Are CBD Gummies Bad For Your Kidneys

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Cannabinoids and the kidney: effects in health and disease Address for reprint requests and other correspondence: C. P. Kovesdy, Univ. of Tennessee Health Science Center, Memphis, TN 956 Court Why is CBD oil considered a possible treatment for kidney disease? In this post, we discuss what kidney disease is and how CBD oil may help in dealing with it. Here's the information you need to understand CBD oil side effects on kidneys, backed up by the latest research – A helpful guide

Cannabinoids and the kidney: effects in health and disease

Address for reprint requests and other correspondence: C. P. Kovesdy, Univ. of Tennessee Health Science Center, Memphis, TN 956 Court Ave., Memphis TN 38163 (e-mail: [email protected]).

Abstract

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 (CB1 and CB2) 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 CB1 or CB2 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 ).

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.

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 (CB1 or CB2) 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 CB1 and CB2 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 (CB1) and 2 (CB2) 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 CB1 and CB2 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 CB1 and CB2 receptors are sensitive to pertussis toxin, which demonstrates the functional dependency of these receptors on the activation of heterotrimeric G proteins consisting of Gαi subunits (13). The CB1 receptor association with the Gαi 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, CB2 receptors interact with the Gαi 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 CB1 and CB2 receptors, their signaling output can be distinct and, in some cases, lead to opposite biological effects. The diversity of the CB1 and CB2 response on cell signaling pathways remains to be fully described, but likely depends on several factors. First, other Gα subunits, including Gαq/11, have been shown to associate with CB1 to promote a variety of effects, including increased intracellular calcium (28). Second, the relative abundance and distribution of the CB1 and CB2 receptors can differentially change during normal and diseased states. Third, the Gα subunits associated with the CB1 and CB2 may not be localized to the same cell types. As an example, the Gαo subunits, which are primary G protein subunits, interact with CB1 and CB2 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 CB1 and CB2 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 CB1 or CB2 expression changes and localization in the kidneys from mice, rats, and humans. In human kidneys, CB1 receptor protein has been detected in proximal convoluted tubules, distal tubules, and intercalated cells of the collecting duct (27). In rodents, CB1 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 CB1 and CB2 mRNA has also been detected. Furthermore, CB2 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-CB1 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 CB1 and CB2 receptor localization in mammalian kidneys

Animal Model Kidney Region/Cell Type Expression Technique Used to Measure Changes
CB1 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
CB1 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
CB2 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

STZ, streptozotocin; HFD, high fat diet; ZDF, Zucker diabetic fatty; UUO, unilateral ureteral obstruction; PCT, proximal convoluted tubule; Glm, glomerulus; DT, distal tubule; IC CD, intercalated cells of the collecting duct; BV, blood vessels; TAL, thick ascending limb of Henle; +/−, presence or absence of transcript or protein expression. The change in expression, if any, is shown as an increase (↑), decrease (↓), or no change (↔). The molecular techniques used to identify the expression of the cannabinoid 1 (CB1)/CB2 receptors were RT-PCR, Western blot analysis (WB), immunohistochemistry (IHC), and immunofluorescence (IF).

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 CB1 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 CB1 receptor. Another study showed that infusion of AEA into the renal medullary interstitium led to a rapid diuretic effect through a CB1-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-CB1 receptor mechanism (49). No change in systemic blood pressure was measured, even with alterations in renal medullary blood flow (49).

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Renal tubular epithelial cells.

To determine whether a tubular component was involved in the CB1-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 CB1 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 CB1 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.

Cannabinoid receptor signaling in renal glomerular and tubular epithelial cells. Cannabinoid 1 (CB1) 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; PLA2, phospholipase A2; BV, blood vessels; TRPV1, transient receptor potential vanilloid 1; DAG, diacylglycerol; PIP2, phosphatidylinositol 4,5-bisphosphate; IP3, inositol 1,4,5-trisphosphate.

Glomerulus.

The physiological function of CB1 and CB2 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 CB1 and CB2 in the glomerulus ( Fig. 3A ). For instance, in the CB1 transgenic mice, overexpression of the CB1 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 CB1 agonist, WIN55212-2 (15). Increased stimulation or production of the CB1 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 CB1 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 CB1 mRNA (29). Concomitant with the increased levels of CB1 receptor, there is evidence that glomerular CB2 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 CB1 receptor or activation of the CB2 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 CB1 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 CB1 receptor resulted in a reduction in microalbuminuria and decreased expansion of mesangial cells in the glomerulus (43). In Zucker diabetic obese rats, CB1 inverse agonist, JD5037, improved renal function and reduced albuminuria after long-term chronic administration (22). On the other hand, activation of the CB2 receptor has been shown to play a protective role in the diabetic nephropathy (3, 20). Functionally, CB2 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 CB1 receptor (21). In addition to the improvement in glomerular function, blockade of the CB1 receptor has been shown to reduce the progression of renal fibrosis in the unilateral ureteral obstruction mouse model (29). The mechanism by which the CB1 receptor antagonism reduces protein excretion may involve VEGF production, which is known to be linked to nephrin expression. In addition, CB1 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.

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 CB1 and CB2 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 CB1 and CB2 receptors, resulted in partial prevention of renal tubular injury following bilateral renal ischemia/reperfusion (9). More recently, CB2 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 CB1 receptor (39) or activation of the CB2 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 CB2 agonist (12).

The mechanism by which CB1 and CB2 receptors regulate tubular epithelial cell survival and/or recovery following sublethal damage remains to be fully determined. On a molecular level, renal CB1 mRNA (39) and protein (39, 55) or CB2 protein (55) were not significantly altered using multiple rodent models of AKI. However, biopsied kidney samples from humans with acute interstitial nephritis showed increased CB1 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 CB1 and CB2 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, CB1 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-A2 metabolism of palmitic acid could promote apoptosis by stimulating CB1 receptors (31). Conversely, the role of the CB2 receptor in proximal tubules remains largely unknown, but there is evidence that activation of the CB2 receptor reverses the proapoptotic signaling mediated by the CB1 receptor (38, 40). In addition, activation of the CB2 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 CB1 and CB2 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.

Table 2.

In vitro changes in CB1 and CB2 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

HK-2, immortalized proximal tubule epithelial cell line from normal adult human kidney; LLC-PK1, porcine kidney proximal tubule cell line; EC, endothelial cells; BV, blood vessels. +/−, presence or absence of transcript or protein expression. The change in expression, if any, is shown as an increase (↑), decrease (↓), or no change (↔). The molecular techniques used to identify the expression of the CB1/CB2 receptors were RT-PCR, WB, and IF.

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 CB1 and CB2 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).

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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 CB1 and/or CB2 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.

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.

CBD and Kidney Disease: Benefits, Dosage, and Side Effects

The kidneys are an essential organ that filters the blood and removes toxins from our bodies. In order for our kidneys to function properly, they need a steady supply of water and nutrients. When the kidneys don’t receive these substances, complications like kidney disease may happen.

With more and more people becoming aware of the effects of kidney disease on the human body, studies are now being conducted to find possible treatments for it.

And one substance that researchers find promising is CBD oil. A non-psychoactive cannabinoid derived from hemp plants, CBD may be beneficial in treating some symptoms associated with kidney diseases, such as inflammation or pain.

This blog post will explore how CBD oil works against kidney disease and what research has been done on this topic so far.

What Is Kidney Disease?

Kidney disease, also known as kidney failure, is a condition where the kidneys are not able to remove waste and excess water from the body. When a person is diagnosed with kidney disease, high levels of fluid, electrolytes, or toxins may be found in the blood, leading to other health conditions, like heart problems, anemia, bone loss, and other serious health consequences.

According to the National Kidney Foundation, this debilitating condition affects about 37 million people in the United States alone. And what’s worse is that about 90% of those with this condition don’t even know they have it.

Kidney disease may manifest in various forms. But the most common ones are:

  • Chronic Kidney Disease – It is a long-term condition that is commonly caused by high blood pressure. When there is high blood pressure in the kidneys, more pressure is also asserted on the glomeruli – the tiny blood vessels found in the kidneys where blood is filtered and cleaned. Increased pressure on these vessels may result in damage to the kidneys and a decline in kidney function.
  • Glomerulonephritis – This condition is a result of inflammation in the glomeruli. It is caused by congenital defects and improper use of drugs, but it can also be caused by infections. Unlike other forms of kidney disease, it usually gets better on its own.
  • Urinary Tract Infection – This is a form of kidney disease caused by a bacterial infection in the urinary system. While it can be easily treated, if ignored for long periods, it can spread to the kidneys and result in kidney failure.
  • Kidney Stones – Another common kidney problem, kidney stones form when minerals in the blood start to crystallize in the kidneys, forming stone-like solid masses. These stones can be released during urination, but the process of releasing them can be painful.

Treatment for kidney disease may include dialysis (where your blood is filtered and cleaned outside of your body using a machine), peritoneal dialysis (where fluids move through your abdomen), erythropoietin therapy (a medication that stimulates red cells production), or transplantation surgery.

What Causes Kidney Disease?

The kidneys help regulate the blood pressure and filter waste materials that enter the bloodstream. Our kidneys are quite precise in eliminating waste as they filter on a microscopic level. The functional unit that is responsible for all the filtration processes is called the nephron.

In every kidney, about 1 million nephrons work, pulling foreign compounds out from the bloodstream. In a day, around 180 liters of blood is being filtered by the kidneys.

While these nephrons do a great job at filtering unwanted foreign compounds, they are generally very sensitive. They can easily get damaged if toxic compounds are detected in the blood. For instance, in the case of a diabetic, blood sugar levels are often high, and the tissues in their bodies can easily get damaged, including the very sensitive nephrons.

When these nephrons become damaged, more strain is added onto the remaining nephrons, further putting them at risk of more damage.

What Are the Symptoms of Kidney Disease?

It’s not always easy to identify what kidney disease can do to you. In fact, it is so hard because the symptoms are often vague and might seem unrelated. There are a few telltale signs, however, that indicate a problem. Some are:

  • Loss of appetite
  • Chronic pain
  • Extreme fatigue
  • Muscle cramps
  • Sleep problems
  • Foamy urine
  • Hypertension
  • Darkened skin
  • Lack of concentration
  • Swelling in the wrists or abdomen
  • Swelling of ankles and feet

How to Diagnose Kidney Disease

Kidney disease is diagnosed by performing different tests and scans. To test whether the kidneys are normal or not, the hallmark sign, estimated glomerular filtration rate (eGFR), is used. This metric refers to the volume of fluid that can pass through the kidney. If the value is low, it means that the kidneys are not fully functioning.

Aside from checking the eGFR values, the common procedures and tests that are generally performed to know the severity of kidney disease include:

  • Blood Test – Waste product levels in the blood are examined in this test.
  • Imaging Test – Doctors may use ultrasound devices to check the size and structure of a patient’s kidneys.
  • Urine Test – Urine samples are often needed to check if there are abnormalities in your urine that can lead to chronic kidney failure.
  • Kidney Biopsy – In this test, a sample of kidney tissue may be asked from the patient. The process may involve the use of local anesthesia using a long, thin needle that is inserted through the skin and into the kidney.

CBD: A Potential Treatment Option for Kidney Disease

The patient population for kidney disease is large. If you are one of these patients or you happen to know one, it’s quite a relief to know other treatment options are being studied today that may be able to help slow or even reverse the disease.

One of these treatments involves the use of CBD oil as an alternative form of medication for kidney disease symptoms like pain and inflammation. Though research on this subject is still at preliminary stages, there is a lot of potential for this treatment.

Let’s find out more about how CBD can potentially help with kidney disease in the succeeding sections.

Can CBD Oil Really Help with Kidney Disease?

Once the kidneys fail, it means that they have already stopped working and that the person may need a kidney transplant or regular dialysis to survive. Although these treatment options are beneficial for survival, they, too, have adverse side effects.

At this point, many of you may ask: what about CBD oil for kidney disease? To date, there are no studies that can attest to the effect of using CBD oil on our kidney health. But there are limited published studies that focus on the effects of cannabis on kidneys.

According to one study, cannabis may have promising effects when used as a treatment for the symptoms of advanced CKD and end-stage renal disease. Based on the study, some patients with CKD have used CBD to treat chronic symptoms like nausea, anorexia, anxiety, and pain. It is worth noting, though, that CBD oil has not been proven to prevent or treat chronic kidney disease itself.

Is It Safe for Patients with Kidney Disease to Use CBD?

Though more tests need to be done, CBD is generally considered a relatively benign substance. No reports have been recorded about the dangers that CBD poses among patients with kidney disease as well.

CBD is just released from the body via the fecal route, and it does not even involve so much kidney interaction. The only side effects known to be associated with CBD use are diarrhea, loss of appetite, to name a few.

CBD vs. Kidney Disease Symptoms

Kidney disease has no established cure. Therefore, the treatment often focuses on the symptoms. This is where CBD comes into the picture.

Based on recent medical studies, the possible health benefits of CBD may overlap with the symptoms of kidney disease in some ways. Let’s discuss some of them below.

Reduced Inflammation

Some forms of kidney disease, like pyelonephritis and glomerulonephritis, lead to kidney inflammation. And while some studies reveal that CBD may have anti-inflammatory properties, they were done on patients with multiple sclerosis. Other studies were performed on rats with sciatic nerve inflammation. This means more studies need to be done to identify the real impact of CBD on kidney inflammation.

Here’s a more recent study that looked into the potential of CBD for inflammation. Using an animal model, researchers explored if CBD can reduce cytokine storms and treat acute respiratory disease syndrome (ARDS). It was then found that the substance may reduce cytokine storms, protect pulmonary tissues, and promote inflammatory homeostasis.

Pain Management

There’s a lot of pain involved in kidney disease. It could be caused by kidney inflammation, urinary tract infection, or kidney stones. Research shows that CBD has promising abilities to reduce pain caused by arthritis, chronic pain, and surgical incisions. That explains why some are considering this substance as a treatment option, too.

Loss of Appetite

Another common symptom of kidney disease is loss of appetite. When left untreated, it can lead to dangerous weight loss or unwanted weight gain.

In an animal test performed on rats, it was found that CBD may help regulate appetite. The subjects of the study experienced a loss of unwanted body weight. But in any case, this animal test does not translate to human results. Some kidney disease patients, though, have considered CBD as a treatment for their loss of appetite as there are also claims that CBD is a moderate appetite stimulant.

Mood Management

CBD may help boost your body’s anandamide levels once they drop. A study in 2012 found that CBD may enhance the signaling of anandamide – a naturally occurring acid derivative that plays a significant role in mood management, memory, and appetite.

See also  Non Psychoactive CBD Oil

Experts also believe that CBD may have a positive effect on the brain’s serotonin receptors, which are responsible for regulating mood and physiological processes like vomiting.

Now, while there is not enough evidence that shows CBD may boost the brain’s serotonin levels, experts report that it may affect how the brain’s chemical receptors react to the existing serotonin hormones in the system.

Preclinical studies also suggest that CBD may modulate the brain’s GABA levels. GABA plays a role in how humans perceive fear, stress, and anxiety, slowing or blocking nerve signals in the brain. This shows that CBD helps to relieve patients’ anxiety and stress by regulating their moods and emotions.

In the study, mice were exposed to an infection that affected the balance between glutamate and GABA levels. With the introduction of CBD, the glutamate and GABA balance was restored and normalized.

CBD Oil Dosage for Kidney Disease

We’ve mentioned that several studies have been performed to deal with the symptoms of kidney disease. But before you consider using CBD oil for treating them, take note that kidney disease is a serious condition. Therefore, any potential treatment option must first be discussed with a doctor.

The thing with CBD oil is that it can be challenging to find the correct dosage because its components may have varying effects on the human body. And unfortunately, there is no study or research to date that can prove the effectiveness of CBD oil for kidney disease. So far, only animal testing and experiments have been done to explore the effects of CBD on the kidney.

Still, there are people with kidney disease who are using CBD oil along with other lifestyle changes and medications. As for the dosage, they are using existing dosage information from similar conditions like liver disease. These conditions may require higher doses of CBD oil for the effects to show.

In a report by the World Health Organization, it was stated that in clinical trials and research, CBD is generally administered orally in 100 to 800 mg dosage per day. This can be challenging for patients with kidney disease because they need to calculate the exact amount of CBD per milliliter of oil. This becomes even more challenging because CBD oils come in different concentrations.

If you plan to use CBD for kidney disease, we suggest that you begin with a small dose. As your body gets accustomed to it, you will know its effects on your body. By then, you can gradually increase your dosage. Again, because of the uncertainties about the proper dosage, patients are strongly advised to talk to their doctors first.

As a general rule of thumb, it’s best to start with 2–5 mg of CBD for every 10 pounds of your body weight.

Summarizing the Health Benefits of CBD Oil for Kidney Disease

Due to the limited treatment options for patients with kidney disease, it’s not surprising why therapeutic alternatives like CBD are in high demand. And despite the lack of research on the use of CBD for kidney disease symptom management, many are willing to take the risk and start experimenting with CBD.

Although CBD is now widely used in various health conditions, its efficacy with kidney disease is still being researched. So, while studies are ongoing, consult with a professional first before you decide to use CBD oil for kidney disease.

What are your thoughts on using CBD oil for kidney disease? Let us know your thoughts in the comments!

References:

  • Kidney disease: The basics. National Kidney Foundation. (2021, May 20). Retrieved October 12, 2021, from https://www.kidney.org/sites/default/files/web_kidneybasics_v4.pdf [1]
  • Rein, Joshua L. The nephrologist’s guide to cannabis and cannabinoids, Current Opinion in Nephrology and Hypertension: March 2020 – Volume 29 – Issue 2 – p 248-257 doi: 10.1097/MNH.0000000000000590 [2]
  • Ho, C., Martinusen, D., & Lo, C. (2019). A Review of Cannabis in Chronic Kidney Disease Symptom Management. Canadian journal of kidney health and disease, 6, 2054358119828391. https://doi.org/10.1177/2054358119828391 [3]
  • Khodadadi, H., Salles, É. L., Jarrahi, A., Chibane, F., Costigliola, V., Yu, J. C., Vaibhav, K., Hess, D. C., Dhandapani, K. M., & Baban, B. (2020). Cannabidiol Modulates Cytokine Storm in Acute Respiratory Distress Syndrome Induced by Simulated Viral Infection Using Synthetic RNA. Cannabis and cannabinoid research, 5(3), 197–201. https://doi.org/10.1089/can.2020.0043 [4]
  • Argueta, D. A., Ventura, C. M., Kiven, S., Sagi, V., & Gupta, K. (2020). A Balanced Approach for Cannabidiol Use in Chronic Pain. Frontiers in pharmacology, 11, 561. https://doi.org/10.3389/fphar.2020.00561 [5]
  • Ignatowska-Jankowska, B., Jankowski, M. M., & Swiergiel, A. H. (2011). Cannabidiol decreases body weight gain in rats: involvement of CB2 receptors. Neuroscience letters, 490(1), 82–84. https://doi.org/10.1016/j.neulet.2010.12.031 [6]
  • Leweke, F. M., Piomelli, D., Pahlisch, F., Muhl, D., Gerth, C. W., Hoyer, C., Klosterkötter, J., Hellmich, M., & Koethe, D. (2012). Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Translational psychiatry, 2(3), e94. https://doi.org/10.1038/tp.2012.15 [7]
  • de Mello Schier, A. R., de Oliveira Ribeiro, N. P., Coutinho, D. S., Machado, S., Arias-Carrión, O., Crippa, J. A., Zuardi, A. W., Nardi, A. E., & Silva, A. C. (2014). Antidepressant-like and anxiolytic-like effects of cannabidiol: a chemical compound of Cannabis sativa. CNS & neurological disorders drug targets, 13(6), 953–960. https://doi.org/10.2174/1871527313666140612114838 [8]
  • Osborne, A. L., Solowij, N., Babic, I., Lum, J. S., Newell, K. A., Huang, X. F., & Weston-Green, K. (2019). Effect of cannabidiol on endocannabinoid, glutamatergic and GABAergic signalling markers in male offspring of a maternal immune activation (poly I:C) model relevant to schizophrenia. Progress in neuro-psychopharmacology & biological psychiatry, 95, 109666. https://doi.org/10.1016/j.pnpbp.2019.109666 [9]
  • World Health Organization. (2018). CANNABIDIOL (CBD).
Nina Julia

Nina created CFAH.org following the birth of her second child. She was a science and math teacher for 6 years prior to becoming a parent — teaching in schools in White Plains, New York and later in Paterson, New Jersey.

CBD Oil Side Effects on Kidneys, Effects, Doses, a Guide

Can CBD oil be beneficial for your kidneys? And are there any CBD oil side effects on kidneys that you need to be aware of?

The non-psychoactive component of cannabis, which is often prepared as an oil (CBD oil), has recently been suggested as a potential treatment for many medical issues.

So, is there a link between CBD oil use and kidney damage? Or could CBD oil actually benefit overall kidney health?

CBD Oil Side Effects on Kidneys: Current research doesn’t point to any specific side effects on kidneys. As there is no official dose of CBD oil, it can be difficult to know if you are taking too much. More recent research indicates that CBD oil may benefit kidney health. However, more studies are necessary.

Preclinical and clinical studies have indicated a potential benefit of CBD use in chronic pain associated with multiple conditions.

However, some might question if CDB oil has side effects on the kidneys or if CDB is safe to use if you have kidney problems.

With this summary in mind, let’s begin by recapping exactly what CBD oil is, so we can better understand its effects on the kidneys.

What is CBD oil?

Cannabidiol, or CBD, is a non-psychoactive compound found in hemp and marijuana. CBD is one of at least 85 active cannabinoids identified within the Cannabis plant.

Most CBD oil available is a mix of CBD and carrier oil.

These oils can be coconut oil or hemp seed oil. This bottled oil, sometimes referred to as a tincture, is sold in various concentrations.

CBD oil is also available as capsules, CBD gummies, and under-the-tongue CBD sprays.

The endocannabinoid system

CBD or ‘cannabidiol’ is a naturally occurring compound found in the cannabis plant. It is one of many cannabinoids present in the plant that interact with the body’s endocannabinoid system.

So we can more easily understand if there are any CBD oil side effects on kidneys, we will discover more about the endocannabinoid system and how it works.

What is the endocannabinoid system?

The endocannabinoid system or ECS is a complex cell-signaling system identified in the early 1990s by researchers exploring THC.

Although much research has been carried out on the endocannabinoid system, it is still not fully understood.

However, what we do know is that it plays a pivotal role in regulating many processes and functions within our bodies which include:

  • Memory
  • Sleep
  • Mood
  • Reproduction and fertility
  • Metabolism
  • Liver function
  • Pain
  • Inflammation
  • Responses of the immune system
  • Memory and learning
  • Appetite
  • Cardiovascular function
  • Formation of bones
  • Bone growth
  • Stress
  • Nerve and skin function
  • Motor control

It’s important to understand that the endocannabinoid system exists and is also active in your body even if you don’t use cannabis or cannabis products.

But how does this system relate to your kidneys? And what CBD oil side effects on kidneys could occur?

Effects of cannabinoids on the kidneys

As CBD oil connects with the endocannabinoid system in the body, it’s worth investigating how that might affect the kidneys.

According to research, while both CB1 and CB2 receptors are present in the kidneys, the endocannabinoid system’s (ECS) effects on the kidneys are not well understood.

Let’s explain if CBD oil has any general side effects so we can understand more about if it might affect the kidneys.

Does CBD oil have side effects?

Though CBD is generally well tolerated and considered safe, it may cause adverse reactions in some people.

Some side effects noted in some studies include

  • Diarrhea
  • Fatigue
  • Changes in appetite
  • Changes in weight

CBD interacts with certain medications also. For example, it can increase the level of Coumadin (a blood thinner medication) in your blood.

Grapefruit has a similar effect, which explains why many medication guides direct patients to avoid consuming grapefruit or grapefruit juice.

The reason for this is because both grapefruit and CBD contain enzymes that are important for how successfully drugs metabolize in your body.

So the crucial point to remember is that before you start to use CBD oil, make sure you discuss it with your doctor to ensure it’s safe to mix with your existing prescriptions.

Although there appears to be no significant research that has been undertaken on how CBD oil affects the kidneys, there has been a study performed on the liver.

The results of this study did show that CBD oil had the potential to cause toxicity of the liver.

However, it’s important to note that the mice in the study had been force-fed considerably large doses of oil.

Can CBD oil actively assist in kidney diseases?

Cannabis and its derivatives, such as CBD, do not seem to affect kidney function in healthy people.

New research appears to have promising potential when used topically for the treatment of uremic pruritus (chronic kidney disease).

Cannabis may have medicinal benefits for treating symptoms of advanced chronic kidney disease (CKD) and end-stage renal disease. It may also be used to help relieve pain, reducing the need for addictive medications, such as opioids.

CBD oil has not been shown to cure or prevent chronic kidney disease, but it may relieve some of the symptoms of CKD.

According to the above research, renal function should be closely monitored in those with CKD, and the lowest effective doses of CBD oil should be used.

According to nurse Lisa Miller Hedin BSN, RN, the potential for cannabis-related products such as CBD oil has been misunderstood by medics and others.

Speaking at The American Nephrology Nurses Association’s National Symposium recently, she told attendees that it has great potential for treating patients with chronic kidney disease.

“…As nurses, we need to be responsible and find out if our patients are taking it and how we can treat them safely.”

Nurse Lisa Miller Hedin BSN, RN

Dosage and preparation – CBD oil side effects on kidneys

The above information does seem to lead to the fact that CBD may help treat those with kidney disease. However, one of the main issues with taking CBD oil is that there are currently no official guidelines for the appropriate use of CBD oil.

CBD oil is usually delivered sublingually, which is more easily understood as under the tongue.

Most oils are sold in 30-milliliter (mL) bottles with a dropper cap. There is currently no known ‘correct’ dose of CBD oil.

The general rule of thumb is to start with a dose of 10-20 mg a day for a week to see how well it is tolerated. Gradually increase your dose each week until you it begins to have the desired effect.

The World Health Organization reported that clinical research studies on CBD typically used dosages between 100 and 800 milligrams per day.

The difficult part for those looking to use CBD oil for kidney problems is calculating the exact amount of CBD per milliliter of oil. This makes any CBD oil side effects on kidneys harder to ascertain.

It is important to note here that some tinctures will have different concentrations. For example, one tincture may have 1,500 mg per 30 mL, while others have 3,000 mg per mL or more.

Due to the uncertainty of doses, patients are strongly recommended to talk to their doctor and follow their instructions for how much CBD oil they should be taking.

Further CBD help

We hope this has given you some more insight into CBD oil side effects on kidneys. For questions about your specific conditions and treatment options, always consult your doctor.

Here are more articles to help you understand more about CBD and the specifics surrounding it:

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