Consumption of cannabis and various related products (cannabinoids) for both medicinal and recreational use is gaining popularity. Furthermore, regulatory changes are fostering a cultural shift toward increasing liberalization of cannabis use, thereby increasing the likelihood of even larger numbers of individuals being exposed in the future. The two different types of receptors (CB 1 and CB 2 ) that are activated by the pharmacologically active ingredients of cannabis are found in numerous tissues, including the kidneys. Experimental studies suggest that stimulation of these receptors using pharmacologic agents or their naturally occurring ligands could have both deleterious and beneficial effects on the kidneys, depending on receptor distribution, type of renal insult, or the timing of the activation during acute or chronic states of kidney injury. To date, the mechanisms by which the CB 1 or CB 2 receptors are involved in the pathology of these renal conditions remain to be fully described. Furthermore, a better understanding of the impact of exocannabinoids and endocannabinoids on the renal system may lead to the development of new drugs to treat kidney disease and its complications. Given the increasing public health relevance of cannabis exposure, it is clear that more research is necessary to clarify the various physiological and pathophysiological effects of cannabis and related analogs on the kidney. This will help limit the deleterious effects of these substances while promoting their potential beneficial impact on renal function in various types of kidney diseases.

cannabis, also known as marijuana, is an umbrella term used for preparations obtained from plants that fall under the genus Cannabis in the plant family cannabaceae (60). Cannabis and products derived from it have been widely used for recreational and/or medicinal purposes dating back to 4000 B.C. in ancient Asia (7a). The first cannabinoid, cannabinol, was isolated in 1896 and was further synthesized in 1940. Another major cannabinoid, delta-9-tetrahydrocannabinol (THC), was isolated in 1964 in Israel by Raphael Mechoulam, and this subsequently led to the discovery of the cannabinoid receptors (CB) and the endocannabinoid system (23). Currently, two synthetic cannabinoids, dronabinol (schedule III) and nabilone (schedule II), are approved by the FDA for clinical use in patients (5).

Marijuana is presently categorized as a schedule I illegal substance (defined as being a drug with no probable medical use and high abuse potential) (5). Cannabis was used in the United States for centuries as a drug for the treatment of different ailments. However, in 1937, the Marijuana Tax Act was passed, and federal prohibition started, which then led to criminalization of its use, culminating in the 1970s and 1980s with a war on drugs and the placement of marijuana in the most restricted drug category. In the 1990s, California was the first state to approve medical use of marijuana for select diagnoses. Subsequently, legalization of marijuana became a political issue, and in 2012, Colorado and Washington were the first U.S. states to legalize recreational use of marijuana. In 2013, Uruguay became the first country to legalize marijuana nationwide (7a). By 2016, 28 states legalized medical marijuana, and eight states and Washington, D.C. legalized the recreational use of this substance in the United States. The journey of marijuana from prohibition to criminalization and subsequently to decriminalization/legalization has led to an increase in the rate of use of this substance.

Use of cannabis for recreational purposes is popular; it is estimated that 182.5 million people worldwide in the age group 15–64 used cannabis at least once in 2014 (56). On the basis of United Nations Office of Drugs and Crime data, the prevalence of cannabis use was 16.2% in the United States in 2014 (Fig. 1). On the basis of National Survey on Drug Use and Health data, the percentage of people that used cannabis at least once in the prior year increased from 11% in 2002 to 13% in 2014, with the most accentuated increase seen in the age groups 18–25 and 26 or above (7% and 44% respectively; Fig. 2).

Fig. 1.Prevalence of cannabis use worldwide in 2014. Modified from United Nations Office on Drugs and Crime, United Nations Office on Drugs and Crime. http://www.unodc.org/wdr2016/field/1.2.2._Prevalence_cannabis.pdf, accessed on March 27, 2017.

Fig. 2.Percentage marijuana use during the past 12 mo among people aged ≥12 yr, overall and by age group. Modified from National Survey on Drug Use and Health Data. https://www.cdc.gov/mmwr/volumes/65/ss/ss6511a1.htm, accessed on March 27, 2017.

Although cannabis is mostly consumed for its effects on the central nervous system, by activating the CB receptors (CB 1 or CB 2 ) within the endocannabinoid (EC) system, its use may have both beneficial and harmful side effects on many other organ systems. In addition, although the activation of these receptors plays a vital role in numerous physiological processes, including memory, mood, pain sensation, sleep patterns, energy metabolism, and immune function, the effect of cannabinoids can also be mediated via CB receptor-independent pathways, details of which are beyond the scope of this article. Hence, there are a large number of disease conditions, which can be targets of cannabis research, including anxiety, cachexia, obesity, metabolic syndrome, atherosclerosis, depression, emesis and nausea, epilepsy, hypertension, multiple sclerosis (especially for spasms), and rheumatoid arthritis. Furthermore, cannabis users may encounter cardiovascular, pulmonary, dental, and other adverse effects related to activation of the EC system (5, 11, 46, 57, 59). Therefore, a thorough understanding of the risks and benefits of cannabis use is essential for future development of its use in the clinical setting.

The kidneys are among the organ systems where CB 1 and CB 2 receptors are expressed (34), and experimental studies suggest that cannabis can have both beneficial and harmful effects on kidney function (see above). However, there is a paucity of human studies examining not only the impact of cannabis use on healthy kidneys, but also on kidney function in patients with preexisting kidney disease. As a result of the spreading legalization of marijuana, it is expected that the number of patients exposed to cannabis will continue to increase, and this makes understanding the health effects associated with cannabis use, including the impact on renal function and kidney disease, of paramount importance. Furthermore, the potential cannabinoid-related renal physiological effects raise the possibility of targeting this system for the development of novel therapies in the treatment of different forms of kidney disease.

Cannabinoids and Their Cognate Receptors in the Kidney In addition to exocannabinoids, a number of endogenous ligands, known as endocannabinoids, have also been readily detected in the circulating blood (54). The best characterized endocannabinoids are N-arachidonoyl ethanolamide, also known as anandamide (AEA), and 2-arachidonoylglycerol (2-AG) (7), which have also been detected in substantial concentrations in renal tissue. This is further supported by the presence of cellular machinery necessary to synthesize and catabolize endocannabinoids in the kidney (25, 50). These arachidonoyl-containing lipid-derived mediators can be produced on demand by the metabolism of cell membrane glycerophospholipids and, typically, are thought to act locally in an autocrine or paracrine manner by interacting with two distinct receptor types, cannabinoid type 1 (CB 1 ) and 2 (CB 2 ) receptors (41). Moreover, 2-AG and AEA can be rapidly degraded by monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase, respectively, thereby producing arachidonic acid. At present, the biological response elicited by exocannabinoids and endocannabinoids in the kidney remains to be fully understood under normal and pathological conditions, in part, because of the complex regulation of endocannabinoid production and catabolism (13, 14, 25, 50). In addition, the unique distribution and temporal expression profile of the CB 1 and CB 2 receptors within various cell types in the kidney can produce diverse signaling outputs. The two known CB receptors, type 1 and type 2 (41), are categorized as G protein-coupled receptors due to their seven-transmembrane serpentine configuration through the plasma membrane. Many of the signaling outputs controlled by the CB 1 and CB 2 receptors are sensitive to pertussis toxin, which demonstrates the functional dependency of these receptors on the activation of heterotrimeric G proteins consisting of G αi subunits (13). The CB 1 receptor association with the G αi subunit can inhibit adenylyl cyclase activity, reduce activity of MAPK, directly control the activation status of ion channels, and stimulate nitric oxide synthase (14, 27). Similarly, CB 2 receptors interact with the G αi subunit to exert an inhibitory effect on adenylyl cyclase activity, but there has been no data to demonstrate any regulatory effect on ion channels (14, 27). Even though there is a common G protein subunit that facilitates the actions of the CB 1 and CB 2 receptors, their signaling output can be distinct and, in some cases, lead to opposite biological effects. The diversity of the CB 1 and CB 2 response on cell signaling pathways remains to be fully described, but likely depends on several factors. First, other G α subunits, including G αq/11 , have been shown to associate with CB 1 to promote a variety of effects, including increased intracellular calcium (28). Second, the relative abundance and distribution of the CB 1 and CB 2 receptors can differentially change during normal and diseased states. Third, the G α subunits associated with the CB 1 and CB 2 may not be localized to the same cell types. As an example, the G αo subunits, which are primary G protein subunits, interact with CB 1 and CB 2 in the brain, but are absent in the kidney (47). Fourth, the generation of the diverse signaling outputs observed may be related to other accessory proteins that can interact with the CB receptors, such as G protein-coupled receptor kinase and β-arrestin (13). Lastly, the localization of the CB 1 and CB 2 receptors in specific cell types, i.e., vascular, tubular, or interstitial, in the kidney could play a crucial role in the distinct signaling output produced by activation of each receptor. Table 1 provides a summary of the studies describing CB 1 or CB 2 expression changes and localization in the kidneys from mice, rats, and humans. In human kidneys, CB 1 receptor protein has been detected in proximal convoluted tubules, distal tubules, and intercalated cells of the collecting duct (27). In rodents, CB 1 receptor protein was also detected in isolated thick ascending limbs of loop of Henle (53), podocytes in the glomerulus (3, 22), and resistance (i.e., afferent and efferent) arterioles (26). In cultured mesangial and endothelial cells, the expression of CB 1 and CB 2 mRNA has also been detected. Furthermore, CB 2 receptor expression has been reported in cultured proximal tubule (17, 18) or glomerular mesangial cells (6) and sporadically in glomerular podocytes (3, 27). In addition, there are pharmacological studies that have shown that endocannabinoids in the renal vasculature can promote vasodilation via a non-CB 1 receptor mechanism, and this may be one possible mechanism responsible for promoting the vascular effects of CB ligands in the kidney (61). Table 1. Summary of CB 1 and CB 2 receptor localization in mammalian kidneys Animal Model Kidney Region/Cell Type Expression Technique Used to Measure Changes CB 1 receptor Sprague-Dawley rat (18) Whole kidney + RT-PCR, WB Sprague-Dawley rat + STZ (19) Whole kidney + (↑) WB Wistar rat + STZ (33) Whole kidney + (↑) RT-PCR, WB Sprague-Dawley rat + HFD (21) Whole kidney + (↑) WB ZDF rats (22) renal cortex (PCT, Glm) + (↑) RT-PCR, IHC Wistar rats (53) isolated TAL + WB Sprague-Dawley rat (26) afferent/efferent arteriole + RT-PCR CB 1 transgenic mice (15) Whole kidney + (↑) RT-PCR, WB db/db mice (43) Glm + (↑) IF C57BL/6 mice (control) (29) kidney cortex − IHC C57BL/6 mice (UUO) (29) Kidney cortex (interstitial, tubules, Glm) + IHC C57BL/6 mice + cisplatin (39) whole kidney + (↔) RT-PCR, WB Human kidneys (27) PCT, DT, IC CD + IHC BV, Glm − IHC CB 2 receptor Sprague-Dawley (18) Whole kidney + RT-PCR, WB Sprague-Dawley + STZ (17) Whole kidney + (↑) WB Sprague-Dawley + HFD (20) Whole kidney + (↓) WB Wistar rat (53) isolated TAL − WB C57BL/6 + STZ (3) Glomerulus + (↔) IF Human Type 2 Diabetic (3) Glomerulus + (↓) IF Human kidneys (27) kidney cortex − IHC Given the role of these ligands in the activation of the CB receptors under physiological conditions, dysregulation in the synthesis and metabolism of various components of the EC system in disease states has the potential to have pathophysiological consequences. Physiology and Signaling Pathways of the Cannabinoid System in the Kidneys From Animal Model Studies Under normal conditions, the endocannabinoid system plays a critical role in renal homeostasis, as related to the control of renal hemodynamics and tubular sodium reabsorption, in large part through the activation of the CB 1 receptor (6, 15, 26, 30, 49, 53). Renal vasculature and blood flow regulation. The systemic cardiovascular effects mediated by the endocannabinoid system have been extensively studied and reviewed elsewhere (35, 45, 48). To date, however, there remains limited information as to the specific effects of endocannabinoids on renal hemodynamics, including control of blood flow parameters and its direct impact on blood pressure. Intravenous administration of AEA was found to decrease glomerular filtration rate and increase renal blood flow in rats (26). In vitro juxtamedullary preparations demonstrated that AEA could vasodilate either the afferent (6) or efferent arterioles (6, 26) to regulate glomerular filtration rate by activating nitric oxide-dependent pathways through the CB 1 receptor. Another study showed that infusion of AEA into the renal medullary interstitium led to a rapid diuretic effect through a CB 1 -dependent mechanism (30). Similar increases on renal blood flow and its associated rise in urine flow may also involve a metabolic breakdown product of AEA, which could act through a non-CB 1 receptor mechanism (49). No change in systemic blood pressure was measured, even with alterations in renal medullary blood flow (49). Renal tubular epithelial cells. To determine whether a tubular component was involved in the CB 1 -dependent increase in urine flow, isolated thick ascending limbs of Henle’s loop (TAL) were tested for sodium transport and oxygen consumption (Fig. 3C). Sodium transport through Na+/H+ exchanger and sodium-potassium-chloride cotransporter, and oxygen consumption in TAL was inhibited by the activation of CB 1 receptors, an effect mediated via the nitric oxide synthase axis (53). These studies demonstrate that the increased urine and sodium output may be a combination of both vascular and tubular control exerted by the EC system via the CB 1 receptor, but further genetic and pharmacological studies are needed to determine whether renal control mechanisms activated by the CB receptors are capable of manipulating blood pressure regulation. Fig. 3.Cannabinoid receptor signaling in renal glomerular and tubular epithelial cells. Cannabinoid 1 (CB 1 ) receptor activation activates distinct pathways in the podocytes/mesangial cells of the glomerulus (A), proximal tubule (B), and thick ascending limb of Henle (C). ROS, reactive oxygen species; NOX, NADPH oxidase; CARM1, coactivator-associated arginine methyltransferase 1; AMPK, 5′ AMP-activated protein kinase; ERK, extracellular signal-regulated kinase; PPARγ, peroxisome proliferator-activated receptor gamma; IL-1β, interleukin-1β; SOCS3, suppressor of cytokine signaling 3; ICAM-1, intercellular adhesion molecule 1; TNF-α, tumor necrosis factor-α; NO, nitric oxide; NOS, nitric oxide synthase; iNOS, inducible nitric oxide synthase; TGF-β, transforming growth factor-β; CCR2, C-C motif chemokine receptor 2; PARP, poly ADP ribose polymerase; BK, bradykinin receptor; AT-1, angiotensin type 1 receptor; PKC, protein kinase C; PKA, protein kinase A; PA, palmitic acid; PLA 2 , phospholipase A 2 ; BV, blood vessels; TRPV1, transient receptor potential vanilloid 1; DAG, diacylglycerol; PIP2, phosphatidylinositol 4,5-bisphosphate; IP 3 , inositol 1,4,5-trisphosphate. Download figureDownload PowerPoint

Glomerulus. The physiological function of CB 1 and CB 2 receptors in the glomerulus under normal conditions remains to be fully elucidated; however, genetic or biological perturbations that lead to changes in CB receptor levels or activity have provided valuable insights regarding the role of CB 1 and CB 2 in the glomerulus (Fig. 3A). For instance, in the CB 1 transgenic mice, overexpression of the CB 1 receptor throughout the kidney, including the podocytes and mesangial cells of the glomerulus, was associated with increased urinary protein excretion (15). Proteinuria was also detected in normal rats following treatment with a selective CB 1 agonist, WIN55212-2 (15). Increased stimulation or production of the CB 1 receptor was found to elevate VEGF synthesis with a concomitant decrease in nephrin (15), which is known to play a central role in controlling podocyte function through its interaction with podocin. These results would suggest that even normal animals that exhibit dysregulation of the CB 1 receptor or its activity can develop pathological glomerular defects. Animal models of renal disease and injury. Various forms of acute and chronic kidney disease have demonstrated changes in CB receptor expression or activity (1, 3, 22, 43). Biopsied kidney samples from patients with either IgA or diabetic nephropathy have shown elevated expression of CB 1 mRNA (29). Concomitant with the increased levels of CB 1 receptor, there is evidence that glomerular CB 2 receptor levels are decreased in experimental mice and humans with diabetic nephropathy (3, 20). These findings have led to the speculation that modulating CB receptor function and activity may be a viable therapeutic intervention for renal injury and disease. Chronic kidney disease. Toward this end, antagonism of the CB 1 receptor or activation of the CB 2 receptors using selective pharmacological agents have shown to be associated with improvement of the renal structure and function in experimental and genetic models of chronic kidney disease (CKD) (1, 16, 21, 22, 43). In a mouse model of chemically induced diabetic nephropathy, proteinuria was markedly reduced through the preservation of glomerular podocytes following administration of a selective CB 1 receptor antagonist (AM251) (1). Similar findings were observed using genetic rodent models of diabetic nephropathy (22, 43). In db/db mice, chronic blockade of the CB 1 receptor resulted in a reduction in microalbuminuria and decreased expansion of mesangial cells in the glomerulus (43). In Zucker diabetic obese rats, CB 1 inverse agonist, JD5037, improved renal function and reduced albuminuria after long-term chronic administration (22). On the other hand, activation of the CB 2 receptor has been shown to play a protective role in the diabetic nephropathy (3, 20). Functionally, CB 2 receptor stimulation using AM1241 has been shown to ameliorate albuminuria, restore podocyte protein expression, and decrease expression of profibrotic markers (collagen type IV and TGF-β) in diet-induced obese rats (20). Similar findings were observed in a study using streptozotocin-treated mice (3). In other rodent models of CKD, similar protection of the glomerulus was observed in kidneys from rats with diet-induced obesity by blocking the CB 1 receptor (21). In addition to the improvement in glomerular function, blockade of the CB 1 receptor has been shown to reduce the progression of renal fibrosis in the unilateral ureteral obstruction mouse model (29). The mechanism by which the CB 1 receptor antagonism reduces protein excretion may involve VEGF production, which is known to be linked to nephrin expression. In addition, CB 1 antagonism may also improve renal function through reduced glomerular and proximal tubular apoptosis (1, 16, 31), although further in vivo studies are needed to confirm these initial in vitro observations. Table 2. In vitro changes in CB 1 and CB 2 receptor expression Cell Culture Condition Cell Type Receptor Expression Technique used to Measure Changes Normal (18) HK-2 CB1, CB2 + RT-PCR, WB Normal (52) LLC-PK1 CB1, CB2 + RT-PCR, IF Normal (6) Rat mesangial cells CB1, CB2 + RT-PCR EC from renal BV CB1 + RT-PCR ↑ Glucose (17) HK-2 CB2 + (↔) RT-PCR ↑ Glucose + albumin (17) HK-2 CB2 + (↓) RT-PCR ↑ Glucose (19) HK-2 CB1 + (↔) RT-PCR, WB ↑ Albumin (19) HK-2 CB1 + (↑) WB ↑ Glucose + albumin (19) HK-2 CB1 + (↑) RT-PCR, WB ↑ Glucose (32) Rat mesangial cells CB1 + (↑) RT-PCR, WB Acute kidney injury. In acute kidney injury (AKI), there were initially conflicting results as to the role of each respective CB receptor and their ligands following exposure to ischemia/reperfusion injury or nephrotoxic agents. Feizi et al. (8) showed a dose-dependent effect by both selective CB 1 and CB 2 receptor agonists to beneficially reduce tubular damage in the kidney following renal ischemia/reperfusion injury. Conversely, administration of cannabidiol, which functions as an antagonist by weakly binding to both CB 1 and CB 2 receptors, resulted in partial prevention of renal tubular injury following bilateral renal ischemia/reperfusion (9). More recently, CB 2 receptor agonists have been shown to reduce markers of renal injury following bilateral renal ischemia-reperfusion (44). Similar findings were observed in another series of studies using cisplatin-induced renal injury (12, 38–40). Blockade of the CB 1 receptor (39) or activation of the CB 2 receptor (38, 40) was shown to be protective against tubular damage by attenuating renal oxidative stress and inflammation. Similar protection of the kidney from the deleterious effects of cisplatin was observed using a natural product, β-caryophyllene, which can act as a CB 2 agonist (12). The mechanism by which CB 1 and CB 2 receptors regulate tubular epithelial cell survival and/or recovery following sublethal damage remains to be fully determined. On a molecular level, renal CB 1 mRNA (39) and protein (39, 55) or CB 2 protein (55) were not significantly altered using multiple rodent models of AKI. However, biopsied kidney samples from humans with acute interstitial nephritis showed increased CB 1 receptor mRNA (29). These molecular differences may be related to the type of AKI and the species from which the kidneys were obtained. Furthermore, although there may be overlap in the distribution of the CB receptors between specific cell types, the physiological outcome of CB receptor activation is likely dependent upon a number of other factors, such as the expression level of CB 1 and CB 2 receptors relative to each other, the G proteins associated with them, and the type of accessory proteins that are in close proximity of the receptors, which can amplify or dampen the signaling output. In animal models of AKI, CB 1 receptor activation is associated with increased production of reactive oxygen species, which can either activate NF-κβ-dependent transcription of downstream proinflammatory target genes, or alternatively activate p38 MAPK and JNK. In the end, both of these pathways activate programmed cell death by apoptosis (Fig. 3B) (39). This was demonstrated in a series of in vitro studies, which found that phospholipase-A 2 metabolism of palmitic acid could promote apoptosis by stimulating CB 1 receptors (31). Conversely, the role of the CB 2 receptor in proximal tubules remains largely unknown, but there is evidence that activation of the CB 2 receptor reverses the proapoptotic signaling mediated by the CB 1 receptor (38, 40). In addition, activation of the CB 2 receptor had an anti-inflammatory effect causing decreased infiltration of immune cells, specifically leukocytes, into the kidney and attenuating inflammatory cytokine release (40). To date, however, the heterotrimeric G protein and accessory protein signaling complexes associated with CB 1 and CB 2 receptors in the kidney remain to be fully described. The latter point may be significant given the difficulties in predicting the overall outcome of EC system activation based on what is known about the CB receptors at the current time. For instance, a recent study using a bilateral ischemia-reperfusion model of AKI found that renal ischemia-reperfusion injury was associated with a significant increase in kidney 2-AG content. While enhancement of renal 2-AG concentrations using an MAGL inhibitor resulted in improvement of markers of renal function, mRNA expression of genes indicative of renal inflammation (such as cytokines) was unchanged. In fact, there was a nonsignificant trend toward increased expression of these genes (36). Therefore, the totality of EC system activation is dependent on many factors and may be more complex than what is predicted on the basis of CB receptor function alone. Future studies will need to further define the role of the CB receptors in the context of the endocannabinoid system in health and kidney disease. In addition, mechanistic in vivo studies are needed to decipher how the CB receptors are expressed and activated under different conditions similar to the findings in vitro (Table 2), and which signaling cascades are responsible for the effect observed in each specific pathophysiological scenario. Furthermore, CB receptor-independent mechanisms will also need to be delineated to better understand which effects are due to CB receptor activation. These studies will be vital to future development of therapies targeting aberrant renal CB receptor activity and EC axis in kidney disease. Moreover, a thorough understanding of the different components of the EC system, especially the CB receptors, will be key to future research on the impact of cannabis use on renal physiology and disease. Effects of Cannabinoids on Human Acute Kidney Injury and Chronic Kidney Disease The widespread and increasing recreational and medicinal use of cannabis and its synthetic derivatives has resulted in the exposure of a large number of individuals to these agents. On the basis of mounting evidence detailing the physiological and pathophysiological effects exerted by renal CB 1 and CB 2 receptor and EC system activation (see previous sections), it is likely that in individuals using these substances, there may be discernible effects on the development and prognosis of both AKI and CKD. Unfortunately, there continues to be a scarcity of epidemiological observations from large-population cohorts regarding such potential effects of cannabis use. Several reports described the development of AKI in patients exposed to synthetic cannabinoids. A case report of a healthy 22-yr-old male, who smoked an unidentified synthetic cannabinoid (“fake weed”), described the development of AKI, with the kidney biopsy showing acute tubular necrosis (24). Another case report of four previously healthy men consuming the synthetic cannabinoid Spice (also known as K2) described the development of oliguric AKI, with kidney biopsies (performed in three of the individuals) showing changes consistent with tubular necrosis (4). Newspaper reports of clusters of AKI associated with the consumption of synthetic cannabinoids (Spice, or K2) suggest that similar events may be occurring more often than being reported in the medical literature (37, 51). A collaborative investigation by several U.S. State Health Departments uncovered 16 additional cases of AKI associated with synthetic cannabinoid use (42). Most of the available biopsy reports showed acute tubular necrosis, but there were also three reports of acute interstitial nephritis. Because of the illicit nature of the products in these case reports, it is not always possible to identify the components responsible for the kidney injury [nine different street products were identified in the cases where this was available (42)], and the role of noncannabinoid contaminants or adulterant agents in the observed pathology cannot be excluded. It is also unclear whether similar adverse effects could occur with medicinal or recreational cannabis use (as opposed to synthetic cannabinoids). A systematic review of 31 studies (23 randomized controlled trials and 8 observational studies) involving medical cannabis use for an average of 2 wk, described mostly nonserious adverse effects, no cases of acute kidney injury, and only one reported case of hematuria (59). Information about the effects of cannabis and cannabinoid use on the development and progression of CKD is also very limited. In a single center cohort of 647 patients interviewed about illicit drug use, those who consumed any kind of illicit substance had a significantly higher risk of mild kidney function decline over a 7-yr follow-up period, but the association of marijuana use with kidney function decline was not statistically significant (although the risk was nominally elevated) (58). In a small prospective trial, medical marijuana use for pain control over 1 yr did not result in significant changes in serum creatinine. Lastly, in an observational cohort of 1,225 kidney transplant recipients, recreational marijuana use was not associated with increased risk of death or worse renal allograft function at one year after transplant (10). None of these studies reported albuminuria, and the limited size of the cohorts and the relatively short duration of follow-up make it difficult to determine with certainty the long-term effects of cannabis or synthetic cannabinoids on kidney function. Future Directions and Research Recommendations It is plausible to hypothesize that the stimulation of CB 1 and/or CB 2 receptors and activation of the EC system in the kidneys may have a significant impact on renal function, which could include both deleterious and beneficial effects. Thus, it is important to further elucidate the physiological roles of these receptors and their ligands in experimental models of the kidney disease and renal physiology, as well as the circumstances under which their stimulation or blockage could result in renal damage or in beneficial effects. Studies of large cohorts will be paramount to clarify the effects of cannabis and cannabinoid exposure on renal outcomes, including AKI, incident CKD, and worsening or improvement in the progression of established CKD. In addition, cohort studies are especially important to examine deleterious renal (and other) consequences of cannabis exposure, since it would be unethical to conduct randomized controlled trials to study these effects. Finally, randomized controlled trials will ultimately be needed to test the safety and efficacy of potential drugs developed to improve kidney function or alleviate kidney damage based on their effects on CB receptors and EC system in the kidneys. Conclusions The use of cannabis (and related) products for both recreational and medicinal use is prevalent, and it is likely to further increase in the near future. Therefore, understanding the consequences of cannabis use on the kidneys and the body as a whole is of significant relevance from a scientific, medical, and public health standpoint. While experimental data suggest that cannabis and cannabinoids could have important effects on kidney function, there is not sufficient evidence from clinical research studies to determine the dangers faced by users of these products in respect to the development of AKI or CKD. Furthermore, it is possible that under certain circumstances, the application of some cannabis-related products could even be beneficial, hence providing a novel potential area of drug discovery to address different forms of kidney disease. Future research is necessary to provide much-needed clarity in this important and dynamically evolving area.

GRANTS H. Moradi is supported by a career development award from the Office of Research and Development of the Department of Veterans Affairs 1 IK CX 001043-01A2. F. Park is supported by National Institutes of Health R01 DK-90123.

DISCLOSURES No conflicts of interest, financial or otherwise, are declared by the authors.