In-Depth Review

Nephrotoxic Effects of Common and EmergingDrugs of Abuse

William F. Pendergraft III,*†‡ Leal C. Herlitz,§ Denyse Thornley-Brown,| Mitchell Rosner,¶ and John L. Niles†‡

AbstractThe kidneys can be injured in diverse ways by many drugs, both legal and illegal. Novel associations anddescriptions of nephrotoxic effects of common and emerging drugs of abuse have appeared over the pastseveral years. Anabolic androgenic steroids, illicitly used by athletes and others for decades to increase musclemass and decrease body fat, are emerging as podocyte toxins given recent descriptions of severe forms ofFSGS in long-term abusers. Synthetic cannabinoids, a new group of compounds with marijuana-like effects,recently became popular as recreational drugs and have been associated with an atypical form of AKI. 3,4-Methylenedioxymethamphetamine, commonly known as ecstasy, is a widely used synthetic recreational drugwith mood-enhancing properties and a constellation of toxicities that can result in death. These toxic effectsinclude hyperthermia, hypotonic hyponatremia due to its arginine vasopressin secretagogue–like effects, rhab-domyolysis, and cardiovascular collapse. Cocaine, a serotonin-norepinephrine-dopamine reuptake inhibitor thatserves as an illegal stimulant, appetite suppressant, and anesthetic, also causes vasoconstriction and rhabdo-myolysis. Recent adulteration of much of the world’s supply of cocaine with levamisole, an antihelminthic agentwith attributes similar to but distinct from those of cocaine, appears to have spawned a new type of ANCA-associated systemic vasculitis. This review discusses the nephrotoxic effects of these common and emergingdrugs of abuse, of which both community and health care providers should become aware given their widespreadabuse. Future investigation into pathogenetic mechanisms associated with these drugs is critical and mayprovide awindow intoways to lessen and even prevent the nephrotoxic effects of these drugs of abuse and perhapsallow a deeper understanding of the nephrotoxicities themselves.

Clin J Am Soc Nephrol 9: 1996–2005, 2014. doi: 10.2215/CJN.00360114

IntroductionThe kidneys can be injured in diverse ways by manydrugs, both legal and illegal. Susceptibility of thekidneys to such insults is primarily due to their highdegree of filtration and their metabolism by thekidneys to potentially toxic byproducts (1,2). Overthe past several years, novel associations and de-scriptions of the nephrotoxic effects of common andemerging drugs of abuse have appeared. Here we re-view the nephrotoxic effects of anabolic androgenicsteroids, synthetic cannabinoids, methamphetamines(ecstasy), and cocaine and its levamisole-adulteratedcounterpart. It is important to point out that this isnot a comprehensive review of all renal syndromesassociated with drugs of abuse. Other notable neph-rotoxic drugs of abuse include older syndromes ofheroin nephropathy, toluene-induced renal tubularacidosis, and a more recently described syndrome ofAKI seen with bath salts. There is probably a generalpaucity of data in the literature, partly because ofunder-reporting of incidents; thus, it is important torecognize this when examining data presented hereinwith regards to clinicopathologic characteristics andtreatment recommendations. The importance of thespecific nephrotoxic drugs of abuse reviewed here ishighlighted by the widespread use of these drugs andthe ever-growing global burden of illicit drug use anddependence (3).

Anabolic Androgenic SteroidsBackgroundAnabolic androgenic steroids (AASs) are a family of

hormones that include testosterone as well as its nat-urally occurring and synthetic derivatives, which havebeen illicitly used by athletes and other individualswho desire to increase muscle mass and decrease bodyfat since the 1950s. Damage from years of androgenexcess, often 50–100 times physiologic levels (4), maybecome an increasingly important cause of CKD. Awide range of prevalence estimates generally suggestthat at least 3% of young men in Western countriesuse AASs at some time in their lives (5). In selectedpopulations, such as weightlifters, up to 44% of thosesurveyed admit to AAS abuse (6). More relevant forthe nephrologist is the estimate of how many AASusers become long-term abusers who are more likelyto develop clinically significant kidney disease. Stud-ies suggest that approximately 30% of AAS users de-velop dependence and would therefore be at a higherrisk for developing the medical consequences of pro-tracted abuse (7).Confounding the effort to better define the medical

effects of AAS abuse is the high incidence of poly-pharmacy in AAS abusers. Almost universally, AASusers ingest numerous “nutraceuticals” and dietarysupplements, none of which are regulated by theUS Food and Drug Administration. Bodybuilders

*UNC Kidney Center,Division ofNephrology andHypertension,Department ofMedicine, Universityof North Carolina atChapel Hill, ChapelHill, North Carolina;†Division of Nephrology,Department of Medicine,and ‡Vasculitis andGlomerulonephritisClinic, Division ofNephrology,Massachusetts GeneralHospital, Boston,Massachusetts; §Divisionof Renal Pathology,Department of Pathologyand Cell Biology,Columbia UniversityMedical Center, NewYork, New York;|Division of Nephrology,Department of InternalMedicine, University ofAlabama at Birmingham,Birmingham, Alabama;and ¶Division ofNephrology, Departmentof Medicine, Universityof Virginia HealthSystem, Charlottesville,Virginia

Correspondence:Dr. John L. Niles,Division ofNephrology,Department ofMedicine,MassachusettsGeneral Hospital, 151Merrimac Street, Floor3, Boston, MA 02114-4719. Email: jlniles@partners.org

www.cjasn.org Vol 9 November, 20141996 Copyright © 2014 by the American Society of Nephrology

report high protein consumption, sometimes in excess of500 g/d, and the renal effects of this high metabolic bur-den are unknown (8). Nonandrogenic anabolic hor-mones, such as human growth hormone (9) and insulin(10), are used with moderate frequency by AAS users tofurther augment muscle gain. Opioid abuse is common inAAS users, and opioid and androgen dependence mayshare common neurologic pathways in the brain (4). Co-caine abuse also appears to be common in AAS users,with one survey showing 11.3% of AAS users reportingcocaine use within the past month, compared with 4.7%of non-AAS users with otherwise similar characteristics(11).

Clinical and Nephropathologic Findings in AAS AbuseThe cardiac, neuroendocrine, and neuropsychiatric ef-

fects of AAS abuse are well documented in other reviews(4,5). Renal effects of AAS abuse in humans are primarilydescribed in case reports (12–14) and a single small series(8). The series featured 10 long-term AAS abusers whopresented with variable elevations in serum creatinine(mean, 3.0 mg/dl) and substantial proteinuria (mean,10.1 g/d; range, 1.3–26.3 g/d). Three of the 10 patientsin the series had full nephrotic syndrome, and two addi-tional patients had nephrotic-range proteinuria and hypo-albuminemia but lacked edema. Renal biopsy in thesepatients revealed FSGS. Four of the 10 patients had peri-hilar lesions of FSGS, a finding classically seen in hyper-filtration-induced forms of FSGS, but three patientsshowed collapsing lesions, which are uncommon in thesetting of postadaptive forms of FSGS. Electron micros-copy showed a mean of 69% podocyte foot process efface-ment, and five of eight patients had .50% effacement,which is also uncommon in postadaptive FSGS (8,15,16).Figure 1 provides examples of the nephropathologic find-ings seen in the setting of AAS abuse. These unusual bi-opsy features suggest that, in addition to the expectedmetabolic strain that elevated lean body mass and highprotein intake places on glomeruli, androgens may beexerting a toxic effect on podocytes.

TreatmentCessation of AAS is clearly the mainstay of treatment in

cases of AAS-associated toxicity. Additional treatment aimedat reducing hyperfiltration injury, such as renin-angiotensinsystem blockade along with lifestyle modification (includ-ing a reduction of strenuous exercise and weight loss), hasbeen reported to help reduce proteinuria and stabilize renalfunction (8). No evidence supports the use of immunosup-pressive therapies, including corticosteroids. Notably, life-style modifications are difficult to sustain for some patientswho experience AAS dependence. In the published seriesof 10 patients, one patient refused to stop AAS altogether,and two stopped for a period of time but then restarted useafter experiencing depressive symptoms and body imageissues. In one patient, nephrotic syndrome relapsed after re-sumption of AAS use (8).

Pathogenesis of AAS-Associated Renal InjuryThe mechanism of renal injury in the setting of AAS

abuse is not well established and is likely multifactorial.

Hyperfiltration injury is an important factor; patients withmarkedly elevated lean body mass require an increase insingle-nephron glomerular filtration, similar to patientswith obesity-related glomerulopathy (16). Numerous ani-mal models have investigated the influence of sex hor-mones on the development of renal disease, and theygenerally show a protective role for estrogens, while an-drogens either are permissive or accelerate injury (17).Doublier and colleagues recently developed a mousemodel of glomerulosclerosis associated with high testos-terone levels. They demonstrated that podocytes expressboth androgen and estrogen receptors and that in vitro,testosterone can cause podocyte apoptosis, which isblocked by the addition of flutamide (18). In skeletal andcardiac muscle cells, testosterone signals through themammalian target of rapamycin pathway (19,20). Like-wise, the importance of mammalian target of rapamycinsignaling in podocytes and in essential podocyte functions,including autophagy (21) and compensatory hypertrophy(22), is increasingly recognized. Future studies aimed atimproving understanding of the specific role of androgensignaling in these key podocyte processes are needed tobetter understand the mechanism of AAS-induced kidneydisease.

Synthetic CannabinoidsBackgroundThe synthetic cannabinoids are a group of compounds

that have cannabis- or marijuana-like effects. These com-pounds were originally developed in laboratories for re-search and drug development; recently, however, they havebecome popular as recreational drugs. As such, they aresolubilized and sprayed onto herbal mixtures and thenmarketed in the form of incense preparations, bath addi-tives, or air fresheners under a variety of names, such as“Spice” or “K2”. These drugs have become widely usedfor a variety of reasons. They are relatively inexpensiveand have been readily available—online and at conve-nience stores, gas stations, and “head shops”. They are of-ten marketed as herbal or natural products and thereforeperceived as being safe. Effects of these products are sup-posed to mimic those of marijuana, and many are pur-ported to give a more intense high than marijuana itself.That they are not detected by routine urine drug screensmakes them attractive to people who are required to un-dergo random testing.Although recreational use of synthetic cannabinoids is

relatively new, these drugs have very quickly becomewidely available (23–25). Eight percent of University ofFlorida students surveyed in 2010 admitted to havingused a synthetic cannabinoid on at least one occasion(26), and 11.4% of 12th graders in the United States sur-veyed in 2011 admitting to having used a synthetic canna-binoid within the previous 12 months (27).D9-Tetrahydrocannabinol, the principal psychoactive

compound in marijuana, was first synthesized in 1964(28), and two major cannabinoid receptors were clonedin the 1990s. The cannabinoid type 1 (CB1) receptor,thought to be present mainly in the central nervous sys-tem, is responsible for the psychotropic effects of mari-juana and other cannabinoids (29). The CB2 receptor is

Clin J Am Soc Nephrol 9: 1996–2005, November, 2014 Nephrotoxic Effects of Drugs of Abuse, Pendergraft et al. 1997

found in abundance in the immune system, particularlythe spleen (30). Agonists of these receptors stimulate Gi/o

protein–mediated signal transduction pathways. More re-cent studies have demonstrated the presence of low con-centrations of CB1 receptors in almost all tissues, and CB2receptors have been found in parts of the brain as well asother organs and tissues. Endogenous cannabinoids havebeen identified, and the endogenous cannabinoid systemis an area of intense investigation in an effort to developnovel therapies for a broad spectrum of diseases. Whilea detailed discussion of the cannabinoid receptors andthe endogenous cannabinoid system is beyond the scopeof this paper, further information can be found in thereviews of Howlett and colleagues (31) and Pacher andKunos (32).The synthetic cannabinoids are a group of chemically

unrelated compounds that have in common their ability tobind to the cannabis receptors. Several classification schemeshave been used, based on chemical structure and the labo-ratory in which they were discovered. Major categories of thesynthetic cannabinoids include (23) the classic cannabinoids(with a dibenzopyran ring), nonclassic cannabinoids

(cycloheylphenols), naphthylmethylindoles, naphthopyrroles,naphthylmethylindenes, naphthylindoles, phenylacetylin-doles, methanandamine, and other synthetic analogues tothe endogenous eicosanoids.Compounds from most of the classes listed above have

been isolated from recreational herbal preparations (23),and in March 2011, five synthetic cannabinoids were tem-porarily classified as Schedule I drugs under the Con-trolled Substances Act (25). Synthetic cannabinoids thatare used recreationally are an ever-changing group ofcompounds, with new drugs appearing as others are de-clared illegal.

Renal Manifestations of Synthetic Cannabinoid UseSynthetic cannabinoids became of interest to nephrolo-

gists because of reports from local emergency departmentsand the lay press of AKI among users of these drugs (33,34).Bhanushali and colleagues reported four cases of AKIamong users of synthetic cannabinoids from northeastAlabama (35). In response to reports of three cases ofAKI among synthetic cannabinoid users in NatronaCounty, Wyoming, the Wyoming Department of Health

Figure 1. | Light microscopic and ultrastructural findings in anabolic androgenic steroids abusers with FSGS. (A) A glomerulus shows col-lapsing focal sclerosis with retraction of the glomerular tuft and hyperplasia of overlying epithelial cells (arrow) (periodic acid-Schiff; originalmagnification, 3400). (B) A discrete lesion of segmental sclerosis is identified at the glomerular vascular pole (periodic acid-Schiff; originalmagnification,3400) (C) A markedly hypertrophied glomerulus showing the unusual combination of a perihilar lesion of segmental sclerosiswith collapsing features (periodic acid-Schiff; original magnification,3400). (D) Electron micrograph showing .50% podocyte foot processeffacement (original magnification, 38000).

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launched a collaborative investigation among publichealth officials from several states, clinicians, and the Ar-kansas K2 Research Consortium, which identified a totalof 16 cases (36). Kazory and Aiyer have reported an addi-tional case (37). Findings from these publications are sum-marized below and in Table 1.All synthetic cannabinoid users reported were young

(median age, 20 years), and all but one were male. Presentingsymptoms included nausea and vomiting in all patients andabdominal flank or back pain in 15 (71%). Two patientsreported diarrhea. There was a broad spectrum of urinalysisfindings; only two patients had normal urinalyses. Renalultrasonography findings were reported in 17 patients. Infive, the findings were unremarkable; 12 showed increasedechogenicity without hydronephrosis, including one patientwith the additional finding of bilateral symmetrical renalenlargement. Renal biopsies were performed in 13 cases.Because these data were obtained from several publicationsand were based on chart review, diagnostic criteria usedin the histopathologic diagnoses were not standardized;however, 10 of the biopsies showed acute tubular necrosisand three were consistent with acute interstitial nephritis.Five patients required dialysis. Apart from the use of twoibuprofen tablets in one patient with flank pain (37), nopotential precipitating factors for AKI could be identified.Creatine phosphokinase values, available in only four pa-tients, were not markedly elevated (median, 255 U/L;range, 144–357 U/L). Although follow-up serum creatininevalues were not available for most of the patients, renalfunction improved in at least some of them.No specific “brand” of synthetic cannabinoid could be

implicated, and, where stated, nine distinct street productswere named. In a minority of cases, the product or clinicalsamples were available for analysis (36). A common find-ing in the analytes was the synthetic cannabinoid XLR-11,present in five products, two urine samples, and threeblood or serum samples. No synthetic cannabinoid couldbe detected in four blood or serum samples, one urinesample, and one product.

Proposed Mechanisms of Nephrotoxic Effects of SyntheticCannabinoidsThe pathogenesis of AKI among users of synthetic can-

nabinoids is unknown. The predominance of men with AKIis not surprising because men make up almost 80% of theusers of these drugs (38). Given the history of nausea andvomiting before presentation in every case, ischemic acutetubular necrosis secondary to hypovolemia is a plausiblemechanism; however, in the five cases where vital signswere stated, no tachycardia or hypotension was present onpresentation. Moreover, where reported, renal functionworsened, despite aggressive hydration (37). Although itis conceivable that some cannabinoid mixtures contain anoncannabinoid nephrotoxic contaminant, an alternativeexplanation is that some of the synthetic cannabinoidsmay be inherently nephrotoxic. Low levels of CB1 andCB2 receptors have been demonstrated in renal podocytes,endothelial cells, mesangial cells, and proximal tubules(39–41). A pathogenic role involving activation of theCB1 receptor has been demonstrated in experimental mod-els of kidney diseases, such as diabetic nephropathy andcisplatin nephrotoxicity (39,42). Thus, it is possible thatsome synthetic cannabinoids cause derangements in theendocannabinoid system of the kidneys leading to AKI.

TreatmentTreatment for AKI secondary to synthetic cannabinoids

has been largely supportive, including fluid resuscitation,given the presenting symptoms of nausea and vomitingand, where indicated, dialysis. Because three of the patientsdescribed in the literature had evidence of acute interstitialnephritis, a short course of steroids may also be indicated insuch instances.

Methamphetamines (Ecstasy)BackgroundEcstasy (3,4-methylenedioxymethamphetamine [MDMA])

is a widely used, Schedule I, synthetic recreational drug firstsynthesized in 1914 (43,44). Estimates are that approximately39% of college students in the United States have used ec-stasy in the past year (45). Typically, the drug is taken innightclub environments or “rave” parties and has mood-enhancing properties, such as causing energy, empathy,and euphoria. Another similar drug used in “party pills,”N-benzylpiperazine, leads to similar effects and has similartoxicities (46). The pattern of toxicity related to ecstasy isidiosyncratic and not usually due to overdose. In fact,first-time users of “typical” dosages may experience seriouslife-threatening consequences, such as recently seen in twodeaths at a music festival in New York City in 2013 (47).Most deaths secondary to ecstasy use occur in women

and can be accompanied by acute hyperthermia, hypona-tremia, cardiovascular collapse, rhabdomyolysis, and evenpermanent neurologic damage (48,49). The direct mecha-nisms that underlie the toxic actions are difficult to eluci-date because ecstasy is not the only drug involved andpills may be adulterated with other compounds. However,likely effects are due to a combination of a serotonin syn-drome as well as the drug’s sympathomimetic effects andability to lead to the release of arginine vasopressin (AVP)(50). In recent years, ecstasy has been associated with a

Table 1. Clinical findings among 21 users of syntheticcannabinoid (also known as ”Spice”) with AKI

Variable Value

Mean age (yr) 20 (15–33)Male patients, n (%) 20 (95)Presenting symptoms, n (%)Nausea and vomiting 21 (100)Abdominal, flank, and/or back pain 15 (71)Mean peak serum creatinine (mg/dl) 7.7 (3.2–21)

Renal ultrasonograph findings(n=17) (n)

Normal 5Increased cortical echogenicity 12Bilateral symmetrical enlargement 1

Renal biopsy findings (n=13) (n)Acute tubular necrosis 10Acute interstitial nephritis 3

Means are accompanied by ranges. Data obtained from refer-ences 35–37.

Clin J Am Soc Nephrol 9: 1996–2005, November, 2014 Nephrotoxic Effects of Drugs of Abuse, Pendergraft et al. 1999

spectrum of nephrotoxic effects, including AKI and hypo-natremia (51). These effects are usually seen with the morecommonly encountered central nervous system (CNS) ef-fects (Table 2).

Clinical Manifestations of Ecstasy Use and UnderlyingPathogenetic MechanismsThe clinical syndromes associated with ecstasy use are

myriad (Table 2). The drug is usually taken for its effects ofeuphoria and increased sociability. Adverse effects or tox-icities related to its use generally involve greater degreesof CNS and autonomic nervous system activity.Ecstasy and its related compounds and metabolites lead

to release of serotonin, dopamine, and norepinephrine intothe CNS (52). Furthermore, reuptake of these neurotrans-mitters is also inhibited. Ecstasy has also been documentedto lead to the release of AVP, perhaps through the seroto-nin system (52,53).MDMA undergoes metabolism by bothN-dealkylation and

O-demethylation followed by catechol-O-methyltransferasecatalyzed methylation (52). The pathway involvingO-demethylation exhibits genetic variance in its activitylevel through the cytochrome P450 isoenzyme CYP2D6 (54).The significance of this genetic variation is that some peo-ple will have slower metabolism and be at risk for greatertoxicity (54). Because the metabolites of MDMA also forminhibitor complexes with the CYP2D6 enzyme, there is thepotential for greater toxicity with multiple dosings (54).Finally, other drugs that are metabolized through this path-way can increase the risk for toxicity. Thus, the user’s geneticprofiles, as well as interactions resulting from polydrug use,are likely key factors that modulate the individual responseto MDMA and clinical outcomes.AKI has been described in numerous case reports from

ecstasy users (55). The absolute incidence of this compli-cation cannot be determined but is probably low. In mostcases, AKI is associated with nontraumatic rhabdomyoly-sis in the setting of hyperthermia, extreme exertion, andvolume depletion (51). Elevations of creatinine phosphoki-nase are usually pronounced (.100,000 U/L). Althoughdirect nephrotoxic effects of the drug cannot be excluded,there is only one case report of transient proximal tubular

dysfunction in an ecstasy user (56). Thus, AKI is probablynot due to a primary nephrotoxic effect.The most common renal complication of ecstasy use is

symptomatic hyponatremia (51). In these cases, the sodiumlevel at presentation is typically ,130 mEq/L and can beas low as 100 mEq/L. Of note, for public health concerns,most cases occurred in young women who ingested a sin-gle dose of ecstasy; in many cases this was the first use ofthe drug (51). Hyponatremia with ecstasy is dilutional innature. Excessive water or other hypotonic beverage in-take is a likely culprit. A common occurrence at “rave”parties is the use of “chill out” areas, which feature copi-ous quantities of water or sports beverages. These bever-ages are consumed readily because of the hot atmosphereand intense physical activity associated with these parties.The effects of amphetamines, which increase the sensationof thirst as well as cause xerostomia, may increase the in-take of water as well. However, merely the high intake offluids is probably not enough to lead to hyponatremiabecause the kidney can usually excrete free water rapidlyenough to match intake (51). Thus, impairment of renalfree water excretion due to elevated AVP levels is the othermajor factor that ultimately leads to hyponatremia.Ecstasy is a potent inducer of the secretion of AVP

(57–60). Henry and colleagues demonstrated that smalldoses of MDMA (40 mg; common “street dose” is 100 mg)led to a significant increase in AVP levels (from 1.14–1.88 pmol/L to 2.46–9.16 pmol/L) within 1–2 hours afterdosing. As expected, this rise in AVP led to a decrease inserum sodium levels, with a concomitant rise in urineosmolality (53). A more recent study documented aslight fall in serum sodium levels in “rave” attendeeswho used ecstasy compared with a control group of non-users (61).Acutely, the fall in serum sodium can lead to the de-

vastating complication of cerebral edema. This may besignaled by symptoms such as mental status changes,seizures, and coma. Ultimately, in severe, untreated cases,brainstem herniation may occur, resulting in death. Inecstasy users, there is a preponderance of female patientswho have developed life-threatening symptoms (.85% ofpatients with symptomatic hyponatremia) (51). The suscep-tibility of women to the effects of hyponatremia (not spe-cifically in users of ecstasy) may be related to estrogen’seffect on inhibiting the cerebral membrane Na-K-ATPaseactivity. The pump is one of the primary defense mecha-nisms against the osmotic shifts induced by severe hypo-natremia (62).

TreatmentIn general, therapy for acute ecstasy-induced adverse

events relies on supportive care, including aggressivecooling, correction of electrolytes, and intravenous fluids.Treatment of severe, symptomatic hyponatremia is a med-ical emergency, and 100–200 ml of 3% saline should beadministered as soon as possible. The goal is to reducethe serum sodium concentration by 3–5 mEq/L, whichshould acutely lower intracranial pressure and improvesymptoms (63).In milder cases of ecstasy-induced hyponatremia, spon-

taneous free-water diuresis occurs and therapy may be

Table 2. Major clinical manifestations of ecstasy

Central nervous systemMild: Hyperactivity, dry mouth, increased thirst,restlessness, palpitations, dizziness, drowsiness,difficulty concentrating, anxiety, tremor

Serious: acute panic attacks, delirium, psychosisChronic: serotonin depletion leading to depressedmood, potential neurotoxicity with cognitivedeficits

CardiovascularAcute: hypertension, tachycardia, arrhythmias,ischemia, and sudden death

Chronic: cardiomyopathyRenalAcute: AKI and hyponatremia

MusculoskeletalAcute: rhabdomyolysis

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limited to fluid restriction (51). In these cases, AVP levelsfall quickly and the ability of the kidney to excrete freewater returns. It is imperative to continue close monitoringand, if any deterioration is noted, hypertonic saline shouldbe administered at once.The only way to prevent the deleterious effects of ecstasy

is avoidance of the drug. Educational efforts are needed sothat young individuals understand the toxic effects of thissubstance of abuse.

Cocaine and Its Levamisole-Adulterated CounterpartBackgroundCocaine, one of the oldest andmost addictive psychoactive

substances in existence, is extracted from Erythroxylum cocaleaves. It acts biologically as a serotonin-norepinephrine-dopamine reuptake inhibitor (triple reuptake inhibitor) toserve as a stimulant, appetite suppressant, and anesthetic.The two forms of cocaine that are abused are the solublehydrochloride salt, or powdered, form and the insolublebase or freebase, also commonly known as “crack” (64).Euphoric effects of cocaine can occur through intraoral top-ical administration along the gums and oral mucosa, inha-lation, nasal insufflation, intravenous injection, or evenvaginal or anal suppository placement. A recent study es-timated that 14–21 million (0.3%–0.5% of the populationaged 15–64 years) users exist worldwide, and the highestprevalence of cocaine dependence is in North America(3,65).

Clinical Renal Manifestations of Cocaine UseNephrotoxic effects of cocaine are numerous and thought

to be related to changes in renal hemodynamics andglomerular matrix synthesis, degradation and oxidativestress, and induction of renal atherogenesis (66,67). Co-caine is one of many abused drugs that can cause rhabdo-myolysis, and this is probably the most common reasonfor AKI associated with cocaine use (68,69). With regard toaltering renal hemodynamics, it is known that cocainecauses vascular smooth muscle constriction and inhibitsreuptake of serotonin, norepinephrine, and dopamine topromote hypertension and tachycardia (66). Reports impli-cate this may be due in part to increased production ofendothelin-1, which acts on its cognate receptors locatedon vascular smooth muscle cells of renal resistance vesselsto decrease renal blood flow and GFR (70–72). Interest-ingly, however, a recent, large epidemiologic report exam-ining the association of illicit drug use, including cocaineuse, and CKD in the United States found no associationwith CKD (73). A possible explanation for this disconnectmay be related to the fact that cocaine use is associatedwith acute and severe hypertension that is only transientin nature and is not considered to result in chronic hyper-tension (74). Severe and acute hyponatremia associatedwith cocaine exposure has been reported, possibly due tostimulation of AVP and subsequent development of a syn-drome of inappropriate antidiuretic hormone secretion(75,76). Although rare, there are also case reports of co-caine-associated kidney infarction, presumably due tothrombotic or embolic disease, vasospasm, cardiogenicshock, or other forms of occlusive large vessel disease,such as dissection, aneurysmal rupture, trauma, or vascu-litis (77–79). Finally, although not closely examined in

recent literature, pregnant mothers who abuse cocaineplace their fetuses at increased risk in many ways, includ-ing untoward and detrimental effects on the urinary sys-tem (80–82).

Recent Emergence of Levamisole-Adulterated CocaineAn important and interesting association between co-

caine use and the development of a systemic syndromewith renal and nonrenal manifestations has come to light inrecent years after the discovery that drug dealers werecutting pure cocaine with levamisole (83–85). Levamisoleis a nematode-specific nicotinic acetylcholine receptor an-tagonist that is used as an antihelminthic agent in animals.It was also used as an immunomodulator for minimal-change glomerulopathy and rheumatoid arthritis andwas even approved by the Food and Drug Administrationin 1991 as adjuvant therapy for colorectal cancer. In 1999,however, it was withdrawn from the market in the UnitedStates because of adverse effects, most notably agranulo-cytosis (86,87). Of note, it is still under investigation as apossible therapy for aplastic anemia (88). An increased in-cidence of agranulocytosis was first noticed among cocaineabusers in 2008, and toxicologic analysis of urine revealedthe presence of cocaine and levamisole (89). By 2009, levam-isole was detected in 69% of cocaine entering the UnitedStates that was seized by law enforcement officials (86,90).A mini-epidemic of complications related to levamisole-adulterated cocaine use ensued (83,84,91). It is thoughtthat cocaine is cut with levamisole because levamisoleis a white, odorless powder that may potentiate euphoria.Furthermore, levamisole is metabolized to aminorex, ananorectic and amphetamine-like stimulant (87).The most striking association with levamisole-adulterated

cocaine use, based on two key case series, is ANCA-associated vasculitis characterized by constitutional symp-toms, arthralgias, and cutaneous necrotizing vasculitis(Figure 2), with or without pulmonary hemorrhage and/or pauci-immune focal necrotizing and crescentic GN. Se-rologically, almost all patients have antimyeloperoxidase(MPO)-ANCA and at least half of all patients also haveantiproteinase 3 (PR3)-ANCA. In fact, positivity for bothMPO- and PR3-ANCA is now becoming pathognomonicfor levamisole-adulterated cocaine exposure (85). In ad-dition, antinuclear autoantibodies, lupus anticoagulant,and low complement levels are detected in most patients.Although testing for autoantibodies to other neutrophilgranule constituents is not routine, it appears that auto-antibodies are also formed to human neutrophil elastase,cathepsin G, and lactoferrin (83–85). Furthermore, urine de-tection of cocaine and levamisole is an important diagnosticstep. Interestingly, the earliest report of levamisole-inducednephropathy in 1978 described a patient with rheumatoidarthritis treated with levamisole who developed a pruriticrash; leukopenia; thrombocytopenia; circulating immunecomplexes; proteinuria; and a kidney biopsy with granularmesangial deposits of IgA, IgG, IgM, and C3 and skin bi-opsy with granular IgM and C3 deposits located in thedermal-epidermal junction, all of which resolved afterdrug cessation (92). Therefore, it is important to recognizethat levamisole has also been associated with immune com-plex GN.

Clin J Am Soc Nephrol 9: 1996–2005, November, 2014 Nephrotoxic Effects of Drugs of Abuse, Pendergraft et al. 2001

Treatment and Future DirectionsTreatment of the nephrotoxic effects of cocaine, including

levamisole–adulterated cocaine-induced ANCA vasculitis,primarily involves immediate cessation of the causativeagent, BP control, and supportive care focused on appar-ent nephrotoxic effects. Additional treatment modalitiesfor levamisole–adulterated cocaine-induced ANCA vascu-litis often include immunosuppression based on diseaseseverity. However, data on efficacy are limited primarilyto a single center, Massachusetts General Hospital, whereit appears that treatment typically mirrors that of patientswith idiopathic ANCA vasculitis and is necessary and ef-fective in severe cases (83). Furthermore, any potentialtreatment strategy is limited by struggles with adherencein individuals whose main priorities focus on the use andacquisition of cocaine (85). More targeted therapeutic op-tions are needed, which will require in-depth mechanisticinsights. Mechanistic animal studies could prove to bequite useful. Furthermore, it could also be proposed thatlevamisole or one of its byproducts, in the setting of co-caine use, could specifically react with MPO and/or PR3to create neoantigens and spur autoimmunity.

ConclusionsThere is an ever-growing global burden of illicit drug use

and dependence (3), and multiple reports of late implicatespecific illicit drugs as nephrotoxins that were not previouslyknown. Anabolic androgenic steroids, synthetic cannabinoids(also known as “Spice” or “K2”), ecstasy (formally knownas MDMA), and cocaine and its levamisole-adulteratedcounterpart are common or emerging drugs of abusewith severe nephrotoxic effects about which both the com-munity and health care providers should become moreaware.The clinicopathologic characteristics of the illicit drugs

reviewed herein can easily be confounded by impurities oradulterants, dose, frequency, and concomitant polyphar-

macy. In fact, as an example, had levamisole not beendiscovered in cocaine preparations, investigators and cli-nicians alike might assume that cocaine itself was causingthe untoward effects that are actually due to levamisole. Al-though rapid recognition, detection, and diagnosis of theassociations described with these nephrotoxic drugs ofabuse are paramount, it should also be emphasized that thefeatures of untoward renal effects (e.g., timing, duration,and severity of exposure) can easily be modified by con-founding impurities, dose, frequency, and concurrent useof other legal and illegal drugs. These confounders, whichoften remain unknown to medical providers, makeprompt diagnosis challenging. Regardless, treatment pri-marily consists of immediate discontinuation of the of-fending agent and supportive care depending on diseaseseverity. Future investigation into pathogenetic mecha-nisms associated with these drugs is critical and mayprovide a window into ways to impede and even preventthe nephrotoxic effects of these drugs of abuse and per-haps allow a deeper understanding of the nephrotoxicitiesthemselves.

AcknowledgmentsW.F.P. and J.L.N. wish to thank the patients; the clinic manager,

Karen Laliberte; the clinical research coordinator, Andrew P.Murphy; and the clinic nurses dedicated to their care in the Mas-sachusetts General Hospital Vasculitis and GlomerulonephritisClinic, includingDonnaHagstrom,KateCosgrove,EleanorCoughlin,Laura Chambers White, Chelsea Barrett, Stefanie Navarro, LukeCogswell, and Naira Arrellano.W.F.P. is supported in part by National Institute of Diabetes and

Digestive and Kidney Diseases grant no. 1-F32-DK097891-02.Part of this work was presented at the American Society of

Nephrology’s KidneyWeek, November 5–10, 2013, Atlanta, Georgia.

DisclosuresD.T.B. is aparticipant inamulticenter studysponsoredbyGenzyme

(A Sanofi Company). J.L.N. has served as a rituximab-specific

Figure 2. | Representative cutaneous manifestations of levamisole–adulterated cocaine abuse. Large regions of necrotic, raised-edge,weeping ulcerations on the (A) thighs and (B) ankle of a patient with levamisole–adulterated cocaine-induced ANCA vasculitis.

2002 Clinical Journal of the American Society of Nephrology

advisory board member for Genentech and is currently participat-ing in the Genentech-sponsored RAVER study and receivingclinical research funding from Alexion Pharmaceuticals.

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