Aminoglycosides

Aminoglycosides, such as tobramycin, gentamicin, and amikacin, are other common causes of AKI, reported in 10%–25% of patients.^7,50 Aminoglycosides reach the kidney unmetabolized and at high plasma concentrations.⁵¹ They are taken up into proximal tubular cells with subsequent drug accumulation in lysosomes, Golgi bodies, and the endoplasmic reticulum. At a certain threshold, aminoglycosides are released into the cytoplasm and injure the mitochondria by inducing apoptosis.⁵⁰ Some studies suggest that alternative biomarkers other than SCr, such as cystatin C, clusterin, kidney injury molecule‑1, and neutrophil gelatinase‑associated lipocalin, may assist in earlier diagnosis of aminoglycoside toxicity.⁵² Due to proximal tubular dysfunction, there can be electrolyte abnormalities, such as hypokalemia, that resemble Fanconi‑like syndrome.^53,54

Generally, drug cessation is associated with kidney recovery, although their use for over 5 days has been associated with a lower chance of renal recovery.^51,55 Possible benefits of a single daily dose of aminoglycosides have been investigated^50,56,57 (Table 2).

Fluoroquinolones

Fluoroquinolones, such as ciprofloxacin and levofloxacin, are rarely associated with AKI. However, AIN and ATI may occur in the setting of high doses and / or prolonged therapy. The mechanism of ATI, albeit unclear, could be related to cellular toxicity.^54,58 There is limited evidence for preventive strategies, and management generally consists of drug discontinuation. For AIN, the use of steroids may be beneficial if initiation begins early after the onset of AKI.^58,59

Ciprofloxacin can also cause crystalline nephropathy in rare instances (approximately in 2 per 63 000 patients).²⁹ Alkaline urine (pH >7.3) and high‑dose exposure increases the risk of crystallization.²⁹ Urine sediment should be examined to determine if a crystal‑induced etiology is possible. For prevention and management, alkaline urine should be avoided, patients should be volume repleted as needed to maintain euvolemia, and the dose should be adjusted for renal function.^29,54 (Table 2).

Trimethoprim‑sulfamethoxazole

Trimethoprim (TMP) competitively saturates hOAT2, leading to a decrease in creatinine secretion, and a 10%–28% increase in SCr.^54,60 It is one of the common causes of pseudo‑AKI. However, TMP / sulfamethoxazole (SMX) can cause a true AKI as well.⁶¹ Primarily, it evokes AIN, which is generally associated with allergic symptoms, suspected to be related to the sulfa‑containing component of the medication.⁵⁴ TMP/SMX can also precipitate crystalline nephropathy.⁵⁴ This is attributed to low urine solubility, especially in acidic urine (pH <⁠5.5).⁵⁴ Although TMP/SMX can cause crystalluria, it rarely causes nephrolithiasis.^28,54 Urine sediment can contain sulfa crystals, which are commonly described as shocks of wheat and are birefringent on polarization.²⁹ Prevention includes adequate hydration and urine flow, as well as urine alkalinization to pH above 7.1²⁹ (Table 2).

Vancomycin

Although the exact pathophysiology of AKI remains unclear, it is postulated that vancomycin causes ATI through oxidative stress and formation of obstructive tubular casts.⁶² At high concentrations, the medication can interact with uromodulin forming vancomycin casts.²⁸ Traditionally, vancomycin dosing has relied on measuring serum trough levels with a target of 15–20 mg/l as a surrogate for area under the curve (AUC).⁶³ As such, there is concern for vancomycin‑associated AKI when target troughs are supratherapeutic.⁶⁴ More recently, Bayesian dose optimization software has been utilized to calculate AUC to more appropriately guide pharmacokinetic properties and reduce the risk of toxicity.⁶³ Some evidence suggests that the combined cystatin C / creatinine eGFR calculation is more appropriate for predicting vancomycin pharmacokinetic parameters.^65,66 Not all AKI events that occur in patients on vancomycin are due to vancomycin nephrotoxicity, and not all patients with supratherapeutic levels of vancomycin have vancomycin‑induced AKI. Such patients typically have multiple potential causes of AKI that overlap, which complicates a diagnosis. Methods to reduce toxicity include close monitoring of drug troughs to avoid supratherapeutic levels and cautious use of other nephrotoxins that may exacerbate AKI⁵⁴ (Table 2).

Colistin / polymyxin B

Both colistin and polymyxin B have seen increased utilization against multidrug‑resistant organisms. Unfortunately, they remain highly nephrotoxic, especially in the supratherapeutic range. Colistin appears to cause ATI after 5–7 days.⁵⁴ Its toxicity is related to D‑amino and fatty‑acid components, which allow for cellular membrane permeability and cation influx leading to cell destruction.¹¹ This can result in direct tubular injury.¹¹ Strategies for prevention of AKI include limiting both colistin dose and duration, specifically, attempting to limit dosing to below 5 mg/kg and avoiding concomitant nephrotoxins such as vancomycin⁵⁴ (Table 2).

β-Lactam agents

This group includes a wide array of antibiotics, such as penicillin, cephalosporins, carbapenems, and monobactams. These agents disrupt the formation of cell‑wall peptidoglycan by binding to penicillin‑binding proteins.⁶⁷ AIN, particularly in patients on nafcillin, methicillin, and first‑generation cephalosporins, is the most common mechanism of AKI. Prevention of AKI includes avoiding agents with higher propensity to cause AIN (such as nafcillin / amoxicillin) and limiting the therapy duration.⁵⁴ In addition to AIN, amoxicillin can also cause crystalline nephropathy. Its high dose, acidic urine, and low urinary flow are major risk factors.²⁹ Prevention is focused on appropriate drug dosing, ensuring euvolemia, and considering urine alkalinization if its pH is below 6.²⁹ Management includes drug discontinuation and volume repletion.²⁹

Despite a described association between an increase in SCr and a combination therapy with vancomycin and piperacillin‑tazobactam, some evidence suggests this may not be true.^62,68 A recent randomized controlled study showed that treatment with piperacillin‑tazobactam did not increase the incidence of AKI when compared with cefepime⁶⁹ (Table 2).

Acyclovir

Acyclovir is commonly associated with crystal development, particularly at rapid intravenous infusions and / or high doses. Oral therapy rarely produces crystal precipitation, unless other risk factors are present, such as volume depletion or a dose inappropriate for renal function.⁷⁰ Crystals are often present within the tubular lumen and can be identified on urinary sediment evaluation or kidney biopsy.²⁸ Preventive strategies include adequate hydration and slow infusion rates. Regarding treatment, hemodialysis is an effective method for acyclovir removal, but generally it is only employed when neurotoxicity is also present^28,29 (Table 2).

Tenofovir / cidofovir

Tenofovir and cidofovir are acyclic nucleoside analog reverse‑transcriptase inhibitors with activity against viral reverse transcription.⁷¹ Tenofovir is transported across the basolateral membrane of proximal tubular cells by hOAT1 and subsequently interferes with the mitochondrial DNA polymerase, which ultimately results in apoptosis.⁷¹ Tenofovir shows dose‑dependent nephrotoxicity; however, tenofovir alafenamide is less toxic than tenofovir disoproxil fumarate due to its conversion to an active drug in lymphocytes, resulting in lower plasma levels.⁷ As a prelude to AKI, there is often evidence of proximal tubular dysfunction resulting in Fanconi syndrome. There have been some reports of using probenecid, an inhibitor of hOAT1 and hOAT3, to reduce the risk of nephrotoxicity.⁷² SCr, electrolyte, and phosphorus levels and urinalysis (for glycosuria) should be monitored in tenofovir users every 4 weeks during their first year of treatment, and then every 3 months.⁵³ Treatment of AKI is largely based on discontinuation, and recovery of kidney function is seen in about 50% of cases.⁷¹

Cidofovir shows significant renal adverse effects, leading to dose reduction in 20%–30% of patients.⁷³ Cidofovir is eliminated by the kidney in a fashion similar to tenofovir.⁷³ Monitoring and prevention of AKI are similar to tenofovir, with some evidence to suggest at least partial renal recovery with drug cessation⁷³ (Table 2).

Foscarnet

Foscarnet, a pyrophosphate analog, has been used for treatment of cytomegalovirus and herpes virus, although in modern practice it is now used as salvage therapy.^74,75 The pattern of injury is ATI, suspected to be due to direct tubular toxicity.⁷⁴ However, sodium and / or calcium salt crystals in patients on foscarnet can form in the early segments of the nephron resulting in AKI. Foscarnet also inhibits membrane‑associated carbonic anhydrase, which may contribute to nephrotoxicity.⁷⁵ Preventive strategies should focus on hydration and limiting the ability for crystal development. Fortunately, foscarnet nephrotoxicity is almost always reversible on drug discontinuation⁷⁵ (Table 2).

Amphotericin B

Amphotericin B has a unique structure that contains both a hydrophilic and a lipophilic region, which allows it to be incorporated into the cell membrane. Nephrotoxicity occurs via reduced glomerular blood flow from vasoconstriction and from damage caused by pore formation in tubular cell membranes.⁷⁶ The nephrotoxic properties correlate with dose and duration of the treatment.⁷⁷ There have been 3 lipid‑associated formulations which have been intended to reduce available plasma concentrations and limit renal accumulation and nephrotoxicity; namely, liposomal amphotericin B, amphotericin B colloidal dispersion, and amphotericin B lipid complex.⁷⁸ Each lipid formulation has a distinct pharmacokinetic profile but they do not show significant differences in clinical efficacy. Despite an improved safety profile, a risk for lipid formulation–associated AKI is around 9%–25%.⁷⁹ In addition, tubular damage can contribute to development of renal tubular acidosis, Fanconi syndrome, and loss of urinary concentrating ability.⁷⁷

Preventive strategies include volume expansion with 0.9% saline or other isotonic solutions and supplementing potassium and magnesium in addition to using the aforementioned lipid formulations to limit nephrotoxicity^77,80 (Table 2).

Platinum‑based chemotherapy

Cisplatin is one of the most widely used platinum‑based antineoplastic agents.⁸⁴ Its structure contains a square‑planar platinum complex with 2 chloride ligands. The chloride ligands of cisplatin are dissociated upon cell entrance. The drug disrupts DNA strands by interacting with purine bases and increasing the level of reactive oxygen species, which leads to cellular dysfunction and apoptosis.⁸⁴ It is one of the most nephrotoxic antineoplastic agents. Cisplatin enters the tubular cells by passive diffusion or through active transport via the hOAT2.⁸⁴ Commonly, cisplatin affects the proximal tubule, particularly the S3 segment, which shows the highest concentrations of cisplatin (approximately 5 times greater than that in the blood), and can explain significant magnesium wasting that is associated with cisplatin toxicity.⁸⁴ Other kidney adverse events include nephrogenic diabetes insipidus, Fanconi syndrome, distal renal tubular acidosis, and TMA.^84-86 Historically, AKI rate with cisplatin treatment was high, approaching 50%–75% of patients receiving the drug for over 5 consecutive days.⁸⁷ Routine use of prehydration has reduced AKI rates to approximately 20%–30%.⁸⁵ General advice for limiting nephrotoxicity includes adequate hydration, supplementation of magnesium, and consideration of mannitol for forced diuresis, although the use of mannitol has shown conflicting results^87,88 (Table 2).

Ifosfamide

Ifosfamide is an alkylating agent used to treat various neoplasms, such as testicular tumors, sarcomas, and lymphomas.⁸⁹ AKI prevalence in its users ranges from 15% to 60%.⁸⁹ The mechanism of action is due to ATI that can either present as AKI or more insidiously as CKD. Proximal tubular dysfunction and Fanconi syndrome can be present and are related to mitochondrial dysfunction.⁸⁹ Unfortunately, there are no specific therapies to prevent or treat nephrotoxicity from ifosfamide, but general advice is close monitoring of renal function and discontinuation if toxicity occurs⁸⁵ (Table 2).

Methotrexate

Methotrexate is a folate derivative that inhibits the enzyme that produces tetrahydrofolate, an important substrate for synthesis of thymidine, and halts production of DNA and RNA.⁸⁵ It can cause AKI via crystalline nephropathy with an incidence ranging from 2% to 12%.²⁹ Methotrexate is poorly soluble and prone to precipitate into crystals in the setting of acidic urine and reduced urinary flow, especially in large intravenous doses.²⁸ Excretion is mainly executed through hOAT3 and hOAT4.²⁸ Commonly, crystals and crystal‑containing casts are detectable in the urinary sediment. Prevention includes adequate hydration and alkalinizing urine to keep its pH above 7, and fortunately AKI is mostly reversible.²⁹ Leucovorin can be used as an intracellular salvage metabolic therapy but not for crystal formation.⁸⁵ For treatment, glucarpidase, that is, a carboxypeptidase that metabolizes methotrexate to nontoxic metabolites, can be utilized in the setting of AKI.²⁹ In rare cases, high‑flux hemodialysis can be used to clear methotrexate⁸⁶ (Table 2).

Immune checkpoint inhibitors

ICIs, such as nivolumab, ipilimumab, and pembrolizumab have emerged as important immunotherapy in many cancers.⁹⁰ The function of T‑cells is regulated by immune checkpoints, which are blocked by ICIs. This leads to upregulation of T‑cell function of cancer recognition and destruction.⁹⁰ Overall, the risk of immune‑related adverse events (irAEs) is around 54%–76%, ranging in severity from mild to life‑threatening. Severe irAEs occur in 0.5%–13% of patients. They can commonly manifest as AKI, which is estimated to have an incidence of 7%–24% in patients receiving ICIs.⁹⁰ Median time to onset is 12–16 [interquartile range, 6–37] weeks after therapy initiation.⁹¹ Risk factors for ICI‑associated AKI include concomitant use of PPIs or other ICIs, and baseline CKD.⁹²

ICIs induce AKI through unregulated activation of T‑cells and other inflammatory cells (such as macrophages and neutrophils) with direct kidney infiltration or production of autoantibodies through B‑cell activation. It is hypothesized that kidney tissue may lose tolerance to self‑antigen, leading to immune activation. Another mechanism suggests that reactivation of drug specific T‑cells, which have targeted other agents known to cause AIN (such as PPIs), may play a role in ICI‑induced AKI. AIN is the most common pathology in ICI‑induced nephritis and can account for up to 70%–90% of all biopsied cases.⁹³ However, other kidney pathologies, such as ATI, glomerulonephritis, and TMA may occur.⁹³ Electrolyte abnormalities, such as hyponatremia, hypercalcemia, hypokalemia, and renal tubular acidosis have been reported with ICI use.^94,95 Urinalysis may show pyuria in 57.8% of cases, hematuria in 39.7%, and a urine protein:creatinine ratio above 0.3 g/g in 61.7% of patients.⁹⁶ Some biomarkers, such as C‑reactive protein and urine retinol–binding protein / urine creatinine levels may be used to evaluate clinical presentations.⁹⁷ The utility of kidney biopsy remains controversial. Some experts suggest early biopsy, but others suggest the procedure only when patients do not respond to steroid therapy.^98,99

Evaluation and prevention of AKI includes close monitoring of renal function, and limiting additional agents that can contribute to AIN, such as PPIs, NSAIDs, and antibiotics (Table 2). Drug discontinuation and corticosteroid therapy is the mainstay of treatment. Infliximab use has been reported in refractory cases.⁹⁰ Rechallenging with ICIs can be considered when renal function has recovered, with the rate of recurrence being 15%–20%.⁹⁰