US Pharm. 2020;45(7/8):32-35.

Over the past decade, the incidence of acute kidney injury (AKI) in older adults has increased.1 It has been noted that one of the primary reasons is drug-induced nephrotoxicity, which is secondary to a combination of susceptibilities to kidney injury and the increased use of medications in the elderly population.1 Specific drug classes are associated with increased rates of kidney injury, including drugs that block the renin-angiotensin system, antimicrobials, and chemotherapeutic agents.2 Of concern, for this discussion in particular, are angiotensin-converting enzyme (ACE) inhibitors, angiotensin ll-receptor blockers (ARBs), nonsteroidal anti-inflammatory drugs (NSAIDs), and diuretics, which are highly prescribed drugs that are frequently administered together.2 Since treatment for established drug-induced kidney injury is limited—and supportive care is required—early recognition of nephrotoxicity is critical, as are preventative steps, when applicable.1 It is critical, therefore, to limit exposure to nephrotoxic drugs (TABLE 1) to decrease the incidence of AKI in the elderly patient.1 This column will focus on raising awareness of this important issue and provide resources to ultimately assist in mitigating the risk of community-acquired AKI. 

Definition and Diagnosis

AKI is a comprehensive term reflecting the full spectrum of kidney injury—from mild alterations in kidney function through end-stage kidney disease that requires renal replacement therapy— thereby more adequately replacing the former term acute renal failure. The definition of AKI is outlined below, according to the KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline for Acute Kidney Injury. only one criterion is required to be met for a diagnosis of AKI:3

• An increase in serum creatinine (SCr) of at least 0.3 mg/dL (27 µmol/L) within 48 hours

• An increase in SCr of 1.5 times baseline within the prior 7 days, or

• A urine output of less than 0.5 mL/kg/hour for at least 6 hours.

The mechanism of kidney injury may be due to hemodynamic effects, tubular or glomerular toxicity, and interstitial nephritis.1 Potential causes of AKI are classified as4:

• Prerenal (e.g., kidney hypoperfusion)

• Renal (e.g., direct effects on the kidney)

• Postrenal (e.g., urinary-tract obstruction distal to the kidneys)

Common Offending Agents

Studies suggest that ACE inhibitors cause reversible AKI in patients with hypertension, congestive heart failure (CHF), and renal disease; these patients often receive diuretics concomitantly with ACE inhibitors.5 Furthermore, both diuretics and NSAIDs are widely used, and concomitant use may be particularly problematic in older adults. The use of NSAIDs may decrease the efficacy of diuretics and induce CHF in patients treated with diuretics.6 Use of NSAIDs in elderly patients taking diuretics is associated with a twofold increased risk of hospitalization for CHF, especially in those with existing serious CHF.

It is well known that the fluid and electrolyte homeostatic mechanism is decreased in the older- adult population. Since older adults experience more severe dehydration with equal amounts of fluid loss compared with younger adults, this can be particularly problematic with regard to diuretic use in the elderly.7 Prerenal AKI results from glomerular hemodynamic alterations leading to reduced glomerular filtration rate (GFR) with no parenchymal compromise.2 Dehydration or hemorrhage, leading to intravascular volume depletion, is a common cause of prerenal AKI and is a risk in older adults.

Furthermore, NSAIDs, ACE inhibitors, and ARBs can induce functional AKI when they interfere with autoregulatory mechanisms.8 Importantly, as mentioned above, ACE inhibitors, ARBs, NSAIDs, and diuretics (TABLE 2) are highly prescribed drugs that are frequently administered together.2 Double and triple associations have been correlated with increased prerenal AKI incidence, termed “double whammy” and “triple whammy,” respectively.

Prieto-García and colleagues have presented an integrative analysis of the complex interplay among the effects of NSAIDs, ACEIs/ARBs, and diuretics, acting alone and together in double and triple therapies. Additionally, these researchers studied how these drug combinations have the potential to alter the equilibrium of regulatory mechanisms that control blood pressure (renal perfusion pressure) and GFR to increase the risk of inducing AKI via concomitant reduction of blood pressure and the distortion of renal autoregulation.2 Based on this information, the researchers proposed a more general model of prerenal AKI based on a multiassociation model, whereby several factors are necessary to effectively reduce net filtration. They found the triple association was the model associated with prerenal AKI accompanied by a course of other risk factors, among numerous potential combinations of clinical circumstances causing hypoperfusion in which renal autoregulation is not operative or is deregulated.2

Radiocontrast-Induced AKI 

Used during radiologic studies, radiocontrast agents—triiodinated benzoic acid salts that are water soluble—are associated with a well-documented risk of contrast-induced AKI (CI-AKI). Risk factors for CI-AKI include older age, chronic kidney disease, diabetes, dehydration, concomitant nephrotoxic drug administration, and high doses of contrast dye.9 The use of nonionic agents is limited to high-risk patients (due to a significant cost consideration), in whom nephrotoxicity is greater with high-ionic agents as compared with low-risk patients.8

Drug Dosing Considerations

Assessing Kidney Function: Assessing an individual’s kidney function is based on clinical presentation (i.e., symptoms [e.g., diarrhea, pruritis, anuria alternating with polyuria] and physical examination findings [e.g., jugular venous distention, crackles, asterixis, orthostatic hypotension]), laboratory results (elevated SCr, elevated blood urea nitrogen [BUN], BUN-to-creatinine ratio >20:1, hyperkalemia, metabolic acidosis), and urinary indices (i.e., urine osmolality, urine sodium concentration, specific gravity, urine-to-plasma creatinine ratio, fractional excretion of sodium).8 While creatinine alone is not used to evaluate kidney function, and SCr lacks sensitivity in actually detecting AKI, trends in creatinine or acute rises in SCr may be useful in the clinical evaluation of the patient and may assist in recognizing AKI.8,10  Since SCr and BUN rise as kidney function declines, monitoring SCr and BUN and comparing them to baseline can assist in determining if an individual’s kidney function is worsening or improving. Compared with SCr, BUN is a less sensitive marker for the evaluation of AKI; furthermore, other conditions that can cause an elevation in BUN are gastrointestinal bleeding and excessive protein intake.8 Decreased urine output is a more sensitive marker than increases in SCr in early AKI, although it is not present in all cases. Of note, the amount of urine output during AKI does not clearly differentiate between prerenal, renal, or postrenal causes.4

Alterations in Drug Pharmacokinetics: Importantly, alterations in drug pharmacokinetics need to be considered regarding the patient’s comprehensive drug regimen. The following addresses drug dosing considerations in this regard8

• Due to AKI-associated fluid retention, a resultant increase in volume of distribution may occur.

• There is a reduction in excretion of drugs and metabolites eliminated renally. 

• The nonrenal clearance of some drugs may be reduced.

For more extensive and complete drug dosing considerations in AKI, see Table 25-3 in Reference 8.

Other Considerations: With AKI, consider extracellular fluid volume depletion and nephrotoxins, obtain urinary diagnostic indices, and measure bladder residual volume to identify obstruction.4 Avoid using iodinated IV contrast in imaging studies.4

If unresponsive to other treatments, initiate hemodialysis or hemofiltration as needed for pulmonary edema, hyperkalemia, metabolic acidosis, or uremic symptoms.4

Prevention and Risk-Minimizing Measures

In patients at risk, minimizing the risk of AKI may be achieved through the following measures4:

• Maintaining normal fluid balance

• Avoiding nephrotoxins (including contrast    agents) when possible, and

• Taking precautions such as giving fluids or drugs when contrast or cytolytic therapy is necessary.

Severe AKI in Critically Ill PatientS

It is important to underscore that AKI is a potentially life-threatening syndrome that occurs primarily in hospitalized patients; frequently it complicates the course of those patients who are critically ill.8 The complex nature of critical illness often requires the use of multiple drugs, many of which may individually, or in combination, have the potential to cause renal injury.11 In up to 25% of all cases of severe AKI in critically ill patients, the use of nephrotoxic drugs has been implicated as a causative factor.11 While acute tubular necrosis is the most common form of kidney injury from nephrotoxin exposure, other types of renal failure may be seen. In light of the preventable nature of this potentially devastating drug reaction, a comprehensive strategy should be used to avoid nephrotoxicity in critically ill patients (see Reference 11), including the avoidance of nephrotoxins, if possible, and immediate discontinuation of suspected nephrotoxins in the event of renal dysfunction.11


Pharmacists can contribute by raising awareness and reminding all prescribers—through education and recommendation opportunities—that the combination of ACE inhibitors or ARBs, diuretics, and NSAIDs (including COX-2 inhibitors) should be avoided if possible, and great care should be taken with ACE inhibitors and NSAIDS in patients with renal impairment. Pharmacists can assist these healthcare providers by underscoring drug dosing considerations and developing strategies, as appropriate, to minimize the occurrence of drug-induced and radio-contrast–induced AKI.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.



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