is cbd oil safe for kidney transplant

The nephrologist’s guide to cannabis and cannabinoids

Cannabis (marijuana, weed, pot, ganja, Mary Jane) is the most commonly used federally illicit drug in the United States. The present review provides an overview of cannabis and cannabinoids with relevance to the practice of nephrology so that clinicians can best take care of patients.

Recent findings

Cannabis may have medicinal benefits for treating symptoms of advanced chronic kidney disease (CKD) and end-stage renal disease including as a pain adjuvant potentially reducing the need for opioids. Cannabis does not seem to affect kidney function in healthy individuals. However, renal function should be closely monitored in those with CKD, the lowest effective dose should be used, and smoking should be avoided. Cannabis use may delay transplant candidate listing or contribute to ineligibility. Cannabidiol (CBD) has recently exploded in popularity. Although generally well tolerated, safe without significant side effects, and effective for a variety of neurological and psychiatric conditions, consumers have easy access to a wide range of unregulated CBD products, some with inaccurate labeling and false health claims. Importantly, CBD may raise tacrolimus levels.

Summary

Patients and healthcare professionals have little guidance or evidence regarding the impact of cannabis use on people with kidney disease. This knowledge gap will remain as long as federal regulations remain prohibitively restrictive towards prospective research.

INTRODUCTION

Cannabis (marijuana, weed, pot, ganja, Mary Jane; Fig. ​ Fig.1) 1 ) is the most commonly used federally illicit drug in the United States. As of December 2019, 33 states and the District of Columbia have medical cannabis programs. Eleven states and the District of Columbia have legalized recreational use. Several countries worldwide have legalized recreational use whereas many others have medical cannabis and decriminalization laws. The prevalence of cannabis use more than doubled between 2001 and 2013 in the United States [1] particularly among people over the age of 50 and even more so among those over 65 years [2▪,3,4▪,5▪]. These age groups are enriched with chronic illness including chronic kidney disease (CKD) that is associated with excess morbidity and mortality [6].

Cannabis sativa W.O.Müll. (A) flowering male and (B) seed-bearing female plant, actual size; (1) male flower, enlarged detail; (2) and (3) pollen sac of same from various angles; (4) pollen grain of same; (5) female flower with cover petal; (6) female flower, cover petal removed; (7) female fruit cluster, longitudinal section; (8) fruit with cover petal; (9) same without cover petal; (10) same; (11) same in cross-section; (12) same in longitudinal section; (13) seed without hull. From Franz Eugen Köhler’s Medizinal-Pflantzen. Published and copyrighted by Gera-Untermhaus, FE Köhler in 1887 (1883–1914). Original figure is now in the public domain. https://commons.wikimedia.org/wiki/File:Cannabis_sativa_Koehler_drawing.jpg.

Cannabis is the dried flower bud of the Cannabis sativa and Cannabis indica plants, and naturally contains numerous phytocannabinoids. Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most abundant and well described phytocannabinoids, with differing activities and affinities for the ubiquitously expressed Gi/o-protein-coupled cannabinoid receptors CB1 and CB2. THC is the primary psychoactive component of cannabis and is a partial agonist to CB1 and CB2 receptors. In contrast, CBD is nonintoxicating and has little affinity for these receptors but acts as a negative allosteric modulator of CB1 with pharmacological effects on other receptor systems including GPR55, TRPV1, 5-HT1A, adenosine A2A, and nonreceptor mechanisms [7]. Plant breeding has created numerous genetically unique Cannabis chemovars, enhancing certain desired effects. For example, chemovars with a higher concentration of THC are selectively produced for recreational use, because THC activation of CB1 mediates the psychotropic effects of cannabis, whereas medical cannabis generally has higher CBD levels than recreational chemovars, often even exceeding the THC content. In fact, symptom relief may be obtained with THC doses lower than what is needed to induce psychotropic effects. Endogenous cannabinoids are eicosanoids derived from cell membrane phospholipids. The two primary endocannabinoids are anandamide/N-arachidonoylethanolamine and 2-arachidonoylglycerol, which are the natural ligands for the cannabinoid receptors. The endocannabinoid system is present in many tissues including the kidney where it has been shown to influence renal blood flow [8,9], glomerular filtration rate [10], fibrosis [11–13], proteinuria [14–21], and tubular function [22–27]. The endocannabinoid system has been comprehensively reviewed elsewhere [28,29▪,30] including specific interactions with the kidney [31,32,33▪,34▪,35–38]. Whole cannabis contains numerous cannabinoid compounds with different affinities, making the predicted cumulative effect on cannabis receptors, and potential renal effects difficult to predict.

Physicians remain poorly educated with respect to cannabis and the endocannabinoid system [39,40▪]. The federal stigma against cannabis in the United States, leading up to the Marihuana Tax Act of 1937 and the Controlled Substances Act of 1970, have strongly limited research and prevented teaching about the drug in medical education. State legalized consumption of cannabis is in conflict with federal law where it remains a Schedule I controlled substance without accepted medical use and a high potential for abuse. Despite this, the World Health Organization classifies CBD as having no potential for abuse [41] and several oral cannabinoid-based pharmaceuticals are U.S. Food and Drug Administration (FDA) approved, having demonstrated efficacy in treating certain medical conditions. Cannabis derived CBD (Epidiolex) is an FDA approved medication for pediatric epilepsy whereas synthetic THC is FDA approved as dronabinol (Marinol, Syndros), and a synthetic THC analogue as nabilone (Cesamet). The cannabis extract nabiximols (Sativex, THC/CBD 1:1) is approved for medical use outside of the United States. 

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CANNABIS AND CANNABINOIDS

Cannabis can be home grown or purchased from retail and medical dispensaries, dependent on the jurisdiction. Cannabis contains over 200 phytocannabinoids, terpenoids, and flavonoids that may act in concert, described as the ‘entourage effect’, so that the combination of plant components act synergistically to be more efficacious than the individual isolated compounds [42,43]. Cannabis can be consumed as dried flower bud through smoking burned plant material or heated in a vaporizer to the vaporizing points for the various cannabinoids (311°F–428°F) without burning the plant and generating smoke. Recently, electronic cigarettes and vape pens have become a popular means to inhale heated aerosol from a concentrated oil containing cannabinoids and/or nicotine. Unfortunately, some THC oil concentrates from illicit manufacturers/underground vape-makers have been associated with fatal lung injury attributed to inhalation of chemical irritants [44▪,45], including vitamin E acetate, used as an oil diluent [46].

Cannabis and isolated cannabinoids can also be processed into foods or ‘edibles’. Over 90% of current users consume cannabis through inhalation whereas oral consumption accounts for less than 10% of cannabis use [47]. Inhalation provides an onset of action within minutes and allows for real-time dose titration. Peak effects are seen within 15–30 min with a half-life of 1–2 h. After oral consumption, the onset of action may be delayed up to 1–2 h, with peak effects at 2–3 h and half-life of 3–6 h. Inexperienced users who do not feel an effect right away may be tempted to overconsume innocuous appearing edible preparations that can lead to drug accumulation and prolonged adverse side effects. For this reason, edibles have been associated with higher rates of emergency room visits, primarily for acute psychiatric symptoms, intoxication, and cardiovascular symptoms [48▪]. Cannabinoids are highly lipophilic and bioavailability is increased with high fat intake compared to consumption on an empty stomach [49]. THC and CBD may interact with the metabolism of prescription medications [50]. CBD is metabolized by CYP3A4 and CYP2C19 with a growing body of evidence suggesting it is also a potent inhibitor of these pathways [51,52] including CYP2C9 [53] and CYP2D6 [54]. The clinical relevance of these interactions is largely unknown. THC has a large volume of distribution (Vd) with slow elimination from the body. Cannabinoids are primarily cleared by the liver and the minority of inactive metabolites are excreted in the urine, accounting for 20% of metabolite elimination. Terminal half-life varies based on frequency of use: several days in infrequent users to over 1 month in heavy chronic users. Cannabinoid pharmacokinetics have been comprehensively reviewed [55,56▪,57]. Evidence regarding the pharmacokinetics of cannabinoids in people with impaired kidney function is scarce. The only published study evaluated 200mg of oral CBD and found no statistically significant differences in maximum measured plasma concentration (Cmax), time to Cmax, area under the plasma concentration–time curve (AUC) from time zero to last measurable concentration, or AUC from time zero to infinity values between participants with severe renal impairment (mean eGFR ∼22 ml/min/1.73 m2) and normal renal function [58▪]. Given the primary hepatic metabolism, dose adjustments are unlikely to be needed. The large Vd for THC and high protein binding [57] suggest limited clearance with hemodialysis.

Dosing recommendations for cannabis and cannabinoid preparations have been previously published [59▪]. Almost 90% of current adult cannabis use is in part or entirely for recreational reasons and slightly less than half is in part or entirely for medicinal purposes [47]. CBD-infused oils, tinctures, creams, food items, and drinks, along with a host of other products, have exploded in popularity since the passage of the Agriculture Improvement Act of 2018 (2018 Farm Bill), which removed hemp (Cannabis sativa with <0.3% THC) from the Controlled Substances Act and legalized its domestic agricultural production as a commodity. CBD is sold in health food stores, retail shops, dispensaries, pharmacies, convenience stores, and on the internet. Already, 14% of Americans use CBD, primarily for pain, anxiety, insomnia, and arthritis [60]. CBD is well tolerated, safe, and effective for a variety of neurological and psychiatric conditions [61–63,64▪], although at high doses, CBD may increase liver enzymes and interact with some prescription medications [65▪]. Consumers have easy access to a wide range of unregulated CBD products with inaccurate labeling and false health claims. A clinical guide on the therapeutic actions and safety of CBD and hemp oils has been recently published [66▪]. In addition to CBD isolate, hemp extract may be marketed as ‘full spectrum’, which contains whole plant extract and a variety of compounds. Hemp seed oils are also sold but do not contain any phytocannabinoid compounds.

There is no evidence to suggest that CBD has any adverse effect on kidney function. In fact, CBD prevented cisplatin induced nephrotoxicity in a mouse model by reducing oxidative stress [67]. However, some products may contain toxic contaminants such as heavy metals, pesticides, and solvents. A study of 84 CBD products sold online found that 42% of products contained more CBD than stated on the label, 26% were overlabeled, whereas only 31% contained the stated amount [68]. Additionally, 20% of these products were contaminated with THC that could potentially be detected on a urine toxicology screen. Some products do not contain a sufficient quantity of CBD to achieve pharmacological activity.

Consumers should scrutinize labels, ensure that the product has been made with good manufacturing practice, ensure cannabinoid extraction using carbon dioxide, ensure organic certification by the U.S. Department of Agriculture, and purchase from a certified medical dispensary or company that has a certificate of analysis. If CBD is regularly consumed, careful monitoring of clinical parameters and drug interactions is warranted.

SYMPTOMS ASSOCIATED WITH CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE

Over 1.5 million people with advanced CKD and about 750 000 people with end-stage renal disease (ESRD) live in the United States [6]. One-quarter to one-half of patients with CKD experience chronic symptoms such as pain, nausea, anorexia, sleep disturbance, anxiety, and depression [69], several of which are approved indications for medical cannabis. In addition, anxiety, depression, and insomnia are the most common psychiatric conditions that people self-treat with cannabis [70]. Evidence supports the use of cannabis in patient populations without CKD for treating several of these symptoms including chronic pain, nausea, and loss of appetite. The rationale for its use in patients with CKD and ESRD has been previously reviewed by myself and others [71,72,73▪].

Pain prevalence among patients with CKD and ESRD is as high as 50% [74]. Pain attributed to kidney disease occurs from polycystic kidney disease, renal colic from nephrolithiasis, renal osteodystrophy, or uremic neuropathy. Historically, cannabis has been recommended for a wide range of ailments including as a spasmolytic for cases of renal colic and to facilitate the excretion of small kidney stones [75].

Over 60% of dialysis patients receive at least one opioid prescription annually and approximately 20% of them take prescription opioids chronically [76]. Both short-term and chronic use of prescription opioids are associated with increased morbidity and mortality [76,77]. Cannabis could have a therapeutic role in pain management that deserves clinical consideration and further clinical trial investigation. Access to medical cannabis has been associated with decreased opioid prescriptions and dose reductions [78–82,83▪]. The National Academies concluded that substantial evidence exists for the use of cannabis and cannabinoids to treat chronic pain [84] while meta-analyses and systematic reviews of cannabis use, including prescription cannabinoids, have given mixed results for treating chronic pain [85–87].

IMPAIRED KIDNEY FUNCTION

Recreational cannabis is most often smoked (>90%) [47,88] and generally contains higher THC content whereas medical cannabis is vaporized or consumed orally and often has a higher CBD content. Medical cannabis programs in several states only allow for edibles and vaporizers and do not allow smoking. Existing research regarding cannabis is biased towards recreational cannabis consumed by smoking prior to or early into state legalization programs.

Among participants with an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m 2 ) in the multicenter Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) study self-reported chronic cannabis usage was associated with more rapid eGFR decline compared to those with an eGFR more than 60 ml/min/1.73 m 2 over a median 4.1 years [89]. Cannabis usage was not associated with changes in albuminuria over time. Conversely, sicker patients who may already have progressive CKD may be more inclined to use medical cannabis for symptom management. An analysis of the Chronic Renal Insufficiency Cohort (CRIC) Study from 2003 to 2008 among 3939 adults with baseline eGFR between 20 and 70 ml/min/1.73 m 2 did not demonstrate an association between cannabis use and CKD progression over 5.5 years of follow-up [90▪].

Among healthy individuals, analysis of the Coronary Artery Risk Development in Young Adults (CARDIA) Study did not demonstrate a longitudinal association between cannabis use and eGFR change, rapid eGFR decline, or prevalent albuminuria after 15 years of follow-up in 3765 participants [91]. Past or current cannabis use was reported by 83% of participants. The CARDIA study began in 1988 and at that time, cannabis had lower THC content and a lower THC/CBD ratio than current levels. Similar findings were revealed in a cross-sectional analysis of 13 995 adults aged 18–59 years in the nationally representative National Health and Nutrition Examination Survey (NHANES) from 2007 to 2014 that did not find a clinically significant effect of self-reported past or current cannabis use on serum creatinine, eGFR, microalbuminuria, or stage 2 or higher CKD [92].

Renal function in cannabis users with CKD should be closely monitored, the lowest effective dose should be used, and smoking should be avoided. It is currently unknown if other routes of administration attenuate kidney risk but they at least avoid potential pulmonary complications.

ACUTE KIDNEY INJURY

Synthetic cannabinoids are potent CB1 agonists originally developed as research compounds but have emerged on the marketplace as popular and potentially dangerous recreational drugs referred to as ‘spice’ or ‘K2’. Numerous cases during 2012 have linked synthetic cannabinoids to acute kidney injury (AKI) [93–95]. Specifically, the synthetic cannabinoid XLR-11 has been identified as a nephrotoxic compound [95] possibly related to effects on proximal tubule mitochondrial function [96]. Synthetic cannabinoids may be nephrotoxic, but a noncannabinoid contaminant has been proposed as an alternative explanation [97,98]. Nausea, vomiting, and flank pain are common in the majority of cases. Kidney biopsy most often demonstrates acute tubular necrosis with some cases of acute interstitial nephritis [99]. Synthetic cannabinoids are not detected on standard blood and urine toxicology screens. Therefore, nephrologists should have a high index of suspicion when diagnosing unexplained AKI.

Cannabinoid hyperemesis syndrome (CHS) [100] is a rare complication of heavy and frequent cannabis use over many years characterized by intractable vomiting that is relieved with hot showers. CHS is occasionally associated with prerenal AKI [101–106], treated with intravenous fluids and antiemetics. Interestingly, hypophosphatemia was observed in a case series of 6 men with CHS [107].

KIDNEY TRANSPLANTATION

CB2 is widely expressed on immune cells and cannabinoids have immunomodulatory effects in animal models of allogeneic transplantation and autoimmune diseases [108–111]. As such, cannabis and cannabinoids may have immunomodulatory effects among kidney transplant recipients. Interestingly, a study of routine kidney transplant biopsies revealed significant upregulation of glomerular and tubular CB1 expression in those with chronic allograft dysfunction compared to low levels in normal kidney allografts, suggesting a role for CB1 in allograft fibrosis [112].

Cannabis use in potential transplant recipients may have implications for pretransplant screening, such as delayed candidate listing or contributing to ineligibility [113▪], with implications for posttransplant outcomes. There is concern regarding adherence to immunosuppressive medications, the ability to follow instructions, and attendance of follow-up appointments. An American Society of Transplantation survey revealed that about half of transplant centers vary in their policy according to the organ, whereas slightly more than one-quarter of centers rejected all candidates regardless of organ [114▪]. Drug screening of potential transplant donors and recipients should consider the prolonged excretion of THC metabolites which may range from a few days in casual users to several weeks to over 1 month with chronic heavy use.

A retrospective single center study of kidney transplant candidates revealed that cannabis abuse and dependence were associated with a high prevalence of other substance use disorders, psychiatric comorbidities, and strong family histories of addictions, resembling other substance use populations that generally adversely affect kidney graft outcomes [115]. A study of a national kidney transplant database demonstrated that cannabis dependence or abuse (CDOA) in the year before transplant was not associated with death or graft failure in the year after transplant, but was associated with posttransplant psychosocial problems such as alcohol abuse, other drug abuse, noncompliance, schizophrenia, and depression [116▪]. CDOA after kidney transplantation was associated with cardiovascular, pulmonary, psychosocial complications, accidents, and fractures. Accordingly, CDOA was associated with an approximately two-fold increased risk of death-censored graft failure, all-cause graft loss, and death in the subsequent 2 years. Although associations likely, in part, reflect comorbid conditions or behaviors, CDOA after kidney transplantation appears to have consequences for allograft and patient outcomes. Additionally, patients who carry a formal diagnosis of CDOA likely reflect ‘extreme’ users who were not able to hide their use and raised suspicion. Data from patients with CDOA cannot be generalized to all as cannabis does not have adverse effects on life in everyone [117▪]. A single center study of 56 cannabis users out of 1225 kidney recipients from 2008 to 2013 demonstrated that recreational cannabis use, defined by positive urine toxicology screen and/or self-reported recent use, did not affect mortality, graft loss, or graft function 1-year posttransplant [118]. Finally, a single center study of 919 kidney transplant recipients from 2001 to 2015 revealed that smoking status was not significantly associated with acute rejection, eGFR, or pneumonia within 1-year posttransplant. Patients with isolated cannabis use had similar overall graft survival compared to nonusers [119▪].

With regards to kidney donation, a retrospective single center study of 294 living kidney donors and 230 recipients between 2000 and 2016 showed that donor cannabis use did not demonstrate any deleterious effects on donor or recipient posttransplantation eGFR over a mean follow up of 2.1 years for donors and 5.2 years for recipients [120▪]. Among recipients of a kidney from a cannabis user, the rates of acute rejection, graft, and patient survival of the kidney allografts were similar to those from nonusers.

Although rare, fungal contamination of cannabis and pulmonary complications have been reported among kidney transplant recipients, including pulmonary aspergillosis associated with smoking cannabis [121,122] and exogenous lipid pneumonia secondary to smoking weed oil [123]. These cases have occurred prior to current cannabis legalization where microbial testing has become a regulatory requirement in the medical and recreational cannabis markets. Although sterilization of cannabis buds can eliminate fungi and may eliminate the risk of fatal opportunistic infections among immunosuppressed individuals [121,124], several toxigenic fungi and bacteria have been detected in cannabis samples [125,126]. Based on existing evidence, cannabis usage alone should not be the sole deciding factor for declining a patient for kidney transplant listing.

Several case reports demonstrate increased tacrolimus levels associated with CBD in a patient with interstitial nephritis and in non-kidney transplant recipients [127▪,128,129], whereas one small case series of low dose CBD for chronic pain among kidney transplant recipients did not reveal any change in tacrolimus levels [130]. Inaccurate product labeling and batch to batch variability of CBD products [68] may lead to unpredictable CNI levels, potential toxicity, or underdosing, especially with intermittent use of different cannabinoid products. Furthermore, CBD inhibits hepatic cyclosporine metabolism in vitro and in mice [131].

MEDICAL RISKS AND COMPLICATIONS

The public health impact of state legalization of cannabis remains unclear and these policies may have contributed to the increasing perception that cannabis is harmless. In fact, more than one-third of U.S. adults strongly or somewhat strongly agree that edible cannabis prevents health problems and more than a quarter strongly or somewhat strongly agree that smoking or vaping cannabis prevents health problems [132 ▪▪ ]. Medical cannabis as an option for those with CKD or ESRD, will include people who are older, frailer, and have more comorbid conditions and co-medications, potentially increasing susceptibility to adverse effects. The most common side effects are dizziness and dry mouth.

Smoking is associated with increased mortality among people with CKD and ESRD [133]. Although smoked cannabis is a source of oxidative stress to the respiratory tract [134] and associated with bronchial irritation and chronic bronchitis [135], regular heavy use is associated with lower risk for pulmonary complications compared to tobacco use [136,137]. A systematic review and meta-analysis demonstrated low-strength evidence that smoking cannabis more than once per week for at least 1 year was associated with cough, sputum production, and wheezing while evidence regarding cannabis use and obstructive lung disease and pulmonary function was insufficient [138 ▪▪ ].

CKD and ESRD are associated with increased cardiovascular morbidity and mortality [139]. Endocannabinoids are involved in various functions of the cardiovascular system including blood pressure regulation [140–142]. Some observational studies suggest a higher incidence of cardiovascular events with cannabis exposure, [143–145] while other studies do not [146,147]. Low strength evidence suggests that cannabis use is associated with tachycardia [148▪]. Acutely, cannabis may cause orthostatic hypotension whereas long-term cannabis use may be associated with a modest increase in systolic blood pressure [149]. Systematic reviews do not reveal any hemodynamic effects of either CBD [150] or THC [151].

Cognitive impairment is common among people with CKD and ESRD [152–154]. Acute cannabis usage may cause sedation and impair spatial-visual distortion while acute and long-term cannabis use can impair verbal learning, memory, and attention [155]. However, a comprehensive review of recreational cannabis and cognitive function revealed inconsistent findings across studies [156▪].

CONCLUSION

Given the rapidly expanding market for cannabis, large-scale longitudinal studies are needed to explore the long-term effects of chronic and frequent cannabis use. Consistent with recommendations regarding the use of tobacco and other smoked substances among patients with CKD and ESRD, smoked cannabis should be avoided among people with cardiovascular or pulmonary disease. Other routes of administration such as oral consumption may avoid these risks.

With growing acceptance of both medical and recreational cannabis and cannabinoids, further research is required to determine the efficacy, safety, and acceptability of medical and recreational cannabis use among people with CKD and ESRD. As clinicians, we should be informed and able to provide guidance with the most up to date information for our patients.

Acknowledgements

The author thanks Joseph Vassalotti and David Goldfarb for their review of the manuscript.

Lankenau Transplant Newsletter

CBD: What’s the big deal?
By: Cassidy Shaver, MSW, LSW, Transplant Social Worker

CBD stands for cannabidiol, a chemical compound found and extracted from cannabis and hemp plants. It is the second most prevalent active ingredient in marijuana (after THC), however, on it’s own, CBD does not have psychoactive affects. CBD can be purchased in many forms—oils, extracts, vaporized liquid and capsules.

How is it legal? CBD is mainly sold and available as an unregulated supplement, which makes it difficult to know exactly what you are getting. The US FDA considers hemp oil (and CBD) to be a dietary supplement, not a medication. The government classifies hemp as any plant in the cannabis family that contains less than 0.3% THC. Any amount over 0.3% is considered “marijuana.” You therefore need no prescription and can legally purchase and consume CBD in any state, though the debate over CBD legality and regulation continues within the federal government and may be subject to change.

What is it supposed to help? CBD is said to help with a host of things from anxiety and depression to chronic pain, epilepsy, and insomnia.

What’s the risk? There is a large risk of unreliable purity, dosing, content, and concentration in CBD products. “You cannot know for sure the product has active ingredients at the dose listed on the label and the product may contain other unknown elements. We also don’t know the most effective therapeutic dose of CBD for any particular medical condition” (Grinspoon, Harvard Health). Long term safety data on the use of CBD is not available as it is not widely approved for medicinal use. Additionally, CBD could potentially interact with other medications (similar to the effects of a grapefruit). Side effects can reportedly include nausea, fatigue, irritability.

Our best advice? Talk with your doctors and consume at your own risk!

Living donor transplant from a caregiver’s perspective
By: Deb Wright

Deb and her husband John Transplant is an all-encompassing experience not only for patients, but also for their loved ones, caregivers and support persons. Support from family and loved ones is one of the best predictors that we as health care professionals have of how a patient may do following transplant, and it can be a tough job. What can be even more difficult is supporting and loving two patients who are simultaneously a part of the transplant process.

Please meet Deb Wright, the mother of living donor Kevin Wright and the spouse of kidney transplant recipient John Wright. On Tuesday, September 18, 2018, Deb and her daughter in law Devon, along with several other family members, waited anxiously as their loved ones underwent living kidney donation and kidney transplant surgery. Read on to hear a little more about how as a family, the Wright’s got through the process of transplant.

“Our son Kevin went to John’s first appointment with the transplant team. I think from that appointment on, Kevin knew he wanted to donate to his father if it was possible. Our other son Michael also wanted to donate, though he was ruled out as a donor for medical reasons.

He was so upset he couldn’t even get tested but was a strong support to all of us as his brother and father went through the process.

Kevin and his wife Devon spoke a lot about the possibility of donation. Devon was fully on board and supportive the whole time. She asked the right questions and attended most of his evaluation appointments with him. She said that she would do the same thing if it were her dad. Kevin talks about the workup process bringing its own hope and changes at each step. He states he would wonder if all the time and energy he was putting into being evaluated and completing testing was going to be worth it or would lead to his clearance for donation.

Kevin was ultimately a match, and when we did find out, I was so grateful and so nervous about the whole idea. I remember thinking, he is so young, he has a wife and a young son, but I knew there was no way I would be able to change his mind. He saw firsthand how his dad’s health was declining, and he wanted to help. Kevin and John didn’t talk much about the transplant beforehand. I think they were both nervous. John says the hardest part of the whole process was this anticipation.

Kevin (left, living donor) and his father, John (recipient) The morning of the transplant was rough. I was a mess. John and I arrived at the hospital before Kevin and Devon, and when they arrived, there was a lot of quiet. I think the nerves really got to us all. Kevin and John were in rooms right next to each other getting prepped for surgery and I was walking back and forth between them, trying to be in both places at once. I didn’t really know where I should be, I wanted to be with both my husband and my son, and as the clock ticked towards surgery, Kevin started to get emotional.

I asked him one last time if he was sure he wanted to do this and told him he could still change his mind. He said, “no way”. He was going to do this! Finally, Kevin was taken to surgery, and we told him we loved him and wished him luck. The day seemed to last forever from that moment on. Our whole family was in the waiting room, visiting, talking, and drinking a lot of coffee. The support of our family was huge for me during that day.

Finally, both Kevin and John were out of surgery and did a wonderful job. We were told the kidney started working right away for John, and I tell everyone now that I’ve never seen so many people so excited about urine. Every nurse, doctor, and provider made comments about all the urine in his bag. We were very happy.

It was a short stay in the hospital for both Kevin and John. They were discharged on the same day, Kevin about two hours before John, and were both happy to be going home. We made lots of trips to Lankenau after the surgery over those next couple of weeks- at first appointments every couple of days and then eventually we graduated to every other week, once a month, and now every couple of months. I think I can do the drive in my sleep! The first couple of weeks were rough for John, with lots of blood work and medication changes, but he was such a trooper through it all.

Now, about nine months later, Kevin is doing great. He had some pain and discomfort while he was recovering but nothing extraordinary. He felt he was almost back to normal (besides some soreness) after about a week. He says he feels no different now than he had prior to donation. He thinks it’s so awesome he was able to help his dad and sees it as a win-win. He remembers vividly the lack of energy and constraints of dialysis affecting his dad and says to see him now is totally worth it.

Today John really can do so much more than he could nine months ago. He is back to his old self- walking every day, mowing the grass, and being more social. He didn’t have any energy to do these things before transplant, he didn’t want to go anywhere and couldn’t walk distances because he would get so tired. Now, he looks forward to spending time with his grandson, being outside, going for walks, and even hopes to fish and go deer hunting when the season arrives. He hasn’t been able to do that for a couple of years. And we just attended our son Michael’s wedding in Maryland!

Overall, our experience was very positive. As a family, our biggest advice to other patients who might be facing similar concerns is to get as much information as possible and talk with as many people as you can. Doctors, other medical providers, and patients or family members that have been through the process can provide such valuable insight. Get your questions answered and follow the recommendations of your doctors. Lean on your support system and family members, and though it may be hard at times, try to keep a positive mindset.”

Parenting, post-transplant
By: Naomi Barton, MSN, CRNP

The first successful pregnancy in a solid organ transplant recipient occurred in 1958 in a woman who had received a living donor transplant from her twin sister. Since then many women with transplants have become mothers but there are some special considerations to keep in mind.

Can I get pregnant after getting a transplant? Yes . In most cases, a woman of childbearing years who was not getting her period before transplant will resume getting her period a month or two after the surgery. It is very important to use birth control, in some cases two different forms, before you begin having sex. In most cases it is recommended to wait at least a year after transplant before planning to have children to ensure that your medication doses are stable, and your kidney is working well.

It is extremely important to discuss your family planning goals with your physicians. Once you and your doctor decide it is a good time to grow your family, you will most likely need to adjust some of your medication. Mycophenolate (aka Cellcept) in particular, is dangerous to fetuses and will need to be stopped before conceiving. Some of your other medications may need to be adjusted, and throughout the pregnancy levels need to be closely monitored. In a small number of cases organ rejection has occurred during pregnancy but most of the time, pregnancy is safe for the kidney. And in most cases, if the mother is in good health with a good working kidney, it is safe for the mother as well.

What about the baby? Babies of transplant recipients are more likely to be born early. However, if the mother has stopped any unsafe medication, there is no increased risk of babies being born with birth defects, and overall most babies born to transplant recipients are healthy. Because we just haven’t been studying this long enough though, we don’t really know if there are any long-term risks to those babies.

What about breastfeeding? The answer is complicated. There are pros and cons to breastfeeding and formula feeding. But if breastfeeding is you goal, discuss it with your doctor to see if it may be the right choice for you and your baby.

What about male recipients of transplants who want to become fathers? While there is one immunosuppression drug which may reduce a man’s chances of getting a woman pregnant, most of the time, men who have received transplants do not have any problems with fertility and their babies are just as healthy as those of men without transplant.

If you are a transplant recipient who has become a parent after transplant, or are considering becoming one, check out the Transplant Pregnancy Registry International.

Staff spotlight: Dr. Adam Bodzin
By: Cassidy Shaver, MSW, LSW, Transplant Social Worker

Dr. Bodzin and his family Meet our newest transplant surgeon, Dr. Adam Bodzin! Adam returned to the Philadelphia area after his fellowship at UCLA and subsequent work in Chicago and joined the Jefferson Transplant Institute Team in September 2018. We have so enjoyed having Adam on our team as he brings charisma, charm, and a plethora of clinical experience. Read on to learn more about our fabulous transplant surgeon.

Cassidy Shaver (CS): How did you decide to specialize in transplant surgery?

Adam Bodzin (AB): I fell in love when I was thrown into it during my first rotation in my first year of residency. We had a skeleton crew and I was involved in a lot of liver transplant surgeries early in my training. It totally altered my mindset in medicine, and I fell in love with the surgical complexity, critical care, and overall life changes transplant can make for patients. That is the best part of my job really, seeing lives transform almost immediately after surgery. Patients are so grateful and thankful for the hope transplant can provide, and I love being a part of that.

CS: What is something our patients might be surprised to learn about you?

AB: I was a bat boy for the Phillies when I was in my teens. I got connected with the team and worked long hard hours during high school. It was a pretty cool experience. Curt Schilling used to help me study by quizzing me when we were on the bench.

CS: What is your vice?

AB: I am partial to all things Vernick food and drink. My best childhood friend Greg Vernick is the mastermind and I’m so proud of him. I love supporting him and he has inspired me to be a little more present in my own kitchen. After a long day, I enjoy coming home and winding down by cooking for my wife, Julia.

CS: What is something you would like to improve about transplant?

AB: I’d like to improve the health disparities we see in transplant. There is a lot of work to be done on this front.

CS: What are you most looking forward to this summer?

AB: Some time down the shore with my family. I have to force myself to take some time off, it’s not really in my nature, but I know it’s important. We will have a nice time with family and our girls.

Joan’s cooking corner

Homemade pan sausage

Homemade pan sausage is a yummy, kidney-friendly breakfast recipe that will help start anyone’s day on a positive note.

A quarterly recipe shared with you from your Transplant Dietitian, Joan Diorio, RD.

Why do I need… to wait for a kidney
By: Kristina Bryson, RN, CCTC

If you ask someone who is waiting for a kidney transplant what the hardest part of the process is, they will most likely tell you, “it’s the waiting.” The average wait for a deceased donor kidney in this region is somewhere between five and seven years from a person’s “qualifying date,” which is either the day they are added to the transplant list or the day they start chronic dialysis, whichever comes first. There are several factors that can influence the waiting time such as blood type, antibody level and what types of donors recipients will consider.

Kidney transplant is one of the only types of organ transplants that is driven by waiting times and not by how sick the patients are. The reason for this is that ESRD patients can use dialysis as a bridge to transplant. Dialysis will maintain patients until they can receive their transplant.

There are some strategies that can be used to potentially decrease the wait for a kidney. The first is to find a living donor. This is a living person that chooses to donate a kidney to someone in need. You do not have to be related to your living donor. Once both recipient and donor are cleared for surgery, the transplant is scheduled. Always be open to living donation. If you do have a potential living donor, please call our Living Donor Coordinator, Naomi Barton, at 484.476.8485.

Another strategy is to consent for all possible deceased donor options for which you are a candidate. This will maximize the amount of offers you receive and can potentially shorten the amount of time you wait for a transplant. Your transplant coordinator reviews deceased donor options with you at the time of your evaluation and at each of your annual visits. If you have questions or would like to review these options now, please contact our Pre-Transplant Coordinator, Kristina Bryson, at 484.476.8485.

Clinical impact of marijuana usage in liver transplant recipients

Contributions: (I) Conception and design: EM Wu, S Saab; (II) Administrative support: S Saab; (III) Provision of study materials or patients: S Saab, KG Meneses, S Kang, AK Lee; (IV) Collection and assembly of data: EM Wu, KG Meneses, S Kang, AK Lee, S Neogi; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Background: Marijuana use for both medical and recreational purposes is increasing in the US. There is a paucity of data on marijuana usage in post-liver transplant patients.

Methods: This is a retrospective descriptive study examining patients >18 years of age who underwent liver transplantation at the University of California Los Angeles Medical Center between 1985 to 2019 who had positive urine drug screen for marijuana post-transplant. Exclusion criteria included lack of blood chemistries at time of positive marijuana screen and a positive marijuana screen obtained only before transplant.

Results: Of 22 patients, 16 (72.7%) were male with an average age at transplant of 39.9 years. Alcoholic cirrhosis (40.9%) and hepatitis C (18.2%) were common indications for transplant. Urine drug screen was done most often for evaluation of transaminitis (6/22, 27.3%) and gastrointestinal symptoms (6/22, 27.3%). Elevated liver enzymes were found in 14 patients, with a cause identified in eight patients. The most common cause of elevated liver enzymes was non-adherence with immunosuppression (6/8, 75%).

Conclusions: Non-adherence with immunosuppression was the most commonly identified cause of elevated liver enzymes. A majority of these patients had biopsy proven rejection. Further studies are needed to evaluate whether there is a link between marijuana usage and immunosuppression non-adherence.

Keywords: Marijuana; clinical decision-making; compliance/adherence

Received: 08 August 2020; Accepted: 31 December 2020; Published: 30 December 2020.

Introduction

Currently, 33 states in the United States have approved medical marijuana laws while 11 states have approved recreational use of marijuana (1). From a federal standpoint, marijuana is the most commonly used illicit drug (2) and as usage is projected to increase, physicians will be challenged to appropriately counsel their patients on the health effects of marijuana. This is a formidable challenge as the medical literature is still expanding and there is a lack of guidance from professional organizations.

The two most common active compounds in marijuana are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC acts on CB1 and CB2 receptors (endocannabinoid receptors) and is commonly used to measure the potency of a marijuana formulation and is responsible for its psychoactive effects, a result of CB1 receptor activation in the brain leading to increased release of dopamine. CBD, in contrast lacks the psychoactive high associated with marijuana usage (3). Current FDA approved indications for THC-based medications (dronabinol, nabilone) include nausea in patients undergoing chemotherapy and appetite stimulation in AIDS cachexia, while the CBD-based medication cannabinol (epidiolex, Greenwich Biosciences, Inc., Carlsbad, CA) is approved for Dravet and Lennox-Gastaut syndrome, severe childhood epilepsy syndromes (4). Data also support clinically significant reduction in pain in chronic pain patients and improvement in patient-reported spasticity symptoms in multiple sclerosis (5). While the potential of marijuana-based therapies for various conditions is appealing, it must be balanced against data that suggest an association with lower educational attainment, acute impact on cognitive function and increased risk of motor-vehicle accidents and development of schizophrenia (6-9).

What then, should the approach be for patients undergoing or post-liver transplantation? A recent study surveying 49 United Network for Organ Sharing (UNOS) transplant centers in North America found that 14% of programs transplanted patients actively using marijuana while 28% additionally transplanted patients as long as cessation was achieved by time of transplant (10). Furthermore, 7 US states (Arizona, California, Delaware, Illinois, Maine, New Hampshire, Washington) have recently introduced laws that prohibit denial of transplantation based on marijuana use (11). Governing organizations such as the American Association for the Study of Liver Diseases (AASLD) leave the decision to transplant or not up to each transplant center (12). Data that suggest cannabinoids can possibly lead to increased immunosuppression drug (tacrolimus) levels in the blood are also concerning given known systemic toxicities such as nephrotoxicity and neurotoxicity (13). As each organ is a precious resource, concerns regarding marijuana’s impact on the allograft, treatment non-adherence, increased risk of infections, and drug-drug interactions are most cited as prohibiting factors for transplant.

More data on marijuana usage in the liver transplant population is needed. In our study, we aim to characterize patients in our center who screened positive for marijuana usage to delineate the demographics, biochemical status and other comorbidities that these patients face with the goal of identifying data that may impact post-transplant success. We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/dmr-20-120).

Methods

We performed a retrospective chart review of all patients >18 years of age who underwent liver transplantation at the University of California Los Angeles Medical Center (UCLA) between 1985 to 2019. Inclusion criteria included patients that were actively being followed post-transplant and known usage of marijuana at any point post-transplant defined as a positive screen on urine drug. Exclusion criteria were lack of blood chemistries at time of positive marijuana screen and a positive marijuana screen obtained only before transplant. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the UCLA Institutional Review Board (IRB #19-001546) and individual consent for this retrospective analysis was waived.

Analysis of the UCLA Liver transplant database identified 22 patients who met our inclusion criteria (Table 1). Data were obtained by review of the patients’ electronic medical record (EMR). Data collected include age, sex, date of transplant, age at transplant, race, indication for transplantation, concurrent drug usage, reason for marijuana usage, type of marijuana used, reason for urine drug screen, liver enzymes at time of positive marijuana screen, immunosuppression regimen and level at time of marijuana usage, abdominal ultrasound and liver biopsy pathology at time of usage. Elevated liver enzymes were defined as an elevation above normal range in either AST, ALT, total bilirubin, or alkaline phosphatase. For patients that were documented to have elevated liver enzymes, electronic medical records were reviewed for an identified cause of elevated enzymes and subsequent management. Of note, the majority of data collected relied on objective measurements which decreased recall bias that could be associated with our study design. Given the descriptive nature of the study, the patients with minimal missing data related to reason for marijuana usage and reason for urine drug screen were not removed from data analysis.

Table 1

Patient # Sex Age Age at transplant Date of transplant Race Indication for transplant Concurrent drug usage Reason for urine drug screen Elevated Liver enzymes? Type of Marijuana Reason for marijuana usage
1 M 37 37 9/25/18 Hispanic Alcoholic cirrhosis None History of usage, Inpatient evaluation of transaminitis Yes CBD oil, smoking Chronic back pain
2 M 35 35 9/7/04 Hispanic Fulminant Wilson’s disease None Inpatient evaluation of transaminitis Yes Denies usage Not documented
3 M 49 47 7/3/17 Hispanic Alcoholic cirrhosis, alpha-1 anti-trypsin disease, HCV None Inpatient evaluation for toe cellulitis Yes Edibles Toe pain
4 M 52 51 2/19/19 Hispanic Alcoholic cirrhosis Benzodiazepines, ethanol, opiates ED evaluation of fatigue, nausea, diarrhea No CBD gummies Stress, decreased appetite, energy
5 M 49 44 10/1/14 White Alcoholic cirrhosis Amphetamines, alcohol, tobacco History of usage, psych evaluation during ED visit Yes Smoking Anxiety back pain
6 M 53 50 2/11/16 Hispanic Alcoholic cirrhosis Alcohol, opiates History of usage, Inpatient evaluation of transaminitis Yes Smoking Pain, depression
7 F 41 38 6/24/17 Asian Alcoholic liver disease, hepatitis B Tobacco, opiates ED evaluation for abdominal pain Yes Smoking Chronic pain
8 M 32 29 2/28/17 White Cryptogenic hepatic fibrosis E-cigarettes, alcohol ED evaluation for nausea, abdominal pain Yes Vaping, edibles Pain, nausea
9 F 40 31 11/9/10 Black Acetaminophen overdose Methamphetamine, tobacco, opiates History of usage, admission for Total abdominal hysterectomy-bilateral salpingo-oophorectomy Yes Smoking Chronic shoulder/back pain
10 F 35 33 5/8/17 Other Autoimmune hepatitis None Inpatient evaluation for transaminitis Yes Denies Denies usage
11 F 60 56 7/19/16 Black Alcohol liver disease, Hepatitis B Cocaine, tobacco Inpatient evaluation of syncope No Edibles Abdominal pain
12 F 64 41 9/22/96 Hispanic Alcoholic cirrhosis None Random drug screen No Smoking Chronic pain
13 M 71 65 6/7/13, 2/25/14 Black Fibrosing cholestatic hepatitis, hepatitis C None ED evaluation for acute encephalopathy No Smoking Sleep
14 M 36 5 1/23/88 Black Biliary atresia None Inpatient evaluation for transaminitis Yes Smoking Appetite, stomach pain
15 M 56 50 1/13/14 White Hepatitis C cirrhosis None Drug screen in pain clinic No Smoking Chronic pain
16 M 61 51 1/13/09 Black Hepatitis C cirrhosis None Inpatient evaluation for nausea, vomiting Yes Smoking Not documented
17 M 59 48 4/22/08 Other Cryptogenic cirrhosis None Inpatient evaluation for transaminitis Yes Denies Denies usage
18 M 34 30 2/12/15 White Alcoholic cirrhosis Alcohol, opiates Inpatient evaluation for abdominal pain Yes Smoking Not documented
19 F 55 41 3/15/06 White Acetaminophen overdose Vaping Psychiatric hospitalization for suicidal ideation No Smoking, vaping Insomnia
20 M 25 20 10/10/14 Hispanic Fulminant Wilson’s disease None Random drug screen (history of abuse) No Smoking Not documented
21 M 31 22 8/19/10 White Acetaminophen overdose None Inpatient evaluation for nausea, diarrhea Yes Smoking, THC chews Nausea
22 M 67 55 1998, 7/18/07 Hispanic NASH, hepatitis C cirrhosis None Not documented No Smoking Pain

Statistical analysis

All analyses were performed using Excel and Graphpad Prism (GraphPad Prism version 7.00 for Mac, GraphPad Software, La Jolla California USA, www.graphpad.com). Categorical variables were analyzed using Fisher’s exact test and numerical variables were analyzed using unpaired two-tailed t-tests. P values <0.05 were considered significant.

Results

Of our 22 patients (Table 1), 16 (72.7%) were male and average age at transplant was 39.9 years. Racial breakdown is as follows: Hispanic (8/22, 36.4%), White (6/22, 27.3%), Black (5/22, 22.7%), Asian (1/22, 4.5%) and Other (2/22, 9.1%). Indications for transplant in this population included End stage liver disease (ESLD) secondary to alcoholic cirrhosis (9/22, 40.9%), Hepatitis C (4/22, 18.2%), acetaminophen overdose (3/22, 13.6%), Hepatitis B (2/22, 9.1%), fulminant Wilson’s disease (2/22, 9.1%), Cryptogenic cirrhosis (2/22, 9.1%), Non-alcoholic steatohepatitis (NASH) (1/22, 4.5%), biliary atresia (1/22, 4.5%), alpha-1 anti-trypsin disease (1/22, 4.5%), autoimmune hepatitis (1/22, 4.5%) and fibrosing cholestatic hepatitis (1/22, 4.5%). The type of marijuana used included smoking THC (16/22, 72.7%), edible THC (4/22, 18.2%), CBD chews (1/22, 4.5%) and CBD oil (1/22, 4.5%). Interestingly, 3 (13.6%) patients denied marijuana usage. The reasons for marijuana usage were highly varied and most commonly included chronic pain, nausea, insomnia, appetite enhancement and depression. Reasons for why patients underwent a urine drug screen included evaluation of transaminitis (6/22, 27.3%), evaluation of non-specific GI symptoms (6/22, 27.3%), random drug screen (3/22, 13.6%), evaluation of psychiatric symptoms (2/22, 9.1%) and hospital evaluation for non-transplant related reasons (4/22, 18.2%). Concurrent drug usage was found in 9 (40.9%) patients, with most common drugs including alcohol (5/22, 22.7%), opiates (5/22, 22.7%), tobacco (4/22, 18.2%%), vaping (2/22, 9.1%), methamphetamine (1/22, 4.5%), amphetamine (1/22, 4.5%), cocaine (1/22, 4.5%) and benzodiazepines (1/22, 4.5%). Four patients did not have documented reasons for why marijuana was being used, and one patient did not have a documented reason for urine drug screen.

Elevated liver enzymes were present in 14 patients (63.6%), with a cause identified in eight patients (Tables 2,3 ). The most commonly identified cause was noncompliance with immunosuppressive regimen (6/8, 75%), while other causes included biliary obstruction secondary to stone (1/8, 12.5%) and alcoholic hepatitis (1/8, 12.5%). Comparing the patients with elevated liver enzymes to those without (Table 4), there was no statistically significant difference in the percentage of patients who smoked THC (11/14, 78.6% vs. 7/8, 87.5%, P=1.0), or used CBD products (0/14, 0% vs. 1/8, 12.5%, P=0.36). Similarly, when comparing patients by the type of marijuana used (THC vs. CBD), there was no significant difference in rates of concurrent drug usage (8/15, 60% vs. 3/6, 50%, P=1.0) or presence of elevated liver enzymes (8/15, 60% vs. 4/6, 66.7%, P=0.66).

Table 2

Patient # Identified cause of elevated liver enzymes Type of marijuana used Reason for marijuana usage AST ALT Total Bilirubin Alkaline Phosphatase Immunosuppression Biopsy results Management
1 Non-adherence with immunosuppression Smoking, CBD cream Chronic back pain 379 686 1.4 530 FK 9.6 Moderate acute T-cell mediated rejection Steroid pulse, thymoglobulin resume immunosuppression
2 Non-adherence with immunosuppression Denies usage Not documented 386 282 6.1 281 Cyclosporine 218 Late onset acute cellular rejection, consider viral, autoimmune/drug induced hepatitis Steroid pulse thymoglobulin, resume immunosuppression
5 Non-adherence with immunosuppression Smoking, vaping Anxiety, back pain 64 31 0.2 77 FK 3.4 Not done Steroid pulse, resume immunosuppression
7 Biliary obstruction secondary to stone Smoking Chronic pain 1,058 504 0.7 172 FK 9.6 No features of acute T cell-mediated rejection, r/o biliary obstruction ERCP
14 Non-adherence with immunosuppression Smoking Appetite, stomach pain 173 317 0.5 155 FK 3.5 Acute t-cell mediated rejection Steroid pulse, resume tacrolimus, mycophenolate
16 Non-adherence with immunosuppression Smoking Not documented 42 70 1.8 99 FK 7.3 Not done Resume tacrolimus
17 Non-adherence with immunosuppression Denies usage Denies usage 490 758 8 278 FK 7.1 Severe acute cellular rejection Steroid pulse, home tacrolimus, mycophenolate,
18 Alcoholic hepatitis Smoking Not documented 126 67 1.2 269 FK 4.5 Not done Alcohol cessation, tacrolimus, prednisone, ursodiol

Table 3

Patient # Identified cause of elevated liver enzymes Type of marijuana used Reason for marijuana usage AST ALT Total Bilirubin Alkaline Phosphatase Immunosuppression Biopsy results Management
3 N/A Edibles Toe pain 43 110 0.6 289 FK 8.9 Not done Resumed home tacrolimus, mycophenolate, prednisone
6 N/A Smoking Pain, depression 101 70 3 1,172 Cyclosporine 249 Hepatitis with marked interface and lobular lymphoplasmacytic inflammation Resume cyclosporine, mycophenolate, ursodiol
8 N/A Vaping, edibles Pain, nausea 55 61 0.9 444 FK 10.5 Not done Resume tacrolimus, prednisone
9 N/A Smoking Chronic shoulder/back pain 68 111 0.5 301 FK 7.2 Not done Resume home tacrolimus, prednisone, mycophenolate, ursodiol
10 N/A Denies Denies 442 496 0.9 145 FK 6.2 Moderate acute rejection Steroid pulse, resume tacrolimus, mycophenolate, prednisone
21 N/A Smoking, THC chews Nausea 65 65 0.6 97 FK 6.3 Not done Continue home tacrolimus

Table 4

Identified cause of liver enzymes (n=8) Confidence interval (95%) No identified cause of liver enzymes (n=6) Confidence interval (95%) P value
Mean AST (SD) 340 (333.9) 60.9–619.1 129 (154.6) −33.2–291.2 0.18
Mean ALT (SD) 339 (284.9) 100.8–577.2 152 (169.9) −26.3–330.3 0.18
Mean Total Bilirubin (SD) 2.5 (2.9) 0.08–4.92 1.1 (1.0) 0.05–2.1 0.28
Mean Alkaline Phosphatase (SD) 233 (144.4) 112.3–353.7 408 (394.1) −5.6–821.6 0.26
Biopsy performed 5/8 (62.5%) 30.4–86.5% 2/6 (33.3%) 9.3–70.4% 0.59
Received steroid pulse treatment 5/8 (62.5%) 30.4–86.5% 1/6 (16.7%) 1.1–58.2% 0.14

Discussion

This study attempted to better characterize the demographics and hepatocellular function of patients that screened positive for marijuana usage post-liver transplant. Our population was male predominant with transplants indicated most commonly for ESLD secondary to alcohol usage and hepatitis C. The majority of patients were screened for urine toxicology during evaluation of elevated liver enzymes, non-specific GI symptoms or psychiatric issues. Reasons for marijuana usage were varied but most commonly included chronic pain, psychiatric comorbidities such as anxiety and depression, and insomnia. Interestingly, comorbid drug usage was not as common as expected in this population. A possible explanation is that the majority of these patients were using marijuana for medical comorbidities. Although several of our study patients were concurrently using drugs of abuse, it is likely that the majority of patients with significant substance abuse habits did not pass pre-transplant evaluation.

Marijuana’s impact on liver function is controversial. One animal study investigating oral CBD usage in mice demonstrated hepatotoxicity of a cholestatic nature secondary to high dose CBD (14). In contrast, CBD may have anti-inflammatory and antioxidant effects (15), with one study by Avraham et al. demonstrating improvement in liver function after CBD administration in mice with liver failure (16). The data on THC’s effect on liver function are similarly varied, with data implicating worsening fibrogenesis in patients with chronic hepatitis C (17) and hepatomegaly/splenomegaly with elevations in AST, ALT and Alkaline Phosphatase, although this may have been confounded by numerous factors. Clinically significant hepatotoxicity to our knowledge has only been reported in several case reports (18-21). In contrast, THC has also been linked to a decreased prevalence of nonalcoholic fatty liver disease (22) and to have antifibrinogenic properties through apoptosis of pro-inflammatory hepatic stellate cells (23). While our study cannot make conclusions on marijuana’s impact on hepatotoxicity, our data suggest that a sizeable portion of our study population presented with liver dysfunction. In our study, there was no significant difference in the presence of elevated liver enzymes between patients using CBD vs. THC or a difference in the rates of concurrent drug usage. Significant headway has been made investigating the impact of marijuana on liver function, but further research is necessary given contradictory findings thus far.

Despite the increase of marijuana usage in the US, the data on marijuana usage in relation to liver transplantation is sparse. In the few studies that examine marijuana consumption in liver transplant recipients, survival between users and non-users does not appear to be significant different (24), nor do users have increased rates of post-transplant inpatient complications or overall adverse outcomes (25). This suggests that it may be unwarranted to deny marijuana users transplant evaluation strictly based on marijuana usage, indeed Rai et al. encourages a holistic evaluation of transplant candidates who use marijuana rather than automatically excluding these patients from evaluation (11).

Interestingly, the most commonly identified cause of liver enzyme elevation in our study was non-adherence with immunosuppression. In a large meta-analysis, Dew et al. found that the overall immunosuppressant non-adherence rate among all types of transplants was 22.6 cases per 100 persons per year (PPY). Liver transplant recipients had a lower non-adherence rate to immunosuppressants (6.7 cases per 100 PPY) and illicit drugs (0.2 cases per 100 PPY) (26), which is possibly explained by stricter psychosocial criteria for candidate selection (liver vs. kidney) and more severe consequences of graft loss in liver transplant vs. kidney transplant. In a multi-site study examining only liver transplant recipients, Rodrigue et al. found that risk factors for nonadherence included male sex, time elapsed since transplant and pre-transplant mood disorders and social support instability (27). Unfortunately, substance abuse was not included in that analysis. Lieber found pre-transplant substance abuse to be an independent predictor of post-transplant non-adherence to medical therapy (28). Although our study cannot show causation, our data suggest that liver transplant recipients that use marijuana may be at risk for non-adherence with immunosuppression.

Although this study to our knowledge is the first to characterize marijuana usage post-liver transplant and liver enzymes at time of drug usage, there are several limitations to this study. First, this data is retrospective in nature and cannot be used to determine causation. Secondly, this was a single center study with a small study population meeting our inclusion criteria. Due to our sample size, statistical analysis would likely be underpowered to detect differences between the different sub-populations (elevated liver enzymes vs. not, cause identified vs. not), and thus we kept our study descriptive. Lastly, although it appears that non-adherence to immunosuppression was common in our study population, an alternate explanation is that males overall are more likely to use marijuana (29), and thus the rate of non-adherence may be more reflective of male sex as a risk factor. Further consideration will be given to expanding the size of this cohort along with non-marijuana users with the goal of comparing these two populations to find statistically significant clinical differences between them. However, the strengths of this study include strict criteria for inclusion (positive UDS), generalizability to other major academic transplant centers and detailed examination of how elevated liver enzymes were managed in these patients.

Understanding how marijuana usage can impact post-liver transplant recipients is of the utmost importance as marijuana usage becomes more common from both a medical and recreational standpoint. We found that liver transplant recipients who use marijuana post-transplant and had elevated liver chemistries were often found to be non-compliant with immunosuppression, leading to transplant rejection in most cases. Although this is concerning, it is not possible to conclude currently whether marijuana usage should be prohibited in pre/post-transplant patients; further studies are needed to determine long term adverse effects of marijuana usage and its impact on the graft. Our study suggests that further work should be done to establish if there is a link between marijuana usage and immunosuppression non-compliance, as this has significant implications for post-transplant health and longevity of the graft.

Acknowledgments

Thanks to Pfleger Liver Center staff and NPs for their assistance with this project.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist Available at http://dx.doi.org/10.21037/dmr-20-120

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/dmr-20-120). Dr. Saab serves as an unpaid editorial board member of Digestive Medicine Research from Apr 2020 to Mar 2022. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the UCLA Institutional Review Board (IRB #19-001546) and individual consent for this retrospective analysis was waived.