Crystalline-induced acute kidney injury

INTRODUCTION — 

Crystalline-induced acute kidney injury (AKI) is caused by the intratubular precipitation of crystals, which results in obstruction. Crystalline-induced AKI most commonly occurs as a result of acute uric acid nephropathy and following the administration of drugs or toxins that are poorly soluble or have metabolites that are poorly soluble in urine [1,2]. Other drugs or medications may be metabolized to insoluble products such as oxalate (ethylene glycol, vitamin C), which are associated with precipitation of calcium oxalate crystals within tubular lumens and kidney injury.

This topic review discusses drug-related crystalline-induced AKI. Uric acid nephropathy and acute phosphate nephropathy are discussed elsewhere. (See "Uric acid kidney diseases" and "Acute phosphate nephropathy".)

ETIOLOGY — 

Multiple drugs and toxins cause intratubular crystal-induced obstruction and tubulointerstitial injury. Common agents are discussed below.

Acyclovir — Acyclovir is rapidly excreted in the urine (being both filtered and secreted) and has a relatively low solubility [3]. Thus, bolus intravenous (IV) therapy, especially if the patient is volume depleted, may lead to the deposition of acyclovir crystals in the tubules, resulting in intratubular obstruction and foci of interstitial inflammation [3,4].

●Prevention – To prevent AKI in patients receiving IV acyclovir, we administer IV fluid (see 'Prevention' below). Oral acyclovir therapy is usually well tolerated, presumably due to a less rapid rate of acyclovir excretion. However, AKI rarely can develop with oral acyclovir in patients with underlying kidney disease (and excessive dosing) and severe volume depletion [5,6].

●Clinical course and features – Kidney function in affected patients typically begins to deteriorate within 24 to 48 hours after therapy with acyclovir is initiated [1,7]. Patients may complain of nausea and flank or abdominal pain at this time, presumably induced by the urinary tract obstruction [3]. In some cases, birefringent, needle-shaped acyclovir crystals, occasionally engulfed by white cells, can be seen in the urine, particularly under polarized light (image 1).

The decline in kidney function is usually mild but occasionally may be severe, with marked increases in the plasma creatinine concentration in some cases [8,9]. However, complete recovery typically occurs within four to nine days after acyclovir is discontinued.

●Related agents – Ganciclovir, another antiviral agent that is structurally related to acyclovir and is also excreted in the urine, appears to be associated with a much lower risk of crystalline-induced acute kidney injury (AKI) compared with acyclovir [3,10,11]. In addition, oral valacyclovir may rarely precipitate AKI and crystalluria if an overdose is taken, or when given to patients with other risk factors for AKI (eg, chronic kidney disease (CKD), hypovolemia, nonsteroidal antiinflammatory drug use) [12,13].

Sulfonamide antibiotics — Some sulfonamide antibiotics are relatively insoluble in acid urine, particularly sulfadiazine and sulfamethoxazole, which are used in high doses to treat toxoplasmosis and Pneumocystis jirovecii infection in immunocompromised patients [3,14-16]. Intrarenal sulfadiazine precipitation may result in AKI and nephrolithiasis [16].

●Prevention and treatment – To prevent AKI in selected high-risk patients who are treated with high-dose IV sulfonamide antibiotics, and to treat selected patients with sulfonamide-associated AKI, we administer IV sodium bicarbonate (see 'Prevention' below and 'Treatment' below). Alkalinization of the urine to a pH >7.15 increases sulfadiazine solubility more than 20-fold [3,14].

●Epidemiology and risk factors – Up to 29 percent of patients treated with sulfadiazine are at risk to develop AKI [1,14-17] because this drug is highly insoluble in urine with a pH of ≤5.5 [17]. The risk of crystal precipitation increases with doses of sulfadiazine of 4 to 6 g/day and of sulfamethoxazole of 50 to 100 mg/kg/day [14-17]. Additional AKI risk factors include underlying kidney dysfunction, hypovolemia, hypoalbuminemia, and acidic urine [18].

●Clinical course and features – AKI usually resolves when the sulfonamide is discontinued. Sulfonamide crystals can assume many shapes, in part dependent upon the specific sulfonamide present. The most common morphology includes needle-shaped crystals, rosettes, and those resembling shocks or sheaves of wheat (picture 1). Sulfadiazine sludge or small calculi in the calyces can also be detected in some cases as bilateral, layered clusters of echogenic material on kidney ultrasonography [3,17].

Methotrexate — Approximately 90 percent of administered methotrexate is normally excreted unchanged in the urine. High-dose IV methotrexate can both precipitate in the tubules and cause direct tubular injury [19-21].

●Prevention and treatment – Our approach to the prevention of methotrexate toxicity is detailed elsewhere (see "Therapeutic use and toxicity of high-dose methotrexate", section on 'Practical tips for managing high-dose methotrexate'). To treat selected patients with methotrexate-associated AKI, we administer IV sodium bicarbonate. (See 'Treatment' below.)

●Epidemiology and risk factors – The incidence of methotrexate-induced AKI in the era of routine intravascular volume administration and urinary alkalinization was 1.8 percent in an analysis of data from clinical trials in osteosarcoma [22]. However, the incidence of AKI may be 10 percent or higher in patients with risk factors for AKI, such as CKD [23,24].

The risk of methotrexate-induced nephrotoxicity is increased with an acidic urine (since methotrexate is poorly soluble in an acidic urine) and with volume depletion (which decreases urine flow rate and increases the concentration of methotrexate in tubular fluid). In addition, the risk of methotrexate nephrotoxicity is higher when there is sustained elevation in the plasma methotrexate concentration [25]. Mutations in the renal proximal tubular efflux transporter MRP-2 elevate intracellular methotrexate concentrations and may increase nephrotoxicity [26].

●Clinical course and features – Methotrexate-induced AKI is often nonoliguric and usually reversible [21,25]. Methotrexate crystals may be evident on urine microscopy (image 2). The plasma creatinine concentration usually peaks within the first week and returns well toward baseline levels within one to three weeks [21].

Protease inhibitors

●Atazanavir – Atazanavir, a protease inhibitor used in the treatment of human immunodeficiency virus (HIV) infection, can lead to stone formation and, less commonly, AKI due to its relative insolubility in the urine [27-29]. The mechanism by which atazanavir causes both nephrolithiasis and AKI is by the precipitation of atazanavir crystals.

•Prevention – We encourage fluid intake among patients taking atazanavir (see 'Prevention' below). Atazanavir is much more soluble at lower pH values, especially pH <3 [30]. However, although acidification of urine may increase the solubility of atazanavir, this is difficult to achieve and potentially harmful. Thus, acidification of urine is not recommended.

•Clinical features – An initial case series described 11 patients who developed nephrolithiasis while taking atazanavir [28]. Analysis of the stones demonstrated crystals of atazanavir base, but not metabolites. Eight stones contained a core of atazanavir, while four had a core of calcium oxalate (one patient had two stones). Subsequently, several case reports and 30 cases of atazanavir-associated nephrolithiasis were reported upon review of the US Food and Drug Administration Adverse Event Reporting System database [31,32]. One study estimated a prevalence of atazanavir stones of 0.97 percent among those taking the drug [28].

One case of AKI due to atazanavir-associated crystal nephropathy has been reported [30]. In this case, rod-like atazanavir crystals were noted on urine microscopy (picture 2), as well as within tubular lumens and kidney interstitium (along with granulomata) on kidney biopsy (picture 3).

●Other protease inhibitors – Darunavir has been associated with crystalluria and crystalline-associated AKI [33], while nelfinavir and saquinavir have been associated with crystalluria and urolithiasis [34].

Oxalate — Drugs or medications may be metabolized to oxalate (eg, ethylene glycol, vitamin C) or increase the intestinal absorption of dietary oxalate (eg, orlistat); calcium oxalate crystals may subsequently precipitate within the tubular lumen and cause kidney injury.

●Causes – AKI due to oxalate deposition in the kidney has been described in several settings:

•Primary hyperoxaluria (see "Primary hyperoxaluria")

•Ethylene glycol poisoning (see "Methanol and ethylene glycol poisoning: Pharmacology, clinical manifestations, and diagnosis")

•Secondary hyperoxaluria due to enteric disease (eg, pancreatic insufficiency, inflammatory bowel disease, bowel resection, or gastric bypass) (see "Chronic complications of the short bowel syndrome in adults")

•High doses of vitamin C [35,36]

•Exposure to topical hair-straightening products containing glycolic and glyoxylic acid derivatives [37-40]

•Therapy with the weight loss drug orlistat [41-43] (see "Nephrocalcinosis", section on 'Clinical features')

•Contamination of pediatric cough syrup with ethylene glycol and diethylene glycol [44]

●Risk factors and clinical course – Many patients with oxalate-mediated AKI have preexisting CKD as a risk factor and/or multiple precipitants (eg, volume depletion and enteric hyperoxaluria) [45,46]. A kidney biopsy case series of 31 patients with oxalate nephropathy (mean serum creatinine of 7.6 mg/dL at presentation) reported the following characteristic risk factors and outcomes [47]:

•Twenty-four patients (77 percent) had preexisting CKD. The mean baseline serum creatinine in the study was 1.8 mg/dL (estimated glomerular filtration rate [eGFR] 48 mL/min/1.73 m²).

•Eleven patients (36 percent) had an unclear etiology for oxalate nephropathy. Of the 20 remaining patients, the etiology was determined to be multifactorial in 10. Enteric hyperoxaluria was present in 17 patients, and high oxalate intake (from food, tea, or from oxalate precursors such as vitamin C) was identified in 16. Only one patient had primary hyperoxaluria.

•Of 26 patients with available follow-up data, 21 patients (81 percent) required dialysis, only one of whom recovered kidney function, and five (19 percent) died within one year.

Oral sodium phosphate purgatives — Oral sodium phosphate preparations have been used as laxatives or purgatives for bowel cleansing before colonoscopy, CT virtual colonoscopy, or bowel surgery. AKI secondary to acute phosphate nephropathy has been reported following the use of oral sodium phosphate preparations. Acute phosphate nephropathy is discussed elsewhere. (See "Acute phosphate nephropathy".)

Ciprofloxacin — The widely used fluoroquinolone antibiotic, ciprofloxacin, is known to cause AKI from acute interstitial nephritis [48-50]. Ciprofloxacin has also been reported to cause crystalluria in experimental animals [51] and both crystalluria [52-54] and crystalline-induced AKI [55-59] in humans.

●Prevention – Among other measures, ciprofloxacin dose adjustment for impaired kidney function is important to prevent crystalline-induced AKI. (See 'Prevention' below.)

●Risk factors – Risk factors for crystalline-induced AKI include impaired kidney function, volume depletion, and a urine pH >6 (although acidic urine pH does not preclude a diagnosis of ciprofloxacin-induced crystal deposition).

●Clinical course and features – In case reports, patients developed oliguric AKI within two days to two weeks of ingestion of oral ciprofloxacin [59]. Kidney function returned to baseline upon withdrawal of ciprofloxacin. Urinalysis revealed crystals of varying shapes, which were composed of ciprofloxacin salt (picture 4).

Ciprofloxacin crystals typically precipitate in an alkaline pH [52,60]. However, crystals have been described in association with acidic urine pH in several case reports [55,58]. Ciprofloxacin crystals have been shown to display a wide array of appearances, including needles, sheaves, stars, fans, butterflies, and other unusual shapes. All crystals have had a lamellar structure, with sizes ranging from 30 x 5 microm to 360 x 237 microm, and are strongly birefringent under polarizing light [61].

Histology obtained by kidney biopsy in three patients revealed needle-shaped birefringent crystals within the tubules (picture 5) without evidence of acute or chronic interstitial nephritis [58,59].

Other agents — Other agents that have been described in case reports to cause crystalline-induced acute kidney injury include triamterene, foscarnet, and high-dose amoxicillin [1,62,63].

RISK FACTORS AND PATHOGENESIS

●Risk factors – Risk factors for crystalline-induced kidney injury include the following:

•Low urine output, which increases the concentration of crystal-forming drugs in the urine. A decreased urine volume is typically due to intravascular volume depletion or to reduced effective arterial blood volume (as seen in patients with congestive heart failure or advanced liver disease).

•Underlying kidney disease.

•Metabolic perturbations that change urinary pH [1,2,7]. The effect of urine pH on crystal formation varies depending upon the specific causative agents. As an example, whereas sulfonamides tend to form crystals in acidic urine, protease inhibitors such as atazanavir form crystals in alkaline urine.

Excessive drug dosing for a given glomerular filtration rate (GFR) also may contribute to the risk of kidney injury [1].

●Pathogenesis – The kidney dysfunction in patients with crystalline-induced AKI is due to two main factors [64]:

•The intratubular precipitation of crystals, which results in obstruction.

•Crystal-induced inflammation and cell necrosis, which cause and perpetuate tubulointerstitial kidney injury. Crystal uptake into tubular cell lysosomes triggers cathepsin-B-mediated cell death and leads to crystal deposition in the renal interstitium. Dendritic cells and macrophages phagocytose interstitial crystals and subsequently activate a broad range of inflammatory pathways via NLRP3 inflammasome formation and the secretion of IL-1 beta and other pro-inflammatory cytokines.

CLINICAL PRESENTATION — 

Patients with drug-related crystalline-induced acute kidney injury (AKI) are usually asymptomatic, and kidney injury is detected by an increased serum creatinine [4]. The time interval between administration of the causative agent and the increase in serum creatinine varies but is often as short as 24 to 48 hours. Occasionally, patients present within one to seven days after initiation of the offending drug with renal colic symptoms such as flank or abdominal pain, nausea, or vomiting. Urine output is variable; crystalline-induced AKI is usually oliguric but ranges from oligoanuric to non-oliguric.

Urinalysis often reveals hematuria, pyuria, and crystalluria [1,3]. Significant proteinuria (ie, >500 mg/day) is not commonly observed, unless the patient has underlying proteinuric kidney disease and subsequently develops crystalline-induced AKI.

DIAGNOSIS

●When to suspect crystal-induced AKI – Crystalline-induced acute kidney injury (AKI) should be suspected in any patient who develops AKI shortly after exposure to a causative agent, especially if no other cause of AKI is readily apparent. The diagnosis is suggested by the appearance of crystals in the urine, the morphology of which depends upon the specific causative drug (see 'Etiology' above). However, crystalluria may also be observed in patients who have no evidence of AKI [3].

●Diagnostic evaluation – Patients with suspected crystalline-induced AKI should be thoroughly evaluated for other causes of AKI, as detailed elsewhere. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting" and "Evaluation of acute kidney injury among hospitalized adult patients".)

●Making the diagnosis – Definitive diagnosis is obtained by examination of histology obtained by kidney biopsy. However, we diagnose crystalline-induced AKI without a kidney biopsy in patients with AKI who meet all the following criteria:

•A clear temporal relationship exists between starting a drug known to cause crystalline-induced AKI and the development of AKI.

•Alternative causes of AKI have been excluded (see "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting" and "Evaluation of acute kidney injury among hospitalized adult patients"). This criterion includes the absence of atypical features (such as significant proteinuria in a patient who does not have underlying proteinuric kidney disease) and the absence of ultrasonographic findings indicative of urinary obstruction.

•Crystal-containing casts are present in the urine sediment. Such casts are generally reflective of crystalline-mediated kidney injury. Although the presence of free urinary crystals (ie, not within casts) may suggest crystalline-induced AKI, we do not include free urinary crystals as a diagnostic criterion because they often occur in the absence of AKI.

Failure of AKI to improve after cessation of the implicated drug suggests that another cause of AKI is present. Crystalline-induced AKI is generally reversed following discontinuation of the causative drug, although temporary dialysis may be necessary in some cases, and chronic kidney disease (CKD) may be a long-term consequence of crystalline-induced AKI [7].

●Differential diagnosis – The differential diagnosis for crystalline-induced AKI is AKI from any cause and, among patients who present with hematuria and even modest proteinuria, glomerulonephritis. The diagnostic approaches to these disorders are discussed elsewhere. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting" and "Glomerular disease: Evaluation and differential diagnosis in adults".)

TREATMENT — 

Therapy of established crystalline-induced acute kidney injury (AKI) primarily consists of supportive measures (see "Overview of the management of acute kidney injury (AKI) in adults") and volume repletion. In selected patients, we also administer loop diuretics and intravenous (IV) sodium bicarbonate.

Optimize volume status — The correction of volume depletion and the maintenance of optimal volume status is critical in the treatment of established AKI. Among all patients with established crystal-induced AKI from any cause, we correct volume depletion with IV fluid. In the absence of an indication for IV bicarbonate, such as for the treatment of sulfonamide- or methotrexate-induced AKI (see 'Bicarbonate for selected agents' below), the preferred IV fluid is usually isotonic saline.

Loop diuretics — Among all volume-replete patients with established crystalline-induced AKI from any cause, we suggest administration of a loop diuretic. Fluid loss induced by the diuretic must be replaced to prevent volume depletion and a late slowing of flow within the tubules. The use of loop diuretics may be effective in clearing obstructing casts in crystal-induced AKI.

The use of loop diuretics is of theoretical benefit only; no high-quality data have demonstrated efficacy in this setting.

Bicarbonate for selected agents — In addition to volume repletion and loop diuretics, administering bicarbonate to raise urine pH may be of benefit among patients with crystalline-induced AKI due to sulfonamide antibiotics and methotrexate. We do not use bicarbonate to treat crystalline-induced AKI from other causes. Our approach is detailed below:

●Sulfonamide antibiotics and methotrexate – Among patients with sulfonamide-associated or methotrexate-associated AKI, we generally administer IV bicarbonate to raise urine pH provided that the following conditions are met:

•No indications for acute hemodialysis (see "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose")

•Oliguria is not present

•Hypocalcemia is not present

•Arterial pH is less than 7.5

•Serum bicarbonate is less than 30 mEq/L

Urinary alkalinization is often difficult in patients with established AKI. IV sodium bicarbonate represents a volume load, and potential risks to alkalinization of the plasma include calcium phosphate deposition (which is more likely if hyperphosphatemia is present) and inducing or worsening the manifestations of hypocalcemia by both a direct membrane effect and a reduction in ionized calcium levels [65]. Manifestations of severe hypocalcemia include tetany, seizures, and cardiac arrhythmias. (See "Clinical manifestations of hypocalcemia".)

A forced alkaline diuresis may provide benefit by increasing the solubility of sulfadiazine and methotrexate. However, there are no high-quality data demonstrating that bicarbonate administration in this setting lessens the duration or severity of AKI.

●Administration of bicarbonate – Among patients selected for bicarbonate infusion (see above), we generally administer a solution (mixed by the pharmacy) containing 140 mEq of sodium bicarbonate per liter of sterile water at a rate of 125 mL/hour along with a loop diuretic such as furosemide. The rate of infusion is adjusted to achieve the following targets:

•Urine pH >7.15 for sulfonamide antibiotics

•Urine pH >7 for methotrexate

●Monitoring – If bicarbonate is given, the arterial pH and serum calcium should be monitored approximately every eight hours during the infusion. The bicarbonate infusion should be discontinued if the urine pH does not rise to target after 12 hours, or if the patient develops volume overload, an indication for acute hemodialysis, symptomatic hypocalcemia, arterial pH >7.5, or if the serum bicarbonate exceeds 30 mEq/L.

Additional therapy for methotrexate — Methotrexate-induced AKI often results in an elevated plasma methotrexate concentration, which may increase the systemic toxicity of methotrexate. In addition to treatment with IV sodium bicarbonate in selected patients (see 'Bicarbonate for selected agents' above), leucovorin rescue, with or without glucarpidase, may be effective in this setting. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Practical tips for managing high-dose methotrexate'.)

In patients with methotrexate-induced AKI, the use of glucarpidase therapy is associated with higher odds of, and faster time to, kidney recovery [66].

Limited role for extracorporeal therapy — Drug removal with extracorporeal therapies (eg, hemodialysis) has not been shown to reverse or limit the duration of crystalline-induced AKI from any cause. However, in patients with crystalline-induced AKI, extracorporeal therapy may be required to correct the metabolic sequelae of AKI. (See "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose".)

Salient points about the role of extracorporeal therapy in crystalline-induced AKI secondary to acyclovir or methotrexate are presented below:

●Acyclovir – Hemodialysis is not used to treat acyclovir-associated AKI. However, neurotoxicity may develop in patients who develop severe acyclovir-induced AKI [6,67,68], and, in this setting, hemodialysis may be indicated in order to remove the drug [8].

●Methotrexate – Although the clearance of methotrexate may be improved with daily high-flux hemodialysis or with albumin-based continuous venovenous hemodialysis (CVVHD) [69,70], we generally do not use extracorporeal therapies to remove methotrexate among patients with AKI for the following reasons [71]:

•Extracorporeal treatments do not appear to improve clinical outcomes [71]. This lack of benefit is likely due to methotrexate’s large extravascular volume of distribution and the slow efflux of accumulated methotrexate from intracellular stores [72,73].

•Extracorporeal treatments remove leucovorin, which is used to treat methotrexate toxicity. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Practical tips for managing high-dose methotrexate'.)

•Rapid reductions in blood methotrexate levels are rarely required; however, in such cases glucarpidase therapy is more effective than any extracorporeal modality [71]. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Glucarpidase (carboxypeptidase G2)'.)

PREVENTION

General measures — The correction of volume depletion and maintenance of optimal volume status is critical in the prevention of crystalline-induced acute kidney injury (AKI).

Additional measures for specific agents — Evidence supporting the preventive measures below is derived from physiologic data and clinical experience.

●Acyclovir – For patients receiving intravenous (IV) acyclovir, we generally administer IV isotonic saline at a rate of 125 mL/hour, starting at least one hour prior to the administration of acyclovir and continuing for six hours after the acyclovir infusion is finished. Most cases of acyclovir nephrotoxicity likely can be prevented by maintaining urine output above 75 mL/hour and slow IV drug infusion over one to two hours.

Patients with a history of acyclovir-mediated AKI can usually be safely rechallenged (if necessary) by limiting the acyclovir dose to ≤250 mg/m² [3].

●Sulfonamide antibiotics – Patients with preexisting kidney disease who are receiving high-dose IV sulfonamide antibiotics should be monitored with serial urinalyses. For such patients who have urine pH <6 or develop crystalluria, we administer an IV bicarbonate solution to prevent AKI. We generally give approximately 3 L/day (ie, infusion rate of 125 mL/hour) of IV sodium bicarbonate, the composition of which depends on intravascular volume status and serum sodium concentration:

•For patients who are euvolemic and have a normal serum sodium concentration, we give a solution containing 75 mEq sodium bicarbonate per liter of sterile water.

•For patients who are hypovolemic or hyponatremic, we give an isotonic solution (containing 75 mEq sodium bicarbonate per liter of one-half isotonic saline).

Patients who are receiving prophylactic IV bicarbonate should be closely monitored by physical exam for volume overload and by daily measurement of serum creatinine and electrolytes for development of AKI, alkalosis, or other electrolyte abnormalities.

●Methotrexate – The risk of developing AKI due to IV methotrexate therapy should be minimized by appropriate dosage adjustments for underlying kidney dysfunction, volume administration (both to maintain a high urine flow and to lower the concentration of methotrexate in the tubular fluid), and by alkalinization of the urine to a pH >7, which can increase the solubility of methotrexate by as much as 10-fold [20].

These preventive measures are detailed elsewhere. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Practical tips for managing high-dose methotrexate'.)

●Protease inhibitors – For patients taking atazanavir, we encourage fluid intake of ≥1.5 L/day. We do not give specific advice on fluid intake for patients taking other protease inhibitors.

●Ciprofloxacin – To prevent ciprofloxacin crystalline-induced AKI, ciprofloxacin should be dose adjusted for level of glomerular filtration rate (GFR), the patient should be volume replete, and alkalinization of the urine should be avoided [74].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute kidney injury in adults".)

SUMMARY AND RECOMMENDATIONS

●Etiology and risk factors – Acute kidney injury (AKI) due to intratubular crystal precipitation is observed in association with many medications. Risk factors for crystalline-induced kidney injury include low urine output, underlying kidney disease, and metabolic perturbations that change urinary pH. (See 'Etiology' above and 'Risk factors and pathogenesis' above.)

●Clinical presentation – Patients are generally asymptomatic, although occasionally present with flank pain. Urinalysis may show hematuria, pyuria, and crystals with a characteristic morphology. (See 'Clinical presentation' above.)

●Diagnosis – Crystalline-induced AKI should be suspected in any patient who develops AKI shortly after exposure to a causative agent, especially if no other cause of AKI is readily apparent. The diagnosis is suggested by the appearance of crystals in the urine, the morphology of which depends upon the specific causative drug. Although definitive diagnosis is obtained by kidney biopsy, crystalline-induced AKI also may be diagnosed based upon characteristic features and the exclusion of other causes of AKI. (See 'Diagnosis' above.)

●Treatment of established AKI

•Optimize volume status – The correction of volume depletion and the maintenance of optimal volume status is critical in the treatment of established AKI. Among all patients with established crystal-induced AKI from any cause, we correct volume depletion with intravenous (IV) fluid. In the absence of an indication for IV bicarbonate, such as for the treatment of sulfonamide- or methotrexate-induced AKI, the preferred IV fluid is usually isotonic saline. (See 'Optimize volume status' above.)

•Loop diuretics – Although efficacy has not been shown in this setting, the use of loop diuretics may be effective in clearing obstructing casts in crystalline-induced AKI. Among all volume-replete patients with established crystal-induced AKI from any cause, we suggest administration of a loop diuretic (Grade 2C). Fluid loss induced by the diuretic must be replaced to prevent volume depletion. (See 'Loop diuretics' above.)

•AKI associated with sulfonamide or methotrexate – For patients with sulfonamide-associated or methotrexate-associated AKI who are not oliguric, we suggest the administration of IV sodium bicarbonate (Grade 2C) to achieve the following targets (see 'Bicarbonate for selected agents' above):

-Urine pH >7.15 for sulfonamide antibiotics

-Urine pH >7 for methotrexate

However, sodium bicarbonate should not be administered to patients who have hypocalcemia, alkalemia, volume overload, or indications for acute hemodialysis.

•Additional therapy for methotrexate – In addition to treatment with IV sodium bicarbonate, leucovorin rescue, with or without glucarpidase, may be effective in the treatment of methotrexate-induced AKI. (See 'Additional therapy for methotrexate' above and "Therapeutic use and toxicity of high-dose methotrexate", section on 'Practical tips for managing high-dose methotrexate'.)

●Prevention of AKI – The maintenance of optimal volume status and correction of volume depletion is critical in the prevention of crystal-induced AKI from all causes. We suggest the following approach for patients who are receiving specific agents (see 'Additional measures for specific agents' above):

•Acyclovir – For patients who are receiving IV acyclovir, we suggest the administration of IV isotonic saline (Grade 2C).

•Sulfonamide antibiotics – For patients with preexisting kidney disease who are receiving high-dose IV sulfonamide antibiotics and who have urine pH <6 or develop crystalluria, we suggest the administration of IV sodium bicarbonate (Grade 2C).

•Methotrexate – The risk of developing AKI due to IV methotrexate therapy should be minimized by appropriate dosage adjustments for underlying kidney dysfunction, volume administration, and by alkalinization of the urine to a pH >7. These preventive measures are detailed elsewhere. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Practical tips for managing high-dose methotrexate'.)