Two endogenous cannabinoid receptors have so far been identified: CB1 and CB2 [1]. CB1 receptors are predominantly found in the central and peripheral nerve terminals, where they portend an inhibitory effect on γ-aminobutyric acid (GABA). CB1 activation is responsible for the neuropsychiatric effects of SC such as elation, irritability and anxiety. CB2 receptors are located in tissues related to the immune system (e.g. spleen) and are suggested to have a role in the control of emesis and pain. These two receptors are also expressed within human glomeruli predominantly by podocytes [5]. Animal studies suggest that activation of these receptors could have a protective effect on diabetic nephropathy through reduction in albuminuria [5, 6], and CB1 might have a role in protecting kidneys from injury and fibrosis through improvement in insulin resistance in diabetes [7].

SCs are non-polar agonists of CB1 and CB2 receptors with variable affinity/selectivity for each one [1]. Compared with THC, SCs have a substantially higher potency often resulting in exaggerated neuropsychiatric effects. Little is known about pharmacology of SC. It has been suggested that detoxification and elimination of these products initially take place through hepatic cytochrome P450 oxidation followed by conjugation and renal excretion [1].

The recreational use of SC has been increasing since they were marketed a few years ago in part due to their easy accessibility and relatively low cost. They are distributed under names such as ‘Spice’ and ‘K2’ within packages that frequently bear labels such as ‘incense’ or ‘aromatherapy’. Due to their structural dissimilarity to cannabis, these products (also referred to as ‘synthetic marijuana’ and ‘fake weed’) were legal when they first became popular. However, mounting evidence on their harmful effects led to state and federal legislations [8]. Recently, the US Drug Enforcement Administration temporarily designated five of these chemicals as Schedule-I substances. SCs are structurally unrelated to THC and therefore, routine drug screening tests do not detect them. However, specific techniques with limited availability have recently made it possible to measure SC and their metabolites in the urine.

While a variety of adverse physical and neuropsychiatric effects associated with SC abuse have previously been recognized [8, 9], emerging reports are suggestive of potential nephrotoxicity of these products. For the first time in the medical literature, in 2012 Bhanushali et al. reported four cases of AKI associated with SC abuse in Alabama [3]. All patients presented with nausea, vomiting and abdominal pain after using SC; three had severe oliguric AKI for which a renal biopsy was performed and demonstrated acute tubular necrosis (ATN). Patients recovered with supportive management and none required renal replacement therapy. In February 2013, Centers for Disease Control and Prevention (CDC) published a notification in which AKI was identified as an unanticipated complication of the SC abuse [4]. Based on this report, 16 patients from five different states in the USA had been hospitalized due to SC-associated AKI in 2012. The median age of the patients was 18.5 years and all but one had nausea and vomiting. Half of the patients underwent a renal biopsy; ATN was the most common histologic finding (six patients), while acute interstitial nephritis was seen in three of the eight patients. Corticosteroids were used in four patients, and five patients required dialysis. No mortality was reported.

The pathogenesis of SC-associated AKI remains to be clarified. Rhabdomyolysis seems to be an unlikely possibility. In our case, creatine kinase (CK) was only mildly elevated, urine myoglobin was negative, and there were no signs of pigment deposition in the renal biopsy. ATN due to prolonged pre-renal azotemia secondary to nausea and vomiting is another possibility. However, in this case, the patient had normal pulse and blood pressure on presentation, had experienced nausea but very limited vomiting, and had not noticed any change in urine volume prior to admission. Given the fact that all reported cases are young and without previous illness or history of taking medications, development of such severe AKI simply due to low fluid intake and intravascular volume depletion, although possible, seems to be less likely as the main cause of AKI in these patients. We propose that toxic, rather than ischemic, tubular injury due to direct effect of SC (or potentially other added constituents such as heavy metals) could be responsible.

The similarities among the 21 thus far reported cases of SC-associated AKI from various geographic areas are illustrative of a certain pattern: first, 95% of the reported cases (20 out of 21) are male, with nausea, vomiting and abdominal pain being the most common presentation (Table 2). In an anonymous online survey by Winstock and Barratt, 79.6% of 953 recent users (as defined by SC use within the previous 12 months) were male [9]. Second, tubular injury is the predominant histologic finding in cases where a renal biopsy has been performed (10 out of 12). Third, although most patients recover with supportive management, nearly 25% have so far required renal replacement therapy (5 out of 21).

Our case supports previous reports of SC-associated AKI and suggests that nephrotoxicity could be a complication of these products. One limitation of our observation as well as previous similar cases is that these reports are only suggestive but not conclusive evidence of a causal relationship. They are meant to increase the awareness of practicing physicians of the possibility of a previously unrecognized association. In fact, similar to other illicit drugs, the exact ingredients of the SC packages are likely to be variable with regard to the quantity of each constituent as well as the presence of other possibly added compounds and stimulants.

Based on this case, coupled with previous reports, we suggest that AKI could be a complication of SC abuse, and that health care providers caring for otherwise healthy young adults who present with unexplained AKI should inquire about SC abuse.

Conflict of interest statement. None declared.