CLINICAL QUIZ
“Smoking” guns: Answers
Tammi Cooks & T. Keefe Davis & June Hu &
Rachel Metheny & Michael Schwartz & Roy Gerona
Received: 8 September 2014 /Revised: 9 September 2014 /Accepted: 29 September 2014 /Published online: 21 October 2014
# IPNA 2014
Keywords Synthetic marijuana . Cannabimimetics . Kidney
injury . TASER . Conducted electrical weapon . Electronic
control device
The diagnosis
Answer 1: Synthetic cannabinoid-induced acute kidney injury
Toxicology studies identified AB-FUBINACA, a fifth generation
synthetic cannabinoid (SC), in the urine (450 ng/mL)
and serum (52 ng/mL). Acute kidney injury (AKI) secondary
to SCs was brought to international attention in a report from
the U.S. Centers for Disease Control and Prevention in February
2013 [1] which detailed 16 cases of AKI after SC use in
six states. A case series of four patients from Alabama, all
from the same county, also implicated SCs as a cause of AKI
[2]. An additional case has since been reported [3]. This is the
first report of a fifth generation SC associated with AKI.
SCs, commonly referred to as “Spice,” are designed to bind
to the same cannabinoid receptors (designated CB1 and CB2)
as the active compound in marijuana, delta-9 tetrahydrocannabinol
(THC). Many SCs demonstrate a high affinity for CB1 and
CB2 despite having markedly different chemical structures
from THC; consequently, these compounds are also referred
to as “synthetic marijuana” or cannabimimetics. SCs are designed
and synthesized in clandestine laboratories. Plant
material/inactive vegetable matter is soaked in solvent containing
the dissolved SC or the SC is sprayed directly onto the
matter [1, 4]. This material is then dried and smoked. The U.S
Drug Enforcement Administration (DEA) has placed multiple
SCs into Schedule I of the Controlled Substance Act (CSA),
including AB-FUBINACA [5–7]. However, illicit use continues
as new drugs are constantly being designed, and many
of the older compounds remain commercially available under
the guise of herbal incense, bath additives, or air fresheners with
the label “not for human consumption.” The illegal use is
further encouraged by affordability, expectation of an
intense high, and avoidance of detection by commonly
used urine drug tests. The synthetic drug industry is a
growing market. In the high school age group, 8–11 %
of seniors have reported use [8].
There are countless street and commercial names for SCcontaining
products (Table 1)—with these names having no
correlation with the presence of a particular SC. These drugs
are made in laboratories with no quality or safety controls, and
thus there is great variability amongst these products in terms
of ingredients, potentially toxic preservatives, adulterants, and
concentration of active SC [4]. There is no assurance that
This article refers to the article that can be found at http://dx.doi.org/10.
1007/s00467-014-2978-1.
T. Cooks
Washington University School of Medicine, St. Louis, MO, USA
T. K. Davis (*)
Division of Nephrology, Department of Pediatrics, Washington
University School of Medicine, 660 S. Euclid Ave., Box 8116,
St. Louis, MO 63110, USA
e-mail: davis_tk@kids.wustl.edu
J. Hu
Pediatrics, St. Louis Children’s Hospital, St. Louis, MO, USA
R. Metheny
Division of Pediatric Psychiatry, Department of Neurology and
Psychiatry, Washington University School of Medicine, St. Louis,
MO, USA
M. Schwartz
Department of Emergency Medicine, Emory University School of
Medicine, Atlanta, GA, USA
R. Gerona
Department of Laboratory Medicine, University of California, San
Francisco, CA, USA
Pediatr Nephrol (2016) 31:63–66
DOI 10.1007/s00467-014-2983-4
“Brain Freeze” always contains AB-FUBINACA or that “Lava”
always contains XLR-11. The variation in product content
and the increasing use has resulted in several “outbreaks” of
adverse health effects which occur in distinct regional and
temporal cohorts [1, 2].
Answer 2: The mechanism of SC-induced AKI remains
speculative
Two findings provide the theoretical basis for a direct nephrotoxic
effect: (1) animal studies have shown that after inhaled
SC exposure these compounds can be isolated directly from
the kidney [9]; (2) both cannabinoid receptors are expressed in
kidney tissue. Most SCs are full agonists of these receptors (as
compared to THC which is only a partial agonist), but increasing
activation of a naturally occurring receptor, even by a nonendogenous
compound, seems unlikely to be causative of
AKI. Some researchers have claimed that the presence of
fluorine or other side-chains in some SC may be responsible
for the injury to the kidney, similar to the injury which results
from fluorinated anesthetics, such as methoxyflurane [10].
Others implicate contamination with heavy metals or other
unsuspected toxic substances. In this case, the AKI is likely to
be secondary to hypovolemia induced by nausea and
vomiting, resulting in kidney ischemia. Kidney biopsy, although
not performed in our case, has shown evidence of
tubular injury (acute tubular necrosis) and/or interstitial nephritis
[1–3].
Answer 3: The only laboratory study not consistent
with the diagnosis was the positive urine drug screen for THC
Alluded to earlier in Answer 1, SCs are often used as
an alternative to marijuana because SCs are not detected
by commonly used urine drug tests. Ironically in our
case, the preliminary urine drug screen used an immunoassay
for THC and was initially positive, though
more specific toxicology studies using mass spectroscopy
ultimately did not confirm THC exposure.
As a general overview, the clinical presentation of SCinduced
AKI is most often nausea and vomiting (>95 % of
the time). The majority of patients also have abdominal, flank,
or back pain (>65 %). In almost all cases the serum creatinine
level follows a relatively consistent pattern, with peak creatinine
occurring within 6 days of symptom onset and improvement
beginning within 3 days of the creatinine peak [1]. This
pattern is consistent with the presentation of our patient.
Anuric AKI is rare (<5 %). Temporary dialysis has been
prescribed in 22 % of reported cases, but no patient to date
has developed end-stage renal disease. Results from urinalysis
are variable, but most patients have hematuria and
leukocyturia, as well as some degree of proteinuria. Renal
ultrasound often shows the non-specific finding of increased
cortical echogenicity (75 % of the time). Rhabdomyolysis/
elevated creatine kinase (CK) and hyperuricemia have been
reported after SC use [2, 3, 11].
Table 1 Some synthetic cannabinoids
Commercial and street
names of products
Isolated chemical products per
generation/class based upon DEA
placement in the Schedule 1 drug
listing or new chemical materials
Albino Rhino Buds
Arctic Spice
Aroma
First generation:
-JWH-018;-073;-200
-CP-47;-497;-47,497 C8 homologue
-Cannabicyclohexanol
Barely Legal
Black Box
Black Mamba
Bliss
Bombay Blue
Brain Freeze
Bunker Buster
Buzz
Second generation:
-AM-2201
-JWH-019
-JWH-250
-RCS-8
Caneff 5 Star
Chill Out
Chill X
Chillin XXX
Clown Loyal
Third generation:
-UR-144
-XLR-11
-AKB48
D-Raw
Dark Matter
Dream
Fourth generation:
-PB22
-BB22
Everlast
Experience
Fifth generation:
-AB-FUBINACA
-ABPINACA
-ADBICA
Fake Weed
Flame 2.0
Fusion
Galaxy
Genie
Herbal Incense
K2a
K2-Blonde
K3
Kronic
Lava
Magic
Mojo
Mr. Happy
Phantom Wicked Dreams
Smoke’n’Skulls
Spicea
Spice Diamond
Spice Gold
Spice K2
Spike 99
Yucatan Fire
Zombie 2010
DEA, Drug Enforcement Agency.
a
Spice and K2 is often used to collectively refer to synthetic cannabinoid
products.
64 Pediatr Nephrol (2016) 31:63–66
Answer 4: It is unclear whether the conducted electrical
weapon encounter contributed to the elevated CK
and hyperuricemia
Conducted electrical weapons (CEWs) incapacitate a subject
by inducing tetany through electric stimulation [12, 13].
Therefore, muscle breakdown and AKI from rhabdomyolysis
are theoretical risks. CEWs have been used by law enforcement
since the 1970s. The Thomas A Swift Electric Rifle
(TASER), the most common electronic weapon used by law
enforcement in the USA, was devised as a non-lethal alternative
to the use of a hand gun which has a 50 % mortality, for
temporarily incapacitating an aggressive subject [14]. The
device causes involuntary muscle contraction by stimulating
peripheral motor neurons at a sub-tetanic rate [12, 13, 15].
Case reports have implied that TASER guns may cause
rhabdomyolysis and AKI [16, 17]. All case reports of TASER
device-associated rhabdomyolysis have occurred in the context
of significant physical exertion and/or drug use (cocaine,
phencyclidine). There is a lack of consensus on how much to
attribute rhabdomyolysis in such an encounter to electrical
weaponry. In fact, various medical experts [18] and authors
of studies of conducted electrical weaponry use on healthy
individuals [19–24] have argued against an association of
severe rhabdomyolysis and TASER encounter. However, these
medical experts are employees and company stockholders
of TASER International, Inc., and most of these studies were
partially funded the company.
In reviewing the studies in healthy volunteers, analysis and
interpretation of the data may be misleading. For instance, the
authors of a pooled analysis of five human studies (n=156)
[19] reported a median change in CK of only 32 U/L when
two electrodes were activated (as in our case) and a median
change in CK of 303 U/L when exposure was for 10 s.
However, the actual range in CK change was up to 1,821
U/L for two points of contact and up to 25,452 U/L for 10 s of
exposure. The authors explain the elevation in CK by
commenting on non-adherence to study protocol due to concurrent
exercise training by some of the subjects (all were
requested not to engage in strenuous activity for 48 h before
and until the last blood draw at 24 h). Ultimately, two of the
patients (1.3 %) in the pooled data had CK levels of >5,000
U/L at 24 h. Although not conclusive, as the results are
confounded by exercise, these values do support that a TASER
encounter could cause severe rhabdomyolysis. A more
accurate analysis of risk may be when the TASER is used in
the field against criminal suspects. Bozeman et al. reported
only one case (<0.1 %) of rhabdomyolysis (CK 61,116 U/L
2 days after arrest) in 1,201 encounters, but again confounding
the association, the suspect admitted to crack cocaine use, fled
on foot, and vigorously resisted arrest [25]. In another study of
218 arrests, the use of TASER resulted in a 1 % occurrence of
“mild rhabdomyolysis and myoglobinuria” [14].
Conclusions
This clinical quiz highlights for the nephrology community an
emerging cause of acquired AKI, namely, synthetic drug use.
SCs are available in all communities, and their use is increasing,
especially among adolescents and young adults. The
American Association of Poison Control Centers reports “exposure
calls” numbering in the thousands since 2011 [26]. The
isolation of AB-FUBINACA in our patient highlights an ever
evolving threat as new SCs are developed in an effort to
circumvent regulatory efforts. Finally, although using a
CEW to subdue an agitated or dangerous suspect has not
conclusively been associated with rhabdomyolysis, by its
mechanism of incapacitation (involuntary muscle contraction),
it should be considered as a potential cause of
rhabdomyolysis.
Conflict of interest None.
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