 is upregulated for patients with ischemic acute tubular necrosis (ATN), appearing in the urine within 12 hours after the ischemic insult.14 Urinary N-acetylglucosamine (NAG) concentrations are a highly sensitive indicator of AKI and have been shown to detect AKI in critically ill patients up to 4 days prior to a rise in Scr was observed.14 Similarly, urinary NGAL is an early marker of AKI, preceding a rise in Scr by up to 3 days. In the future, urinary biomarkers such as KIM-1, NAG, and NGAL may facilitate the earlier detection of kidney injury and diagnosis of nephrotoxicity and minimize the long-term consequences of this common drug-induced disorder.11,12,14


Images The primary principle for prevention of DIKD is to avoid the use of nephrotoxic agents for patients at increased risk for toxicity. Therefore, an awareness of potentially nephrotoxic drugs and knowledge of risk factors that increase renal vulnerability is essential.15 Exposure to these drugs often cannot be avoided, so several interventions have been proposed to reduce the potential for the development of nephrotoxicity, for example, adjustment of medication dosage regimens based on accurate estimates of kidney function, and careful and adequate hydration to establish high urine flow rates.16 Other preventative strategies are still theoretical and/or investigational and relate directly to the specific nephrotoxic mechanisms of a given drug.

The several specific drug-induced renal structural–functional alterations that are responsible for the vast majority of cases of DIKD are listed in Table 31-1. This chapter discusses the pathophysiologic mechanisms responsible for the development of DIKD with these agents in detail, along with clinical presentation, prevention strategies, therapeutic management approaches, and relevant monitoring plans.

TABLE 31-1 Drug-Induced Kidney Structural–Functional Alterations



Images Drugs that lead to renal tubular epithelial cell damage typically do so via direct cellular toxicity or ischemia. Damage is most often localized in the proximal and distal tubular epithelia and is termed acute tubular necrosis when cellular degeneration and sloughing from proximal and distal tubular basement membranes are observed.17 This classically manifests as cellular debris-filled, muddy-brown, granular casts in the urinary sediment.17,18 Specific indicators of proximal tubular injury include metabolic acidosis with bicarbonaturia; glycosuria in the absence of hyperglycemia; and reductions in serum phosphate, uric acid, potassium, and magnesium as a result of increased urinary losses. Indicators of distal tubular injury include polyuria from failure to maximally concentrate urine (i.e., nephrogenic diabetes insipidus), metabolic acidosis from impaired urinary acidification, and hyperkalemia from impaired potassium excretion.

Acute Tubular Necrosis

ATN is the most common presentation of DIKD in the inpatient setting. The primary agents associated with this type of injury are aminoglycosides, radiocontrast media, cisplatin, amphotericin B, foscarnet, and osmotically active agents such as immunoglobulins, dextrans, and mannitol.9,19

Aminoglycoside Nephrotoxicity

Incidence Aminoglycoside antibiotic-associated nephrotoxicity has been reported to occur in between 10% and 25% of patients receiving a therapeutic course.9,20,21 Critically ill patients appear to have a higher risk for nephrotoxicity with reported rates as high as 58%.20 The large variance is in part a result of the use of different definitions of toxicity, variability between agents in the class, and the risk factors present in the study population.

Clinical Presentation Clinical evidence of aminoglycoside-associated nephrotoxicity is typically seen within 5 to 10 days after initiation of therapy and manifests as a gradual progressive rise in Scr and BUN and decrease in creatinine clearance.9 Patients usually present with nonoliguria, that is, they maintain urine volumes greater than 500 mL/day and sometimes have microscopic hematuria and proteinuria.9,19Although renal magnesium wasting can occur (i.e., daily excretion of more than 10 to 30 mg), the risk of symptomatic hypomagnesemia is generally low. Full recovery of kidney function is common if aminoglycoside therapy is discontinued immediately upon discovering signs of toxicity.11 However, severe AKI may develop occasionally, and for these individuals renal replacement therapy may be required (see Chap. 28). The diagnosis of aminoglycoside-associated nephrotoxicity is often difficult, particularly in critically ill patients with multiple comorbidities and is confounded by other factors that are independently associated with the development of AKI.20 For instance, concurrent dehydration, sepsis, hypotension, ischemia, and use of other nephrotoxic drugs frequently contribute to AKI in patients who are receiving aminoglycosides.17

Pathogenesis Aminoglycoside-associated ATN is primarily due to accumulation of high drug concentrations within proximal tubular epithelial cells, and subsequent generation of reactive oxygen species that produce mitochondrial injury, which leads to cellular apoptosis and necrosis.10,19 This results in cell sloughing from proximal tubular basement membranes into the tubular lumen, which can result in tubular obstruction and back leakage of the glomerular filtrate across the damaged tubular epithelium. Toxicity is related to cationic charge of the drugs in this class, which facilitates their binding to negatively charged renal tubular epithelial membrane phospholipids in the proximal tubules, followed by intracellular transport and concentration in lysosomes. The number of cationic groups on the drug molecule appears to correlate with the degree of nephrotoxicity, which is consistent with the observation of higher rates of toxicity with neomycin versus gentamicin, followed by tobramycin, then amikacin.9,15

Risk Factors Multiple risk factors for aminoglycoside-associated nephrotoxicity have been identified: the aggressiveness of aminoglycoside dosing, synergistic toxicity as the result of combination drug therapy, and preexisting clinical conditions of the patient (Table 31-2).9,15,20

TABLE 31-2 Potential Risk Factors for Aminoglycoside Nephrotoxicity


Prevention Aminoglycoside-associated ATN may be prevented by careful and cautious selection of patients and the use of alternative antibiotics whenever possible and as soon as microbial sensitivities are known. Commonly used alternatives include fluoroquinolones (e.g., ciprofloxacin or levofloxacin) and third-or fourth-generation cephalosporins (e.g., ceftazidime or cefepime). When aminoglycosides are necessary, gentamicin, tobramycin, and amikacin are most commonly used, but therapy should be selected to optimize antimicrobial efficacy.22 Furthermore, it is imperative to avoid volume depletion, limit the total aminoglycoside dose administered, and avoid concomitant therapy with other nephrotoxic drugs. Future therapeutic alternatives may include new aminoglycoside congeners that retain the desired bactericidal activity and yet are devoid of nephrotoxicity, and may also include concurrent use of antioxidant compounds such as vitamin E and N-acetylcysteine.23,24

Prospective, individualized pharmacokinetic monitoring has been used for more than three decades, and its use has been associated with a decrease in the incidence of aminoglycoside-associated nephrotoxicity.25 These studies, however, were often small and statistically underpowered. High-dose intermittent dosing of aminoglycosides, termed once daily dosing, used in combination with other antibiotics, has been intensively investigated as a practical cost-effective method to maintain antimicrobial efficacy while reducing the risk of AKI.24,26,27 The reduction in incidence may be the result of limited proximal tubular aminoglycoside uptake during the transient, high-peak serum concentrations, and because of the presence of low aminoglycoside concentrations for a greater proportion of the dosing interval, which facilitates excretion of the aminoglycoside.22 Although greater clinical efficacy and reduced nephrotoxicity may be realized with once daily compared with standard dosing, seriously ill, immunocompromised, and elderly patients, as well as those with preexisting kidney disease, are not ideal candidates for this approach.24

Management Aminoglycoside use should be discontinued or the dosage regimen revised if AKI is evident (i.e., there is an Scr increase of 0.5 mg/dL [44 μmol/L] or more that is not attributable to another cause). Other nephrotoxic drugs should be discontinued if possible, and the patient should be maintained adequately hydrated and hemodynamically stable.26 Short-term renal replacement therapy may be necessary, but ESRD has rarely been reported to be solely the result of aminoglycoside toxicity.28

Radiographic Contrast Media Nephrotoxicity

Incidence The incidence of radiographic contrast media-induced nephrotoxicity (CIN) has declined over the past decade from approximately 15% to 7% of all patients receiving iodinated contrast; yet it remains the third leading cause of hospital-acquired AKI, accounting for up to 11% of cases.29 The incidence varies depending on the population studied and presence of risk factors; rising from <2% for patients with normal kidney function up to 50% for patients with CKD or diabetes mellitus.30 As the number of risk factors associated with CIN increases, there is a proportional increase in the incidence of nephrotoxicity and in hospital and postdischarge mortality rates.29,31 A 5.5-fold increased risk of death has been reported for patients who develop CIN compared with those who do not, with the highest mortality rates observed for patients who developed AKI and required renal replacement therapy.19,21 In-hospital and 2-year mortality rates of 36% and 81%, respectively, have been reported for patients who developed CIN and those that required dialysis. An in-hospital mortality rate of only 7% was observed in those with CIN not requiring dialysis.29

Clinical Presentation CIN is usually transient in nature, presenting most commonly as nonoliguria with kidney injury apparent within the first 24 to 48 hours after the administration of contrast. The Scrconcentration usually peaks between 3 and 4 days after exposure, with recovery after 7 to 10 days.32,33 However, irreversible oliguric (urine volume <500 mL/day) AKI requiring dialysis has been reported in high-risk patients.31 Urinalysis typically reveals tubular enzymuria with hyaline and granular casts but may also be completely void of casts. The urine sodium concentration and fractional excretion of sodium are frequently low, with the latter typically <1% (<0.01).

Pathogenesis The primary mechanisms by which contrast media induces nephrotoxicity are renal ischemia and direct cellular toxicity.29 Renal ischemia likely results from systemic hypotension and simultaneous acute vasoconstriction caused by disruption of normal prostaglandin synthesis and the release of adenosine, endothelin, and other renal vasoconstrictors. Subsequently, a 50% sustained reduction in renal blood flow that lasts for several hours immediately following contrast administration may be evident.29 This reduced renal blood flow leads to increased concentrations of contrast in the renal tubules and exacerbates the direct cytotoxicity. The extent of cellular toxicity is directly related to the duration of tubular cell exposure to contrast. Thus, preservation of high urinary flow rates with adequate hydration before, during, and after contrast administration is vital to keep renal blood flow as high as reasonably possible to minimize tubular cell exposure to the contrast agent.29 In humans, plasma osmolality is normally between 275 and 290 mOsm/kg (275 and 290 mmol/kg). Since low- and high-osmolar contrast agents are hyperosmolar to plasma (i.e., 600 to 800 mOsm/kg [600 to 800 mmol/kg] and ~2,000 mOsm/kg [~2,000 mmol/kg], respectively), their use may result in osmotic diuresis, dehydration, renal ischemia, and increased blood viscosity caused by red blood cell aggregation. Oxidative stress has also been implicated in the development of ATN after contrast administration,34 which may explain the possible benefit of the antioxidant N-acetylcysteine.35

Risk Factors Decreased renal blood flow exacerbates the ischemic and direct cytotoxic effects of contrast media on the renal tubules. Therefore, preexisting kidney disease, particularly in those with estimated GFR <60 mL/min/1.73 m2, is the most important risk factor present in up to 60% of patients who develop CIN.29 Other patient-specific risk factors include conditions associated with decreased renal blood flow (i.e., congestive heart failure, dehydration/volume depletion, and hypotension), and patients with atherosclerosis and reduced effective circulating arterial blood volume appear to also have an elevated risk.33 Diabetes is also a significant risk factor, likely due to coexisting kidney disease (diabetic nephropathy). The presence of multiple myeloma has traditionally been considered a relative contraindication for contrast use, but the risk appears to be associated with concomitant dehydration, kidney disease, or hypercalcemia rather than the diagnosis itself. Larger volumes or doses of contrast and the use of low- as well as high-osmolar contrast agents are also independent predictors of CIN. Intraarterial administration of contrast confers greater risk than IV administration.29 Lastly, concurrent use of nephrotoxins and drugs that alter renal hemodynamics such as NSAIDs and ACEIs also increases risk. Risk factors are additive, and there is a proportional increase in the incidence of CIN and associated mortality as the number of risk factors increases.29,31

Prevention CIN can be anticipated in the majority of patients who are at risk; so the use of preventative procedures is justified for virtually all patients. Table 31-3 lists the recommended interventions for prevention of contrast nephrotoxicity. All patients scheduled to receive contrast media should be assessed for risk factors, and the risk-to-benefit ratio should be considered.29,33,36,37 High-risk patients can be identified by evaluating medical history and indication for the contrast study, along with their most recent Scr concentrations. Nephrotoxicity is best prevented in high-risk patients by using alternative imaging procedures (e.g., ultrasound, noncontrast magnetic resonance imaging, and nuclear medicine scans).36 However, if contrast media must be used, the smallest adequate volume should be administered. If the ratio of the volume of contrast to be infused relative to the patient’s creatinine clearance is ≥3.7 (≥222 if creatinine clearance is expressed in units of milliliters per second), the likelihood of nephrotoxicity is markedly increased.38 Therefore, in general, the volume of contrast administered should not be greater than twice the baseline estimated creatinine clearance.29

TABLE 31-3 Recommended Interventions for Prevention of Contrast Nephrotoxicity29,35,40,41,43


Low-osmolar (600 to 800 mOsm/kg; 600 to 800 mmol/kg) nonionic (iohexol and iopamidol) and ionic (ioxaglate) contrast agents may be used to minimize the incidence of nephrotoxicity. Standard hyperosmolar contrast media (e.g., low- and high-osmolar agent) are not reabsorbed in the kidney and cause osmotic diuresis, which contributes to the renal toxicity observed with these agents. Low-osmolar contrast agents have less than half the osmolality of high-osmolar (~2,000 mOsm/kg; ~2,000 mmol/kg) agents and are associated with less toxicity, especially when used for patients with preexisting kidney disease.39 However, use of low-osmolar agents does not preclude the development of nephrotoxicity. Even low-osmolar agents are hyperosmolar relative to plasma, which is likely the reason they are associated with greater nephrotoxicity than the iso-osmolar nonionic contrast agent iodixanol. Iodixanol has been shown to have the lowest risk for CIN for patients with CKD and diabetes.29,39

Clinical Controversy…

Some clinicians believe that low- or iso-osmolar contrast media should be used for virtually all patients at risk for toxicity. Others believe that the cost-to-benefit ratio of using low-osmolar contrast agents to prevent nephrotoxicity is questionable except for patients at high risk.

Volume expansion and correction of dehydration prior to contrast administration is a mainstay of preventive therapy.36,40 Parenteral hydration with isotonic saline before and after contrast administration reduces the incidence of toxicity, particularly in high-risk patients, and is currently the most widely accepted preventative intervention.40 Volume expansion may exert its beneficial effects through dilution of contrast media, prevention of renal vasoconstriction leading to ischemia, preservation of high urine flow rates, decreased tubular cell exposure to contrast, and avoidance of tubular obstruction. Hydration with isotonic sodium bicarbonate has been shown to provide more protection than saline, perhaps by reducing the formation of pH-dependent oxygen free radicals,41 but recent studies reported contradictory findings.36,42 Larger, adequately powered studies are needed to confirm these findings and to demonstrate conclusively that bicarbonate-based hydration is superior to saline. The use of oral hydration regimens has also been proposed but requires further study to clarify its role and is not currently recommended in lieu of parenteral hydration.40

N-acetylcysteine is a thiol-containing antioxidant that may effectively reduce the risk of developing CIN for patients with preexisting kidney disease. Despite the publication of dozens of clinical trials and meta-analyses, a therapeutic benefit of NAC has not been consistently demonstrated, and its therapeutic role remains controversial.43 Nevertheless, its use should be considered, along with hydration, for all patients who are at high risk of toxicity.35,37,43 The recommended N-acetylcysteine dosing regimen for prevention of CIN is to give four doses of 600 mg to 1,200 mg orally every 12 hours, with the first dose administered prior to contrast exposure (see Table 31-3).29,35,41 Finally, other nephrotoxic drugs should be discontinued if possible, and subsequent contrast studies appropriately timed to minimize cumulative toxicity.

Clinical Controversy…

Some clinicians believe that insufficient evidence exists to justify use of N-acetylcysteine for the prevention of contrast-induced nephrotoxicity, while others feel that its safety profile, ease of use, low cost, and potential for benefit are adequate justification for use for all patients.

Renal replacement therapy, including intermittent hemodialysis and continuous modalities, for example, continuous venovenous hemofiltration (CVVH), effectively removes iodinated contrast, and was considered by some to be a therapeutic option for the prevention of CIN.44 However, because of the logistical issues (e.g., technical difficulty), high cost of renal replacement therapy, and lack of consistent clinical efficacy data, currently this approach is not recommended.44,45

Management Currently there is no specific therapy available for managing established CIN. Care is supportive as described in Chapter 28. Kidney function (e.g., Scr and urine output), electrolytes (e.g., sodium and potassium), and volume status should be closely monitored.

Cisplatin Nephrotoxicity

Incidence Cisplatin is one of the most important and widely used antineoplastic drugs for the treatment of solid tumors, often demonstrating exceptional efficacy (i.e., cure rates over 90% in testicular cancers).46,47 Unfortunately, the primary dose-limiting toxicity of platin-containing compounds is nephrotoxicity. Cisplatin nephrotoxicity occurs in 20% to 30% of patients and is a significant cause of morbidity.46,48 Carboplatin, a second-generation platinum analog, is associated with a lower incidence of nephrotoxicity than cisplatin and thus is the preferred agent in high-risk patients.49

Clinical Presentation Cisplatin administration results in impaired tubular reabsorption and decreased urinary concentration ability, leading to increased excretion of salt and water (i.e., polyuria) within 24 hours of treatment. Polyuria persists, and a decrease in GFR evidenced by a rise in Scr concentration may be seen within 72 to 96 hours after cisplatin administration.47,48 Scr peaks approximately 10 to 14 days after initiation of therapy, with recovery by 21 days. As many as 25% of patients may have reversible elevations in Scr and BUN for 2 weeks after cisplatin treatment. However, kidney damage is dose related and cumulative with subsequent cycles of therapy, so the Scrconcentration may continue to rise, and irreversible kidney injury may result.48,49 Hypomagnesemia is a hallmark finding of cisplatin nephrotoxicity, due to impaired magnesium reabsorption and thus increased urinary losses.47Hypomagnesemia is often accompanied by hypocalcemia and hypokalemia and may be severe, leading to seizures, neuromuscular irritability, or personality changes. Urinalysis typically reveals leukocytes, renal tubular epithelial cells, and granular casts.48

Pathogenesis The pathogenesis of cisplatin nephrotoxicity is multifactorial in nature and likely begins with cellular uptake and accumulation of the drug in proximal tubular epithelial cells to concentrations that may reach five times the serum concentration.46,48 Tubular cell exposure to cisplatin then activates a series of cell signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway, p53, caspase, and the generation of reactive oxygen species, that collectively promote tubular cell injury and death via necrosis and/or apoptosis.49 Simultaneous production of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) within tubular cells activates an inflammatory response, which may worsen the renal insult.46 Although tubular damage is evident in both the proximal and distal segments, the majority occurs in the proximal tubules and is followed by a progressive loss of glomerular filtration capacity and impaired distal tubular function. Renal biopsies generally reveal necrosis of proximal and distal tubules and collecting ducts, with no obvious morphological changes to the glomeruli.48

Risk Factors Risk factors include increased age, dehydration, renal irradiation, concurrent use of nephrotoxic drugs, large cumulative doses, and alcohol abuse.47,48

Prevention The best renoprotective strategy is a combination of interventions, including prospective dose reduction and decreased frequency of administration, which usually requires using the platin compounds in combination with other chemotherapeutic agents, avoiding concurrent use of other nephrotoxic drugs, and ensuring patients are euvolemic or somewhat hypervolemic prior to initiating treatment.46,50 Vigorous hydration with isotonic saline should be used for all patients with a goal of maintaining at least 100 to 150 mL/h of urine output during and after cisplatin treatment. Hydration should be initiated 12 to 24 hours prior to and continued for 2 to 3 days after cisplatin administration at rates of 100 to 250 mL/h, as tolerated, to maintain a urine flow of 3 to 4 L/day.47

Amifostine, an organic thiophosphate that is converted to an active metabolite, chelates cisplatin in normal cells and reduces the nephrotoxicity, neurotoxicity, ototoxicity, and myelosuppression associated with cisplatin and carboplatin therapy. It is also thought to serve as a thiol donor, thereby reducing intracellular reactive oxygen species and corresponding oxidative stress that plays a critical role in the development of cellular injury.23,46 Pretreatment with amifostine should be considered for patients who are at high risk for kidney injury, particularly patients who are elderly, volume depleted, have CKD, or are receiving other nephrotoxic drugs concurrently. The current recommended dose of amifostine is 910 mg/m2 administered IV over 15 minutes, beginning 30 minutes prior to cisplatin administration.51Common toxicities include acute hypotension, nausea, and fatigue.

Other renoprotective strategies include the use of hypertonic saline (e.g., administration of each dose in 250 mL of 3% saline) to reduce tubular cisplatin uptake. Classic antioxidants such as ascorbic acid, thiol-based antioxidants such as α-lipoic acid and N-acetylcysteine, which reduce oxidative damage by acting as a sulfhydryl donor, and the disulfiram metabolite diethyldithiocarbamate to reduce cytochrome P450 2E1-mediated generation of hydroxyl radicals have also been evaluated.52 Finally, reduced renal exposure can be achieved with the use of localized intraperitoneal administration in conjunction with systemic administration of sodium thiosulfate for those with peritoneal tumors.47

Management AKI caused by cisplatin therapy is usually partially reversible with time and supportive care, including dialysis. Kidney function indices should be closely followed, with Scr and BUN concentrations checked daily. Serum magnesium, potassium, and calcium concentrations should be monitored daily and corrected as needed.48,49 Hypocalcemia and hypokalemia may be difficult to reverse until hypomagnesemia is corrected. Progressive kidney disease caused by cumulative nephrotoxicity may be irreversible and in some cases may lead to ESRD and require chronic dialysis support.

Amphotericin B Nephrotoxicity

Incidence Variable rates of amphotericin B nephrotoxicity have been reported that correspond in large part to the cumulative dose administered. Nephrotoxicity may be seen in nearly 30% of patients receiving median cumulative doses as low as 240 mg and reaches an incidence of >80% when cumulative doses approach 5 g.53,54 Although numerous studies demonstrate lower rates of nephrotoxicity with liposomal formulations compared with conventional amphotericin B, it is difficult to compare rates of toxicity between products and studies because of the variability in the study populations, doses administered, and inconsistent definitions of nephrotoxicity and methods of assessment.55,56

Clinical Presentation Dose-dependent nephrotoxicity is often evident after administration of cumulative doses of 2 to 3 g as non-oliguria, renal tubular potassium, sodium, and magnesium wasting, impaired urinary concentrating ability, and distal renal tubular acidosis.9 Although the cumulative dose is a significant risk factor, the time to onset of kidney injury varies considerably, ranging from a few days to weeks.53 Tubular dysfunction usually manifests 1 to 2 weeks after treatment is begun, and potassium and magnesium replacement may be necessary. This is typically followed by a decrease in GFR and a rise in Scr and BUN concentrations. Consequently, kidney function indices should be closely followed, with Scr and BUN concentrations checked daily, and serum magnesium, potassium, and calcium concentrations monitored every other day and corrected as needed.

Pathogenesis Amphotericin B nephrotoxicity occurs predominantly via two mechanisms. The first is direct tubular epithelial cell toxicity resulting from interaction of amphotericin B with ergosterol in the cell membrane, leading to increased tubular cell membrane permeability, lipid peroxidation, and eventual necrosis of proximal tubular cells.53 Tubular injury appears to be exacerbated by ischemic injury, which is a result of a reduction in renal blood flow and GFR due to afferent arteriolar vasoconstriction.9,53

Risk Factors Risk factors that impact the likelihood of developing amphotericin B nephrotoxicity include preexisting kidney disease, large individual and cumulative doses, short infusion times, volume depletion, hypokalemia, increased age, and concomitant administration of diuretics and other nephrotoxins (cyclosporine in particular).9,53

Prevention Permanent decrements in GFR are best prevented by incorporating a low threshold (i.e., if Scr reaches 2 mg/dL [177 μmol/L] on 2 consecutive days) for stopping amphotericin B or switching to a liposomal formulation. Several lipid formulations of amphotericin B (e.g., amphotericin B lipid complex, liposomal amphotericin B) are available and should be used in most high-risk patients as they reduce nephrotoxicity by enhancing drug delivery to sites of infection and reducing interaction with tubular epithelial cell membranes.53,56 Nephrotoxicity can also be minimized by limiting the cumulative dose, increasing the infusion time, ensuring the patient is well hydrated, and avoiding concomitant administration of other nephrotoxins.9 Administration of 1 L IV 0.9% sodium chloride daily during the course of therapy appears to reduce toxicity and a single infusion of saline 10 to 15 mL/kg prior to administration of each dose of amphotericin B are generally recommended.53 A number of other antifungal agents such as itraconazole, voriconazole, and caspofungin are viable alternatives and are now routinely used in lieu of amphotericin B for patients at high risk of developing nephrotoxicity.9

Clinical Controversy…

Although liposomal formulations of amphotericin B are dramatically more expensive than conventional amphotericin B (i.e., $300 to $1,000 per day vs. $5 per day),66 many clinicians recommend using liposomal formulations for all patients with CKD and those at risk for developing nephrotoxicity. Others maintain that the safety and efficacy of liposomal formulations are not yet established enough to warrant their use for all patients.

Management Amphotericin B nephrotoxicity is best treated by discontinuation of therapy and substitution of alternative antifungal therapy, if possible. Renal tubular dysfunction and glomerular filtration will improve gradually to some degree in most patients, but damage may be irreversible. Kidney function indices should be closely followed, with Scr and BUN concentrations checked daily, and serum magnesium, potassium, and calcium concentrations should be monitored daily and corrected as needed.9

Osmotic Nephrosis

It is now known that several drugs, including mannitol, low-molecular-weight dextran, hydroxyethyl starch, and radiographic contrast media, or drug vehicles, such as sucrose, maltose, and propylene glycol, are associated with osmotic nephrosis, which may rarely lead to ATN and AKI.9,57,58 Since osmotic nephrosis does not necessarily negatively affect proximal tubular function, its presence may often go undetected in patients without overt signs of ATN. This likely contributes to the extremely low incidence of osmotic nephrosis reported for causative agents.57 IV immunoglobulin solutions containing hyperosmolar sucrose may cause osmotic nephrosis and AKI in 1% to 10% of cases, which is usually reversible shortly after discontinuing therapy.57 Maltose-based IV immunoglobulin solutions have also been implicated in the development of osmotic nephrosis.59 Although IV immunoglobulin-induced nephropathy is the modern prototype for osmotic nephrosis, it is understood that the vehicle (i.e., sucrose or maltose) is the culprit and not the immunoglobulins themselves.

Clinical Presentation and Pathogenesis

The clinical presentation of osmotic nephrosis is often subtle. While tubular proteinuria or vacuolated tubular cells may be observed on urinalysis for patients with AKI, the definitive diagnosis of osmotic nephrosis is only made via a kidney biopsy.57 IV immunoglobulin-induced AKI typically presents as oliguria after 2 to 4 days of treatment and may persist for up to 2 weeks.9 Kidney injury occurs via uptake of the offending agent through pinocytosis into proximal tubular epithelial cells, subsequent formation of vacuoles, and accumulation of lysosomes, which collectively results in an oncotic gradient and thus cellular swelling, tubular luminal occlusion, and compromised cellular integrity.57 Renal replacement therapy may be necessary for up to 40% of patients developing osmotic nephrosis-associated AKI.57However, it is usually reversible, with nearly all patients recovering normal kidney function following withdrawal of the offending drug.9

Risk Factors

Risk factors for osmotic nephrosis include excessive doses of offending agents, preexisting kidney disease, ischemia, older age (>65 years), and concomitant use of other nephrotoxins. Nephrotoxicity may be prevented by limiting the dose, reducing the rate of infusion, and avoiding dehydration and concomitant nephrotoxins.57


Images Hemodynamically mediated kidney injury generally refers to any cause of AKI resulting from an acute decrease in intraglomerular pressure, including “prerenal” states leading to reduced effective renal blood flow (e.g., hypovolemia, congestive heart failure) and medications that affect the renin–angiotensin system.9,18 The kidneys receive approximately 25% of resting cardiac output, which renders them particularly susceptible to alterations in renal blood flow and enhances their exposure to circulating drugs.15 Within each nephron, blood flow and pressure are regulated by glomerular afferent and efferent arterioles to maintain intraglomerular capillary hydrostatic pressure, glomerular filtration, and urine output. Afferent and efferent arteriolar vasoconstrictions are primarily mediated by angiotensin II, whereas afferent vasodilation is primarily mediated by prostaglandins (Fig. 31-1).60 This specialized blood flow is precisely regulated by interrelations between arachidonic acid metabolites, natriuretic factors, nitric oxide, the sympathetic nervous system, the renin–angiotensin system, and the macula densa response to distal tubular solute delivery.60,61 Drug-induced causes of hemodynamic kidney injury typically stem from constriction of glomerular afferent arterioles and/or dilation of glomerular efferent arterioles. ACEIs, angiotensin II receptor blockers (ARBs), and NSAIDs are the agents that have been most commonly implicated.9


FIGURE 31-1 Normal glomerular autoregulation serves to maintain intraglomerular capillary hydrostatic pressure, glomerular filtration rate (GFR), and, ultimately, urine output. (A II, angiotensin II; PGE2, prostaglandin E2; RBF, renal blood flow.)

Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers

These agents are extensively utilized for the management of hypertension and prevention of the progression of CKD even though they have been associated with the development of AKI.


Patients with renal artery stenosis, volume depletion, and congestive heart failure and those with preexisting kidney disease, including diabetic nephropathy, are most likely to experience a significant decline in kidney function when therapy with one of these agents is initiated.62 For example, between 20% and 25% of hospitalized patients with congestive heart failure develop AKI within weeks after treatment with ACEIs is initiated.63,64 The incidence of ACEI-induced AKI may be as high as 23% for patients with bilateral renal artery stenosis and up to 38% for patients with unilateral renal artery stenosis.8Moreover, ACEIs and ARBs are among the most commonly implicated medications in emergency hospitalizations, contributing to nearly 3% of emergency room visits for adverse drug events.65

Clinical Presentation

Therapy with ACEIs and ARBs will acutely reduce GFR; so a moderate rise in Scr after initiation of therapy should be anticipated.62 Importantly, a distinction must be made between a potentially detrimental reduction in GFR and a normal, predictable rise in Scr. An increase in Scr of up to 30% is commonly observed within 3 to 5 days of initiating therapy and is an indication that the drug has begun to exert its desired pharmacologic effect.9,62 The increase in Scrtypically stabilizes within 1 to 2 weeks and is usually reversible upon stopping the drug. Furthermore, an association exists between acute increases in Scr of ≤30% from baseline that stabilize within the first 2 months of initiating therapy and preservation of kidney function. The Scr threshold for discontinuation of ACEI or ARB therapy is unclear.62 However, an increase in Scr of more than 30% above baseline in the course of 1 to 2 weeks may necessitate discontinuation of the offending drug.


ACEI- or ARB-mediated kidney injury is primarily the result of disruption of normal autoregulation of intraglomerular capillary hydrostatic pressure.9 Normally, the kidney attempts to maintain GFR by dilating the afferent arteriole and constricting the efferent arteriole in response to a decrease in renal blood flow. During states of reduced blood flow, the juxtaglomerular apparatus increases renin secretion. Plasma renin converts angiotensinogen to angiotensin I, and ultimately angiotensin II by angiotensin-converting enzyme. Angiotensin II constricts the afferent and efferent arterioles, but has a greater effect on the efferent arterioles, resulting in a net increase in intraglomerular pressure.62Additionally, renal prostaglandins, prostaglandin E2 in particular, are released and induce a net dilation of the afferent arteriole, thereby improving blood flow into the glomerulus. Together these processes maintain GFR and urine output (Fig. 31-2).18,60,61


FIGURE 31-2 Glomerular autoregulation during “prerenal” states (i.e., reduced blood flow). (A II, angiotensin II; GFR, glomerular filtration rate; PGE2, prostaglandin E2; RBF, renal blood flow.)

When ACEI therapy (e.g., enalapril or ramipril) is initiated, the synthesis of angiotensin II is decreased, thereby preferentially dilating the efferent arteriole. This reduces outflow resistance from the glomerulus and decreases hydrostatic pressure in the glomerular capillaries, which alters Starling forces across the glomerular capillaries to decrease intraglomerular pressure and GFR. This in turn often leads to nephrotoxicity, particularly in the setting of reduced renal blood flow or effective arterial blood volume (Fig. 31-3), that is, prerenal settings (e.g., congestive heart failure) in which glomerular afferent arteriolar blood flow is reduced and the efferent arteriole is vasoconstricted to maintain sufficient glomerular capillary hydrostatic pressure for ultrafiltration.63,64


FIGURE 31-3 Pathogenesis of angiotensin-converting enzyme inhibitor (ACEI) nephropathy. (A II, angiotensin II; GFR, glomerular filtration rate; PGE2, prostaglandin E2; RBF, renal blood flow.)

Risk Factors

Patients at greatest risk are those dependent on angiotensin II and renal efferent arteriolar constriction to maintain blood pressure and GFR.62 These include patients with bilateral renal artery stenosis or stenosis in a single kidney (i.e., renal transplant); patients with decreased effective arterial blood volume (i.e., prerenal states), especially those with decompensated congestive heart failure, volume depletion from excess diuresis or GI fluid loss, hepatic cirrhosis with ascites, and nephrotic syndrome; patients with preexisting kidney disease; and patients receiving concurrent nephrotoxic drugs, particularly other drugs that affect intraglomerular autoregulation such as NSAIDs.9,62,66


Hemodynamically mediated AKI caused by ACEIs or ARBs is frequently preventable by recognizing the presence of preexisting kidney disease or decreased effective renal blood flow as a result of volume depletion, heart failure, or liver disease. A common strategy for at-risk patients is to initiate therapy with very low doses of a short-acting ACEI (e.g., captopril 6.25 mg to 12.5 mg), then gradually titrate the dose upward and convert to a longer-acting agent after patient tolerance has been demonstrated. Outpatients may be started on low doses of long-acting ACEIs (e.g., enalapril 2.5 mg) with gradual dose titration every 2 to 4 weeks until the maximum dose or desired response is achieved. Kidney function indices and serum potassium concentrations must be monitored carefully, daily for hospitalized patients and every 2 to 3 days for outpatients. Monitoring may need to be more frequent during outpatient initiation of ACEI or ARB therapy for patients with preexisting kidney disease, congestive heart failure, or suspected renovascular disease. Use of concurrent hypotensive agents and other drugs that affect renal hemodynamics (e.g., NSAIDs, diuretics) should be discouraged and dehydration avoided.


Acute decreases in kidney function and the development of hyperkalemia usually resolve over several days after ACEI or ARB therapy is discontinued. Occasionally patients will require management of severe hyperkalemia, as described in detail in Chapter 36.

ACEI or ARB therapy may frequently be reinitiated, particularly for patients with congestive heart failure, after intravascular volume depletion has been corrected or diuretic doses reduced. Slight reductions in kidney function (maintenance of a Scr concentration of 2 to 3 mg/dL [177 to 265 μmol/L]) may be an acceptable trade-off for hemodynamic improvement in certain patients with severe congestive heart failure or renovascular disease not amenable to revascularization.

Nonsteroidal Antiinflammatory Drugs and Selective Cyclooxygenase-2 Inhibitors

The overall safety of NSAIDs is evidenced by the nonprescription availability in the United States of several drugs in the class (e.g., ibuprofen, naproxen, ketoprofen). Although potential adverse renal effects from nonprescription NSAIDs had been a concern, conventional nonselective NSAIDs and selective cyclooxygenase-2 (COX-2) inhibitors are unlikely to acutely affect kidney function in the absence of renal ischemia or excess renal vasoconstrictor activity.9,67,68 Nevertheless, given their general safety and widespread availability, NSAIDs are among the most commonly used drugs. More than 30 million people take NSAIDs daily worldwide.69


Although the incidence of NSAID-induced AKI is unclear, historical reports suggest that 500,000 to 2.5 million people develop some degree of NSAID nephrotoxicity in the United States annually.70

Clinical Presentation

NSAID- and COX-2-induced AKI can occur within days of initiating therapy, particularly with a short-acting agent such as ibuprofen, or within days of some other precipitating event (e.g., intravascular volume depletion). Patients typically present with complaints of diminished urine output, weight gain, and/or edema. Urine sodium concentrations (<20 mEq/L [<20 mmol/L]) and fractional excretion of sodium (<1% [0.01]) are usually low, and BUN, Scr, potassium, and blood pressure are typically elevated.17,69 The urine sediment is usually bland and unchanged from baseline but may show occasional granular casts.


The pathogenesis of NSAID- and COX-2-induced AKI lies in the disruption of normal intraglomerular autoregulation.9,67,69 Specifically, NSAIDs inhibit cyclooxygenase (COX)-catalyzed synthesis of vasodilatory prostaglandins, including prostaglandins I2 (prostacyclin) and E2, from arachidonic acid.67 These prostaglandins are synthesized in the renal cortex and medulla by vascular endothelial and glomerular mesangial cells, and their effects are primarily local and result in net afferent arteriolar vasodilation. Vasodilatory prostaglandins have limited activity in states of normal renal blood flow, but in states of decreased renal blood flow, their synthesis is increased and they serve a vital autoregulatory role in the protection against renal ischemia and hypoxia by antagonizing renal arteriolar vasoconstriction due to angiotensin II, norepinephrine, endothelin, and vasopressin.67 Thus, administration of NSAIDs in the setting of reduced renal blood flow will blunt the usual compensatory increase in prostaglandin activity, altering the normal autoregulatory balance in favor of renal vasoconstrictors, thereby promoting renal ischemia and a reduction in glomerular filtration.69

Risk Factors

Risk factors for NSAID- and COX-2-induced AKI include age >60 years, preexisting kidney disease, hepatic disease with ascites, congestive heart failure, intravascular volume depletion/dehydration, systemic lupus erythematosus, or concurrent treatment with diuretics, ACEIs, or ARBs.9,66 The elderly are at higher risk because of multiple comorbidities, multiple-drug therapies, and reduced renal hemodynamics.68 Combined use of NSAIDs or COX-2 inhibitors and concurrent nephrotoxic drugs, particularly other drugs that affect intraglomerular autoregulation, should be avoided in high-risk patients.9


NSAID- and COX-2 inhibitor-induced AKI can be prevented by recognizing high-risk patients, avoiding potent compounds such as indomethacin and using analgesics with less prostaglandin inhibition, such as acetaminophen, nonacetylated salicylates, aspirin, and possibly nabumetone.9 Nonnarcotic analgesics (e.g., tramadol) may also be useful but do not provide antiinflammatory activity. When NSAID therapy is essential for high-risk patients, the minimal effective dose should be used for the shortest duration possible, and NSAIDs with short half-lives should be considered (e.g., sulindac) along with optimal management of predisposing medical problems and frequent kidney function monitoring.9 Moreover, use of concurrent hypotensive agents and other drugs that affect renal hemodynamics (e.g., ACEIs, ARBs, diuretics) should be discouraged in high-risk patients and dehydration avoided.

Traditional, nonselective NSAIDs inhibit COX-1 and COX-2, whereas the selective drugs meloxicam, celecoxib, and valdecoxib preferentially inhibit COX-2. COX-2 inhibitors were anticipated to be beneficial in high-risk patients. However, recent data indicate that they affect kidney function similarly to nonselective NSAIDs, and thus caution is warranted with their use, particularly in high-risk patients.9,68


NSAID-induced AKI is treated by discontinuation of therapy and supportive care. Kidney injury is rarely severe, and recovery is usually rapid. Occasionally, the hemodynamic insult is sufficiently severe to cause ATN, which can prolong injury.

Cyclosporine and Tacrolimus

The calcineurin inhibitors cyclosporine and tacrolimus have dramatically enhanced the success of solid-organ transplantation. As many as 94% of kidney transplant patients are prescribed a calcineurin inhibitor-based immunosuppressive regimen.71 Nephrotoxicity, however, remains a major dose-limiting adverse effect of both drugs. Although delayed chronic interstitial nephritis has also been reported, acute hemodynamically mediated kidney injury is an important mechanism of calcineurin inhibitor-induced nephrotoxicity.


Historically, reversible AKI occurred frequently in transplant recipients during the first 6 months of cyclosporine therapy. The 5-year risk of CKD after transplantation of a nonrenal organ ranges from 7% to 21%, depending on the type of organ transplanted, and the occurrence of CKD in these patients is associated with more than a fourfold increase in the risk of death.72

Clinical Presentation

The clinical presentation of acute nephrotoxicity associated with calcineurin inhibitors (i.e., hemodynamically mediated AKI) is quite different from the presentation of chronic nephrotoxicity (see Chronic Interstitial Nephritis below). AKI may occur within days of initiating therapy, manifesting as a rise in Scr concentration and a corresponding decline in creatinine clearance.9 Hypertension, hyperkalemia, sodium retention, oliguria, renal tubular acidosis, and hypomagnesemia are frequently observed in the absence of urine sediment abnormalities or morphologic lesions.71 On the other hand, renal biopsy may reveal thickening of arterioles, mild focal glomerular sclerosis, proximal tubular epithelial cell vacuolization and atrophy, and interstitial fibrosis. Biopsy is most useful to distinguish acute calcineurin inhibitor nephrotoxicity from acute cellular rejection of the transplanted kidney, the latter being evidenced by interstitial infiltrates composed of activated lymphocytes (see Chap. 70).73,74


The acute hemodynamic changes associated with calcineurin inhibitor nephrotoxicity result from an increase in potent vasoconstrictors including thromboxane A2 and endothelin, activation of the renin–angiotensin and sympathetic nervous systems, as well as a reduction in the vasodilators nitric oxide, prostacyclin, and prostaglandin E2.71,73,74 The net effect is an imbalance in afferent and efferent tone, resulting in predominantly afferent vasoconstriction with reduced renal plasma flow and GFR.9 The mechanism of acute nephrotoxicity is generally thought to be dose related, since kidney function improves rapidly following dose reduction.9

Risk Factors

Risk factors include age over 65, higher dose, concomitant therapy with nephrotoxic drugs (particularly NSAIDs), and interacting drugs that inhibit calcineurin inhibitor metabolism and transport and thus increase systemic exposure, older kidney allograft age, salt depletion, diuretic use, and polymorphic expression of P-glycoprotein.71,73 The incidence of AKI with potential progression to chronic nephropathy has decreased since the introduction of lower-dose-therapy regimens. Unfortunately, there has been no apparent reduction in the incidence of the slow, dose-dependent decline in glomerular filtration.74


Because acute hemodynamically mediated kidney injury secondary to cyclosporine and tacrolimus appears to be concentration related, pharmacokinetic and pharmacodynamic monitoring is an important means of preventing toxicity.71 However, the persistent presence of therapeutic or low cyclosporine concentrations does not totally preclude the development of nephrotoxicity. Calcium channel blockers may antagonize the vasoconstrictor effect of cyclosporine by dilating glomerular afferent arterioles and preventing acute decreases in renal blood flow and glomerular filtration.71 Lastly, decreased doses of cyclosporine or tacrolimus, primarily when used in combination with other nonnephrotoxic immunosuppressants, may minimize the risk of toxicity, but this may increase the risk of chronic rejection.74


AKI usually improves with dose reduction and treatment of contributing illness or the discontinuation of interacting drugs. CKD is usually irreversible, but progressive toxicity may be limited by discontinuation of cyclosporine (or tacrolimus) therapy or dose reduction, with the continuation of other immunosuppressants.71,74 Scr and BUN should be closely monitored (daily if possible), as should cyclosporine or tacrolimus concentrations, to ensure that serum concentrations are within the narrow therapeutic range.


The precipitation of drug crystals in distal tubular lumens can lead to intratubular obstruction, interstitial nephritis, and occasionally superimposed ATN. Nephrolithiasis, the formation of stones within the kidney, results from abnormal crystal precipitation in the renal collecting system, potentially causing urinary tract obstruction with kidney injury. Numerous medications have been associated with development of crystal nephropathy.


The incidence is unclear for most of the implicated agents.


Drugs may induce intratubular obstruction and AKI by direct (precipitation of the drug itself) and indirect means (i.e., promoting release and precipitation of tissue-degradation products or cellular casts). For example, antineoplastic drugs may cause acute renal tubular obstruction indirectly by inducing tumor lysis syndrome, hyperuricemia, and intratubular precipitation of uric acid crystals.75 The diagnosis is supported by a urine uric acid-to-creatinine ratio greater than 1. Uric acid precipitation can be prevented by vigorous hydration with normal saline, beginning at least 48 hours prior to chemotherapy, to maintain urine output 100 mL/h in adults. Administration of allopurinol 100 mg/m2 thrice daily (maximum of 800 mg/day) started 2 to 3 days prior to chemotherapy, and urinary alkalinization to pH 7 may also be of value.76

Drug-induced rhabdomyolysis is another form of indirect toxicity, which can lead to intratubular precipitation of myoglobin and, if severe, AKI.77 The most common cause of drug-induced rhabdomyolysis is direct myotoxicity from 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins, including lovastatin and simvastatin. The risk of rhabdomyolysis is increased when these drugs are administered concurrently with gemfibrozil, niacin, or inhibitors of the CYP3A4 metabolic pathway (e.g., erythromycin and itraconazole).78

A newly recognized complication of warfarin therapy has been called warfarin-related nephropathy (WRN), which is characterized by glomerular hemorrhage with subsequent intratubular obstruction by red blood cell casts.79Patients with underlying CKD appear to be at greatest risk. The incidence of WRN may be as high as 33% in CKD versus 16.5% in non-CKD patients.80 Other risk factors included age, diabetes mellitus, hypertension, and cardiovascular disease. WRN is also associated with an increased mortality rate. In a recent study, the 1-year mortality rate was 31.1% in patients with presumed WRN versus 18.9% in control subjects, an increased risk of 65%.80

Intratubular precipitation of drugs or their metabolites can also directly cause AKI. Precipitation of drug crystals is due primarily to supersaturation of a low urine volume with the offending drug or relative insolubility of the drug in either alkaline or acidic urine.81,82 Volume depletion is an important risk factor for the development of AKI. Urine pH decreases to approximately 4.5 during maximal stimulation of renal tubular hydrogen ion secretion. Certain solutes can precipitate and obstruct the tubular lumen at this acid pH, particularly when urine is concentrated, such as for patients with volume depletion. For example, several antiviral drugs have been associated with intratubular precipitation and AKI.8184 Acyclovir is relatively insoluble at physiologic urine pH and is associated with intratubular precipitation in dehydrated oliguric patients.81,82 Foscarnet complexation with ionized calcium may result in precipitation of calcium-foscarnet salt crystals in renal glomeruli, causing primarily a crystalline glomerulonephritis. The salt crystals may then secondarily precipitate in the renal tubules causing tubular necrosis. The protease inhibitor indinavir has been associated with crystalluria, crystal nephropathy, dysuria, urinary frequency, back and flank pain, or nephrolithiasis in approximately 8% of treated patients.82,85 Intratubular indinavir crystal precipitation can be prevented in nearly 75% of treated patients if one assures that the patient consumes at least 2 to 3 L of fluid per day.82 Sulfadiazine, when used at high doses, and methotrexate may also precipitate in acidic urine and can cause oligoanuric kidney injury.81,82 Massive administration of ascorbic acid can also result in obstruction of renal tubules with calcium oxalate crystals, leading to “oxalate nephropathy”.81 Triamterene and the quinolone antibiotic ciprofloxacin may also precipitate in renal tubules and cause kidney injury.82

Kidney injury caused by intratubular precipitation of most tissue-degradation products or drugs and their metabolites can be largely prevented and possibly treated by administering the drug after vigorously prehydrating the patient, maintaining a high urine volume, and urinary alkalinization.82


Nephrocalcinosis is a clinical pathologic condition characterized by extensive tubulointerstitial precipitation and deposition of calcium phosphate crystals leading to marked tubular calcification.81,86,87 It is most commonly seen in clinical conditions associated with hypercalcemia and hypercalciuria, such as hyperparathyroidism, malignancy, and less frequently increased intake of calcium or vitamin D. However, nephrocalcinosis can also result from hyperphosphatemia and hyperphosphaturia in the absence of hypercalcemia, as is known to occur for patients who have received oral sodium phosphate solution (OSPS) as a bowel preparation.81,86,87

Acute Phosphate Nephropathy

The term acute phosphate nephropathy was coined specifically to describe OSPS-induced nephrocalcinosis, as its pathogenesis is the result of increased phosphate intake rather than hypercalcemia.87 During the last decade, several cases of nephrocalcinosis have been reported after use of OSPS for bowel preparation prior to GI procedures, and strong associations have recently been demonstrated between exposure to OSPS and a decline in kidney function, particularly in the elderly and those with preexisting kidney disease.81,8789

Incidence The incidence of acute phosphate nephropathy is between 1 in 1,000 and 1 in 5,000 exposures, translating to roughly 1,400 to 7,000 new cases annually.90

Clinical Presentation Patients usually present with AKI several days to months after exposure to OSPS. Low-grade proteinuria (<1 g/day), normocalcemia, and bland urinary sediment are usually observed. Extensive deposition of calcium phosphate in the distal tubules and collecting ducts without glomerular or vascular injury is the hallmark of acute phosphate nephropathy.81

Risk Factors Risk factors include advanced age, preexisting kidney disease, female sex, hypertension, diabetes, bowel conditions associated with prolonged intestinal transit, high sodium phosphate dosage, volume depletion, and medications that affect renal perfusion or function (e.g., diuretics, lithium, NSAIDs, ACEIs, or ARBs).87


Nephrolithiasis (formation of renal calculi or kidney stones) does not present as classic nephrotoxicity since GFR is usually not decreased. Drug-induced nephrolithiasis can be the result of abnormal crystal precipitation in the renal collecting system, potentially causing pain, hematuria, infection, or, occasionally, urinary tract obstruction with kidney injury. The overall prevalence of drug-induced nephrolithiasis is estimated to be 1%.91

Kidney stone formation, possibly also accompanied by intratubular precipitation of crystalline material, has been a rare complication of drug therapy. Until the acquired immune deficiency syndrome (AIDS) era, triamterene had been the drug most frequently associated with kidney stone formation, with a prevalence of 0.4%.91 Sulfadiazine is a poorly soluble sulfonamide that has caused symptomatic acetylsulfadiazine crystalluria with stone formation and flank or back pain, hematuria, or kidney injury in up to 29% of patients treated with the drug.81,82 A high urine volume and urinary alkalinization to pH >7.15 may be protective. Numerous other drugs have been implicated in the development of nephrolithiasis, including the antiviral drugs nelfinavir and foscarnet, the antibacterial agents ciprofloxacin, amoxicillin, and nitrofurantoin, and various products containing ephedrine, norephedrine, pseudoephedrine, and melamine.92,93


Proteinuria, particularly nephrotic range proteinuria (defined as urine protein excretion greater than 3.5 g/day per 1.73 m2) with or without a decline in the GFR is a hallmark sign of glomerular injury (see Chap. 32).94 Several different glomerular lesions may occur, including minimal change disease, focal segmental glomerulosclerosis (FSGS), and membranous nephropathy, mostly by immune mechanisms rather than direct cellular toxicity. Although drug-induced glomerular disease is uncommon, a variety of agents have been implicated.95

Minimal Change Glomerular Disease

Drug-induced minimal change glomerular disease is frequently accompanied by interstitial nephritis and is most common during NSAID therapy.94 Lithium, quinolone antibiotics, and interferon-α have also been implicated.19,95Patients present abruptly with nephrotic range proteinuria, hypoalbuminemia, and hyperlipidemia and rarely with hematuria and hypertension.19,94 The pathogenesis is unknown, but nephrotic range proteinuria as a consequence of NSAID therapy is frequently associated with a T-lymphocytic interstitial infiltrate, suggesting disordered cell-mediated immunity. Proteinuria usually resolves rapidly after discontinuation of the offending drug, and a 3- to 4-week course of corticosteroids may help resolve the lesion. More than 90% of adults achieve complete remission over the course of several months.94

Focal Segmental Glomerulosclerosis

FSGS is characterized by patchy areas (i.e., only some glomeruli are partially affected by the disease) of glomerular sclerosis with interstitial inflammation and fibrosis (see Chap. 32). FSGS is becoming the most common cause of nephrotic syndrome in African Americans and whites in the United States.94 It represents a pattern of glomerular injury, not a disease per se, and is the final common pathway by which normal glomerular components are replaced by fibrous scar tissue. FSGS has been described in the setting of chronic heroin abuse (known as heroin nephropathy).96 The pathogenesis is unknown but may include direct toxicity by heroin or adulterants and injury from bacterial or viral infections accompanying IV drug use. The bisphosphonates pamidronate and zoledronate, commonly used to treat osteoporosis, malignancy-associated hypercalcemia, and Paget’s disease, are associated with the development of a particularly aggressive variant of FSGS called collapsing glomerulopathy.97 It presents with massive proteinuria (>8 g/day), and it is typically characterized by rising Scr at diagnosis and rapid progression to ESRD.94 Patients receiving IV formulations, high doses, or prolonged therapy are at highest risk.97

Membranous Nephropathy

Membranous nephropathy is characterized by subepithelial immune complex formation along glomerular capillary loops and, although rarely seen, has classically been associated with gold therapy, penicillamine, captopril, and NSAID use.19,95 Patients present with nephrotic range proteinuria and microscopic hematuria, with hypertension and elevated Scr apparent for patients with more advanced disease.94 The pathogenesis may involve damage to proximal tubule epithelium with antigen release, antibody formation, and glomerular immune complex deposition. Proteinuria usually resolves slowly after discontinuing the offending drug. Patients who remain nephrotic after 6 months should be treated with a 6- to 12-month course of immunosuppressive therapy, which typically consists of prednisone and cyclophosphamide.94


Tubulointerstitial nephritis refers to diseases in which the predominant changes occur in the renal interstitium rather than the tubules. The presentation may be acute and reversible with interstitial edema, rapid loss of kidney function, and systemic symptoms or chronic and irreversible, associated with interstitial fibrosis and minimal to no systemic symptoms.19,98

Acute Allergic Interstitial Nephritis


Images The incidence of drug-induced acute allergic interstitial nephritis (AIN) is unclear and likely varies with clinical setting. For example, the incidence has been estimated to be 0.7 cases per 100,000 young outpatient men but from 10% to 27% of kidney biopsies performed in hospitalized patients with unexplained AKI demonstrate AIN.98,99 Multiple drugs have been implicated in the development of AIN (Table 31-4). It usually manifests 2 weeks after exposure to a drug but may occur sooner if the patient was previously sensitized.98

TABLE 31-4 Drugs Associated with Allergic Interstitial Nephritis


Clinical Presentation

Although methicillin-induced AIN is the prototype for AIN, it is now recognized that AIN is associated with all β-lactam antibiotics (including cephalosporins) and numerous other antimicrobials. Clinical signs present approximately 14 days after initiation of therapy and include (with their approximate incidence) fever (27% to 80%), maculopapular rash (15% to 25%), eosinophilia (23% to 80%), arthralgia (45%), and oliguria (50%).98 Systemic hypersensitivity findings of the classic triad of fever, rash, and arthralgia, often along with eosinophilia and eosinophiluria, strongly suggest the diagnosis of AIN. However, this constellation of findings is not consistently reliable as one or more are frequently absent; so caution is warranted in basing diagnosis on hypersensitivity findings alone.98 Eosinophiluria, an important marker of drug-induced AIN, is frequently absent, possibly because of fragility of eosinophils in urine and inadequate laboratory methodology. Anemia, leukocytosis, and elevated immunoglobulin E levels may occur. Tubular dysfunction may be manifested by acidosis, hyperkalemia, salt wasting, and concentrating defects.98

NSAID-induced AIN has a different clinical presentation than that seen with most other drugs.98 Patients are typically over 50 years of age (reflecting NSAID use for degenerative joint disease), the onset is delayed a mean of 6 months from initiation of therapy compared with 2 weeks with β-lactams, and fever, rash, and eosinophilia are typically not observed in patients with NSAID-induced AIN.98 Concomitant nephrotic syndrome (proteinuria >3.5 g/day) occurs in more than 70% of patients. Prompt diagnosis of AIN is important as discontinuation of the offending drug may prevent irreversible renal damage. Renal biopsy is the most definitive method for diagnosis.


The pathogenesis of the majority of cases of AIN is considered to be an allergic hypersensitivity response. This is supported by the fact that AIN is characterized as a diffuse or focal interstitial infiltrate of lymphocytes, eosinophils, and occasional polymorphonuclear neutrophils.98 Granulomas and tubular epithelial cell necrosis are relatively common with drug-induced AIN. Occasionally a humoral antibody-mediated mechanism is implicated by the presence of circulating antibody to a drug hapten–tubular basement membrane complex, low serum complement levels, and deposition of immunoglobulin G and complement in the tubular basement membrane. More commonly, a cell-mediated immune mechanism is suggested by the absence of these findings and the presence of a predominantly T-lymphocyte.98

Risk Factors

No specific risk factors have been identified because these are idiosyncratic hypersensitivity reactions. Individuals with other drug allergies may have increased risk and warrant close monitoring.


No specific preventive measures are known because of the idiosyncratic nature of these reactions. Patients must be monitored carefully to recognize the signs and symptoms because promptly discontinuing the offending drug often leads to full recovery.98


Corticosteroid therapy is beneficial and should be initiated immediately or soon after diagnosis of AIN along with discontinuance of the offending drug to avoid the risk of incomplete recovery of kidney function. While various regimens have been used, high-dose oral prednisone 1 mg/kg/day for 8 to 14 weeks with a stepwise taper has been used successfully.99,100 Typical kidney function indices (e.g., Scr, BUN) and signs and symptoms of AIN should be monitored closely for improvement.

Chronic Interstitial Nephritis

Lithium, analgesics, calcineurin inhibitors, aristolochic acid, and only a few other drugs have been reported to cause chronic interstitial nephritis, which is usually a progressive and irreversible lesion.


Incidence The prevalence of non-dialysis-dependent CKD stemming from chronic lithium nephrotoxicity in the general population of patients treated with lithium was recently estimated to be 1.2%.101,102 The prevalence of lithium-induced ESRD among all ESRD patients is between 0.2% and 0.8%.101 Several renal tubular lesions are associated with lithium therapy: an impaired ability to concentrate urine (nephrogenic diabetes insipidus) is seen in up to 87% of patients with biopsy proven nephrotoxicity, and incomplete distal renal tubular acidosis is observed in up to 50% of these patients.103

Clinical Presentation Lithium-induced nephrotoxicity is typically asymptomatic and develops insidiously during years of therapy. Blood pressure is normal and urinary sediment is bland, making detection difficult until the disease progresses significantly.104 It is usually recognized by rising BUN or Scr concentrations or the onset of hypertension. Polydipsia (excessive thirst) and polyuria (excessive urination) are observed in 40% and 20%, respectively, of patients with nephrogenic diabetes insipidus (see Chap. 34).103 Although interstitial fibrosis may be observed as early as 5 years after beginning therapy, lithium-induced CKD usually occurs after 10 to 20 years of lithium treatment.104

Pathogenesis The precise mechanism of chronic lithium-induced nephrotoxicity is not well characterized. Impaired ability to concentrate urine is a result of a decrease in collecting duct response to antidiuretic hormone, which may be related to downregulation of aquaporin 2 water channel expression during lithium therapy.104 Chronic tubulointerstitial nephritis attributed to lithium is evidenced most commonly by biopsy findings of interstitial fibrosis, tubular atrophy, and glomerular sclerosis. The pathogenesis may involve cumulative direct lithium toxicity since duration of therapy correlates with the decline in the GFR.104

Risk Factors It is now established that long-term lithium therapy is associated with nephrotoxicity in the absence of episodes of acute intoxication, and that the duration of therapy is the major determinant of chronic nephrotoxicity. Increased age may also be a risk factor, but daily dose is not.102,104

Prevention Prevention of acute and chronic toxicity includes maintaining lithium concentrations as low as therapeutically possible, avoiding dehydration, and monitoring kidney function. It is unknown whether progression to CKD can be prevented by stopping lithium use when mild kidney injury is first recognized. This poses a dilemma as lithium is highly effective for affective disorders and the risks and potential benefits of discontinuing such a beneficial drug need to be carefully considered.104 However, if lithium therapy is continued, kidney function must be monitored and therapy discontinued if it continues to decline. Amiloride has been used for prevention and treatment of lithium-induced nephrogenic diabetes insipidus, since it blocks epithelial sodium transport of lithium into the cortical collecting duct in the distal nephron.104,105

Management Symptomatic polyuria and polydipsia can be reversed by discontinuation of lithium therapy or ameliorated with amiloride 5 to 10 mg daily during continued lithium therapy (see Chap. 34).103,105If polyuria does not resolve within 7 to 10 days of therapy, then the amiloride dose should be increased to 20 mg daily. Progressive chronic interstitial nephritis is treated by discontinuation of lithium therapy, adequate hydration, and avoidance of other nephrotoxic agents. Lithium serum concentrations, as well as kidney function indices, including urine output, BUN, and Scr, should be monitored closely for resolution of signs and symptoms of toxicity.104

Cyclosporine and Tacrolimus

Delayed chronic tubulointerstitial nephritis, considered the Achilles’ heel of calcineurin inhibitor-based immunosuppressive regimens, has been reported after several months of therapy and can result in irreversible kidney disease.71Toxicity is progressive and usually manifests as a slowly rising Scr concentration and decreased creatinine clearance that may not reflect the severity of histopathologic changes. All three compartments of the kidney can be affected, evidenced by typical biopsy findings that include arteriolar hyalinosis, glomerular sclerosis, and a striped pattern of tubulointerstitial fibrosis.71,74,103 The pathogenesis appears to involve sustained renal arteriolar endothelial cell injury and increased extracellular matrix synthesis, which ultimately result in chronic ischemia of the tubulointerstitial compartment because of increased release of endothelin-1, decreased production of nitric acid, and upregulation of transforming growth factor-β.71 Unlike acute nephrotoxicity, chronic toxicity is not dose dependent.

Aristolochic Acid

Incidence Although the true incidence of aristolochic acid nephropathy is unknown, approximately 3% to 5% of patients who consume the natural product develop interstitial fibrosis with tubular atrophy.106

Clinical Presentation Patients with aristolochic acid nephropathy typically present with mild-to-moderate hypertension, mild proteinuria, glucosuria, and moderately elevated Scr concentrations.106 Anemia and shrunken kidneys are also common on initial presentation. The overwhelming majority of cases reported to date have been in women. The main pathologic lesions observed in the kidneys are interstitial fibrosis with atrophy and destruction of proximal tubules throughout the renal cortex; in general, the glomeruli are not affected. Perhaps the most remarkable feature of aristolochic acid nephropathy is the rate at which it progresses. In most individuals, ESRD requiring dialysis or transplantation develops within 6 to 24 months of exposure. An alarming high prevalence (approximately 40% to 45%) of urothelial transitional cell carcinoma has been observed in Belgian patients who underwent renal transplantation.106

Pathogenesis Although the precise mechanism of aristolochic acid nephropathy and urothelial carcinoma has yet to be characterized. The major components of aristolochic acid are metabolized to mutagenic compounds called aristolactam I and aristolactam II, respectively, which have been demonstrated to form aristolochic acid–DNA adducts in humans. Recent data indicate that these adducts cause direct DNA damage and may lead to proximal tubular atrophy and apoptosis.106

Prevention The primary means of preventing aristolochic acid nephropathy appears to be the limitation of exposure to compounds containing aristolochic acids. Several countries, including the United Kingdom, Canada, Australia, and Germany, have banned the use of Aristolochia-containing herbs.106

Papillary Necrosis

Papillary necrosis is a form of chronic tubulointerstitial nephritis characterized by necrosis of the renal papillae, the regions of the kidney where the collecting ducts enter the renal pelvis, which leads to progressive kidney disease.107Papillary necrosis is associated with diabetes, sickle cell disease, obstruction and infection of the urinary tract, and most commonly analgesic use.108

Analgesic Nephropathy

Incidence Prototypical analgesic nephropathy is characterized by chronic tubulointerstitial nephritis with papillary necrosis.108 Chronic excessive consumption of combination analgesics, particularly those containing phenacetin, was believed to be the major cause and led to the removal of phenacetin and phenacetin mixtures from most world markets. However, contemporary analgesics, particularly aspirin, acetaminophen, and NSAIDs, alone or in combination, are also associated with the development of analgesic nephropathy, but there is insufficient causative evidence to definitively link these nonphenacetin-containing analgesics with nephropathy.107 The incidence of analgesic nephropathy has declined significantly since removal of phenacetin from many countries, with the prevalence estimated to now be <5% in the United States adult ESRD population.108

Clinical Presentation Analgesic nephropathy is a progressive disease that evolves slowly over several years.108 It is difficult to recognize in the early stages of the disease because patients are often asymptomatic, and it may be underdiagnosed as a cause of ESRD. It is seen more commonly in women than men. Early manifestations are generally nonspecific and may include headache and upper GI symptoms; later manifestations include impaired urinary concentrating ability, dysuria, sterile pyuria, microscopic hematuria, mild proteinuria (<1.5 g/day), and lower back pain. As disease progresses, hypertension, atherosclerotic cardiovascular disease, renal calculi, and bladder stones are common, and pyelonephritis is a classic finding in advanced analgesic nephropathy.107 The most sensitive and specific diagnostic criteria include (a) a history of chronic daily habitual analgesic ingestion (daily use for at least 3 to 5 years); (b) IV pyelography, renal ultrasound, or renal computed tomography imaging, which reveals decreased renal mass and bumpy renal contours; (3) elevated Scr, that is, up to 4 mg/dL (354 μmol/L); and (4) papillary calcifications.107,108

Pathogenesis Analgesic nephropathy originates in the papillary tip as a result of accumulated toxins, drugs and metabolites, decreased blood flow, and impaired cellular energy production. The metabolism of phenacetin to acetaminophen, which is then oxidized to toxic free radicals that are concentrated in the papilla, appears to be the initiating factor that causes toxicity by mechanisms analogous to acetaminophen hepatotoxicity via glutathione depletion.103 Cortical interstitial nephritis develops secondary to papillary necrosis. Salicylates potentiate these effects by also depleting renal glutathione, and inhibiting prostaglandin-mediated vasodilation, thus further predisposing the renal medulla to ischemic injury.103

Risk Factors The epidemiology of analgesic use and analgesic nephropathy continues to evolve. The classic concept persists that risk for ESRD increases with cumulative consumption of combination analgesics, phenacetin, or acetaminophen and aspirin or NSAIDs. Caffeine contained in combination analgesics may increase risk, but the role is not clear.107,108 Chronic use of therapeutic doses of NSAIDs alone, but not aspirin or salicylates alone, can cause analgesic nephropathy. High-dose acetaminophen use alone is associated with an increased risk for ESRD. However, these associations remain inconclusive as a consequence of study design flaws, as acetaminophen has been the preferentially prescribed analgesic for patients with CKD.107,108

Prevention Prevention has depended primarily on public health efforts to restrict the sale of phenacetin and combination analgesics. This has effectively reduced analgesic nephropathy in Australia and Europe.107 However, risk continues with ongoing availability of nonprescription combination analgesics containing aspirin, acetaminophen, and caffeine in the United States and throughout the world.

Individuals requiring chronic analgesic therapy may reduce risk by limiting the total dose, avoiding combined use of two or more analgesics, and maintaining good hydration to prevent renal ischemia and decrease the papillary concentration of toxic substances. Acetaminophen remains the preferred nonopiate analgesic for patients with preexisting kidney disease.

Management Treatment of established nephrotoxicity requires cessation of analgesic consumption.103 This can prevent progression and may improve kidney function. Kidney function indices, including urine output, BUN, and Scr, should be monitored every several months. Patients should also be monitored for the development of transitional cell carcinoma of the renal pelvis, calyces, ureters, and bladder, which may present years after analgesic nephropathy is diagnosed.


Renal Vasculitis

Drug-induced renal vascular disease commonly presents as vasculitis, thrombotic microangiopathy, or cholesterol emboli.109 Vasculitis implies inflammation of the vessel wall, capillaries, or glomeruli and is typically classified according to vessel size (i.e., small, medium, or large vessel vasculitis).19 Small vessel vasculitides usually affect multiple organ systems, including the kidneys and lungs, and are associated with nonspecific inflammatory symptoms such as fever, malaise, myalgias, arthralgias, and weight loss.94 Numerous drugs are associated with the development of renal vasculitis, including hydralazine, propylthiouracil, allopurinol, phenytoin, sulfasalazine, penicillamine, and minocycline (Table 31-1).109,110 Most drug-induced cases of vasculitis, including hydralazine, propylthiouracil, allopurinol, penicillamine, and the anti-TNF-α drug adalimumab have been implicated in the development of antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis.109111 Patients present with hematuria, proteinuria, oliguria, and red cell casts, frequently along with fever, malaise, myalgias, and arthralgias.109 Treatment typically consists of withdrawing the offending drug and administration of corticosteroids or other immunosuppressive therapy, and usually leads to resolution of symptoms within weeks to months.110

Thrombotic Microangiopathy

Thrombotic microangiopathy is characterized clinically by microangiopathic hemolytic anemia, fragmented red cells, and thrombocytopenia and pathologically by vascular endothelial proliferation, endothelial cell swelling, and intraluminal platelet thrombi in the small vessels, particularly affecting the renal and cerebral capillaries and arterioles.19,112 The absence of inflammation in vessel walls distinguishes thrombotic microangiopathy from vasculitis. Numerous medications, including oral contraceptive agents, cyclosporine, tacrolimus, muromonab-CD3, many cancer chemotherapeutic agents including mitomycin C, cisplatin, and gemcitabine, interferon-α, ticlopidine, clopidogrel, quinine, and several biological agents such as bevacizumab and sunitinib are associated with the development of thrombotic microangiopathy.93,111,112 Patients may present with fever, neurological dysfunction, elevated Scr and BUN, and hypertension, along with microangiopathic hemolytic anemia and thrombocytopenia.19 Kidney injury can be severe and irreversible, although corticosteroids, antiplatelet agents, plasma exchange, plasmapheresis, and high-dose IV immunoglobulin G have each induced clinical improvement.

Cholesterol Emboli

Anticoagulants (particularly warfarin) and thrombolytics (e.g., urokinase, streptokinase, tissue-plasminogen activator) are associated with cholesterol embolization of the kidney.113 These drugs act to remove or prevent thrombus formation over ulcerative plaques or may induce hemorrhage within clots, thereby causing showers of cholesterol crystals that lodge in small diameter arteries of the kidney (renal arterioles and glomerular capillaries). Cholesterol crystal emboli induce an endothelial inflammatory response, which leads to complete obstruction, ischemia, and necrosis of affected vessels within weeks to months after initiation of therapy.113 Purple discoloration of the toes and mottled skin over the legs are important clinical clues. Treatment is supportive in nature, since kidney injury is generally irreversible.


The pharmacoeconomic implications of DIKD are enormous. An increase in Scr of ≥0.5 mg/dL (44 μmol/L) is independently associated with a 6.5-fold increase in the odds of death, a 3.5-day increase in length of hospital stay, and nearly $7,500 in excess hospital costs even after adjusting for age, sex, and measures of comorbidity.7 Amphotericin B-induced AKI leads to a mean increased length of hospital stay of 8.2 days and adjusted additional costs of $29,823 per patient,114 and the mean additional in-hospital cost for each episode of contrast-induced AKI has been estimated to be $10,345 per case.29 The major driver of the increased costs associated with contrast-induced AKI was the cost of the longer initial hospital stay. The increased availability of automated clinical decision support systems and computer-guided medication dosing for hospital inpatients may improve the safety of potentially harmful drugs and minimize the occurrence of nephrotoxicity in this setting, thereby potentially lowering the corresponding economic consequences.114,115




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