Bruno Mégarbane, MD, PhD

Department of Medical and Toxicological Critical Care INSERM U 1144 - Paris-Diderot University

Lariboisiere Hospital, Paris, France

bruno.megarbane@lrb.aphp.fr

Acute kidney injuries associated with the new psychoactive substances

First cathinone

First synthetic cannabinoid

50 cathinones 112 cannabinoids

The New Psychoactive Drugs (availability, seizures, use, fatalities)

European Drug Report 2014

Depressants

Kratom GHB/GBL

1,4 butanediol New opioïds

The new psychoactive substances

Stimulants

Phenetylamines Pipradols

Piperazines Cathinones

Synthetic cocaine

Hallucinogens

Tryptamins Cannabinoids

Glaucine TFMPP

Salvia, mitragyna

>300 new molecules between 2000 and

2015

1345

957 904

711 593

467

315 259 248 245 245 220 186 147 140 136 128 112 92 87

0

200

400

600

800

1000

1200

1400

1600 Co

unt

of d

rug

EuroDEN, unpublished data

Top 20 most commonly reported drugs in the ED in Europe (n=8709 in 5529 presentations)

Synthetic cathinones 1

MDMA analogues

MDMA-like cathinones

Amphetamine analogues

Pyrovalerone cathinones

Cathinones: does structure predict activity?

Amphetamine-like cathinones

Phenethylamine structure + β-keto group on the side-chain

(+ Pyrrolidinil moiety)

Pharmacology of stimulants and empathgens

Methamphetamine o  dopaminergic

o  stimulant o  highly addictive

-10 -9 -8 -7 -6 -5 -4 -30

25

50

75

100

125

MDMA [M]

mon

oam

in u

ptak

e (%

of c

ontro

l)

-10 -9 -8 -7 -6 -5 -4 -30

25

50

75

100

125

Methamphetamine [M]

mon

oam

in u

ptak

e (%

of c

ontro

l)

5-HT

DA

5-HT

DA

DAT/SERT ratio = 22

DAT/SERT ratio = 0.1 MDMA (ecstasy) o  serotonergic o  empathogen o  less stimulant o  less addictive

Simmler & Liechti. BMC Res Notes 2013

Potency to inhibit NE, DA and 5-HT transport into transporter-transfected cells and their efflux from monoamine-preloaded cells

Classification of NPS according to DAT/SERT ratio

5-HT Dominant

DA Dominant

PCC report of cathinone toxicity N= 236

Signes adrénergiques

Signes d’encéphalopathie

Signes sérotoninergiques

Spiller HA. Clin Tox 2011

Signes viscéraux

Clinical data

Synthetic cannabinoids 2

Synthetic cannabinoids: chemical structure

Used to obtain Δ9-THC-like psychological effects

Computational melding of Δ9-THC chemical structure with aminoalkylindole (JWH series), indol (AM) and

cyclohexylphenol (CP) derivates

5F-AMB AM2201 analogue AB-CHIMINACA 5F-AMBICA MEPIRAPIM PP22 analogue FUBIMINFA ADBPINACA

2014

Continuing exponentially expansion with new molecules

Recreational names … … Original manufacturing procedure

Substance Ki (nM) Affinity to CB1 receptors

THC 41 ± 2 1 XLR-11 24 ± 5 X 2

JWH-018 9 ± 5 X 5 JWH-073 8.9 ± 2 X 5 CP 47,497 2.2 ± 0.5 X 20 AM-2201 1 X 40

HU-210 0.06 ± 0.01 X 700

Consequences of powerful cannabinoids

-  Activity duration: up to24h

(instead of4-6h) - Incidence of symptoms x2-4

- Increased severity (5% in the ICU) - Fatalities: 8

published cases

Synthetic cannabinoids related clinical toxicity

Hermanns-Clausen M. Addiction 2012

First generation: nausea/vomiting, occasional seizures More recent generation: seizures, cardiotoxicity, sympathomimetic syndrome serotoninergic syndrome Cardiovascular events Stroke

Synthetic hallucinogens 3

Methoxetamine toxicity (NMDA receptor antagonist)

Hill SL. Emerg Med J 2014

N = 47

Psychedelic phenetylamines

Phenetylamine derivates

NBOMe derivates

Renal toxicity related to the use of NPS

Predictors of AKI in HIV-infected patients

Garg S. Aids Patient Care and STDs 2011

Multivariable analysis adjusted for CD4 cell

count

Multivariable analysis adjusted for HIV

viral load

Illicit drugs & AKI

Kosmadakis G. J Artif Organs 2011

AKI due to rhabdomyolysis in relation to illicit drugs

Both rhabdomyolysis and ARF are more severe in heroin users than in other drug users

Illicit drugs & AKI

Aldeen MA. JIMHICR 2014

Cocaine-induced acute interstitial nephritis

Illicit drugs & AKI

Mechanisms: Enhanced platelet aggregation, thromboxane synthesis, endothelial & vasospastic injury due to inhibition of uptake of cathecolamines

Hirachan P JIMHICR 2015

Cocaine-induced renal infarction Illicit drugs & AKI

Heroin crystals in alkaline pH, resulting in tubular obstruction and AKI Urine crystals with characteristic slender blades & branching threads

Heroin crystal nephropathy

Bautista JEK. Clin Kid J 2015

Illicit drugs & AKI

Hyponatraemia + acute cerebral edema Hyperthermia Dehydration, volume contraction Rhabdomyolysis (pigment nephropathy) MOF Renal arteriolar vasospasm Severe HTA and aortic vasoconstriction Necrotizing vasculitis (negative ANCA) Thrombotic microangiopathy, TPP Interstitial nephritis Glomerulopathy, tubulopathy, obstructive nephropathy Renal infarction Impurities or adulterants (levamisole, oxalogenic plant)

Mechanisms of illicit drug-induced renal and electrolyte abnormalities

Prerenal AKI

ATN

Vascular

Rare

Co-toxicant

Electrolyte

Luciano RL. Nature Rev Nephrol 2014 Nep

hrot

oxic

eff

ects

of

desi

gner

dru

gs

Dose-dependent toxicity: - Patients reported having used more drugs than their asymptomatic contacts - Non-standardized manufacturing processes increase the chance that preparations contain uneven distribution of active compounds, exposing users to different concentrations Host-dependent toxicity: -  Higher predisposition to AKI (young males) -  Gene polymorphism (CYP, conjugation) è variable oxidative and conjugative metabolite profile

Drug pharmacology: binding affinity to receptors (CB1/CB2), increased T1/2 (phosphorylated cannabinoids)

Mechanisms of drug-induced AKI

Age: 15 – 27 yrs (median, 18 yrs), 2 pairs of siblings Intense nausea and flank or abdominal pain - Peak creatinine: 2.6 – 17.7 mg/dL (median, 6.6 mg/dL). - Proteinuria (N=8), casts (N=5), RBC in urine (N=8) - Increased cortical echogenicity (N=9/12) Renal biopsy (N=8): acute tubular injury (N=6)

acute interstitial nephritis (N=3) Detection of fluorinated SCB (XLR-11) (N=4/6) ([1-(5-fluoropentyl)-1H-indol-3-yl](2,2,3,3-tetramethyl-cyclopropyl)methanone) All patients were hospitalized; one required dialysis; none died

Cannabinoids-induced AKI (N=16)

Tait RJ. Clin Tox 2016

Proximal tubular injury: vacuolization of epithelial cells, mitotic figures providing evidence of regeneration, medulla capillaries inflammation Focal interstitial lymphocytic infiltrate with interstitial edema and occasional interstitial eosinophils

Typical cannabinoid-related renal histological injuries

Tubular injury Interstitial nephtritis

Cannabinoid hyperemesis acute renal failure

Habboushe J. Am J Emerg Med 2014

Risk factors: male, intractable vomiting, constant hot showers

30% ketamine users have urological symptoms, including dysuria, increased frequency of micturation, suprapubic pain, and painful microscopic or gross haematuria. Among patients with lower urinary tract symptoms, 75% had decreased bladder capacitance and wall thickening and 50% had hydronephrosis. Abnormal bladder histology, ureteral strictures, papillary necrosis and renal infarcts are seen in patients who regularly use ketamine resulting in substantial kidney dysfunction. In 59 patients with lower urinary tract symptoms, 14% had elevated serum creatinine (124–585 µM), all patients had bilateral hydronephrosis and 14% required ureteric diversions.

Urological complications related to the long-term recreational use of ketamine

Luciano RL. Nature Rev Nephrol 2014

Three-month methoxetamine administration is associated with significant bladder and renal toxicity in mice

Methoxetamine (3-month daily 30 mg/kg IP) è bladder (inflammatory + fibrosis) and renal (glomerular + tubular) toxicity in mice, comparably to those related to chronic ketamine administration

Dargan PI. Clin Tox 2014

Glomerular shrinkage Glomerular damage Tubular damage Bladder PMN infiltration

Conclusions

The increasing use of drugs means clinicians must be aware of the clinical presentation and associated end-organ toxicity. Nephrotoxicity from designer drug use should be considered in the differential diagnosis of any patient with AKI of unknown etiology whether or not there is direct nephrotoxicity due to the drug, an adulterant or to a systemic complication.

It is important for clinicians to recognize the potential for kidney injury with the use of designer drugs.