A systematic review of clinical effects of SCB reported acute anxiety and psychosis as the most common manifestations of SCB toxicity [13]. Other reported features are trouble thinking clearly, headache, dry mouth, vomiting, hypertension, tachycardia, hypothermia, irritability, ataxia, and seizures [7, 8, 14]. Chest pain, elevated troponin levels, electrocardiographic changes consistent with myocardial infarction have also been reported [15]. Renal manifestations are uncommon, and AKI has rarely been reported with SCB usage [1, 8, 10, 11, 16, 17], including in those without a prior history of renal disease [9]. In one multi-center, hospital-based registry of patients with isolated SCB intoxication, AKI was reported in 4% among 277 cases, and 6% had rhabdomyolysis [18]. Among those who sustain AKI, the most common extra-renal symptoms are intense nausea, persistent emesis, and abdominal pain [8, 17]. Indeed, cyclic vomiting, also known as cannabinoid hyperemesis syndrome, has been reported in patients consuming cannabis but without association with AKI [19, 20]. In 2012, Centers for Disease Control and Prevention reported 16 AKI cases among SCB users in six states in the USA [1]. XLR-11 was the synthetic cannabinoid identified from product samples and clinical specimens. The exact pathophysiology of SCB- or XLR-11-induced ATN is unknown. XLR-11 has been shown to primarily target the mitochondrial function in human proximal tubule (HK-2) cells (where endogenous expression of cannabinoid receptors occur) by causing transient hyperpolarization of the mitochondrial membrane and increased adenosine triphosphate (ATP)production, followed by Bax translocation from cytosol into mitochondria. This event is known to trigger energy-dependent apoptotic cell death pathways, as evidenced by increased caspase-3 activity and chromatin condensation [21]. Regarding AIN, one of the possible mechanisms includes antigen processing (such as XLR-11 and its metabolites) and presentation to local dendritic cells, which then activate T cells, and the subsequent effector phase of the immune response is mediated by various cytokines leading to hypersensitivity-type reaction in the renal tubulointerstitial cells. Other proposed mechanisms are the development of antibody to the exogenous antigen and then this complex eliciting the immune response, or haptenization of low molecular weight substance, such as XLR-11 and its metabolites, which then creates an immune response [22]. It is also possible that these SCBs may be adulterated with other known nephrotoxins or previously unknown newer nephrotoxins that could elicit immunological response by the tubulointerstitial cells, leading to AIN [23]. Most of the time, it is difficult to know the exact constituents of these SCBs, given that they are illegally manufactured. Since we were not able to analyze the ingredients of the SCB taken by our patient, the exact trigger for AIN remains uncertain. However, since there was no concurrent usage of other known nephrotoxic agents, such as NSAIDs, it seems reasonable to assume a potential causal association of AIN with SCB. This is unlike other reports that described ATN as the predominant renal histology [8].

Among high school students aged 17 – 18 in the United States, 2.9% reported current SCB use, and 1.4% reported using SCBs on ≥ 3 days in the past month. They were also likely to use polysubstance such as cannabis, lysergic acid diethylamide, cocaine, heroin, and non-medical opioids [24, 25]. In a prospective, observational study of adolescents with SCB intoxication, coma and seizures were more likely than in adolescents with cannabis intoxication [7]. Data on the incidence of SCB-associated AKI in adolescents is scarce. Buser et al. [12] described two adolescents, 15 and 17 years old, who sustained AKI secondary to SCB usage. Both had flank pain and emesis. The renal biopsies showed features of predominant ATN with mild interstitial nephritis and peritubular capillaritis [12]. Both were treated with steroids; one required hemodialysis for oliguria. Similarly, another study [1] reported that out of 8 patients (in a total cohort of 16 patients with SCB-associated AKI) who underwent renal biopsy, 6 had ATN and 3 had AIN; it is not very clear from their report whether these patients had isolated ATN or AIN or combined ATN and AIN. Our report is unique given that the renal biopsy showed isolated severe AIN without ATN, but this could also be due to a sampling error. Clinically, there was no oligoanuria, and since the AKI improved rapidly with pulse steroid, dialysis was not required.

As described in this report, concurrent usage of cannabis and SCB is commonly seen. Gunderson et al. [14] conducted a survey in 2014 of 42 young-adult current cannabis users about their SCB usage and found that 90% were familiar with the SCB products, half had smoked SCB in the past, and a quarter of them reported current use of SCB. Most common reasons for using SCB was to avoid drug detection in urine tests and to achieve a new “high”. Urine drug screening does not detect SCBs as the SCBs and their metabolites do not cross-react with Δ-9 THC [26]. Arnston et al. [26] described two validated ELISAs designed to detect the two common SCBs in urine, and this may aid in the early diagnosis of SCB consumption. XLR-11 N-pentanoic acid metabolite can also be measured in toxicological laboratory work-up in both urine and blood via gas chromatography/mass spectrometry or liquid chromatography/time-of-flight mass spectrometry [1]. Whether severe AKI is a manifestation of combined cannabis-SCB usage or SCB only needs to be investigated in future studies. Cannabis alone has not been shown to increase the risk of AKI in patients with advanced chronic kidney disease (CKD) [27].

Despite normalization of renal function in most reported patients with SCB-associated AKI, repeat insults of AKI with ongoing SCB usage could be a risk factor for development of CKD. Indeed, patients with a history of repeated any-cause AKI episodes have a higher risk of developing CKD and end-stage renal disease (ESRD) [28]. In the subset of patients who continue to consume SCBs, the risk of CKD and ESRD is unknown and would be an interesting area of study for future investigators.

This report highlights the importance of a high index of suspicion of SCB usage when encountering an adolescent with AKI of unclear etiology, especially in association with emesis and hypertension. Timely evaluation with renal biopsy and initiation of steroid therapy may expedite the renal recovery and prevent irreversible damage.