Cannabinoids and the Kidney_260822 (PDF)

Cannabinoids and the Kidney: Friend or Foe Anutra Chittinandana, MD. Bhumibol Adulyadej Hospital

Disclosure I have not intentionally tested any marihuana products. I have not prescribed any marihuana products. I am not an employee, consultant nor stockholder for any of marihuana company. I have no conflicts of interest relative to this presentation.

Cannabinoids and the Kidney: Friend or Foe Endocannabinoid receptors in the kidney Cannabinoids for symptoms of kidney failure Synthetic cannabinoid induced AKI Cannabinoids in kidney transplantation

Cannabinoids and the Kidney: Friend or Foe Endocannabinoid receptors in the kidney Cannabinoids for symptoms of kidney failure Synthetic cannabinoid induced AKI Cannabinoids in kidney transplantation

The endocannabinoid receptors exhibit a “yin-yang” relationship. CB1 Oxidative stress Inflammation CB2 Fibrosis Anti-Inflammatory Anti-oxidant Antifibrotic Federica Barutta, et al. Kidney International (2018) 94, 252–258; https://doi.org/10.1016/j.kint.2018.01.024

Summary of CB1 receptor in mammalian kidneys Animal Model Kidney Region/Cell Type Expression Technique Used to Measure Changes Sprague-Dawley rat Sprague-Dawley rat + STZ Whole kidney + RT-PCR, WB Wistar rat + STZ Sprague-Dawley rat + HFD Whole kidney + (↑) WB ZDF rats Wistar rats Whole kidney + (↑) RT-PCR, WB Sprague-Dawley rat CB1 transgenic mice Whole kidney + (↑) WB db/db mice C57BL/6 mice (control) renal cortex (PCT, Glm) + (↑) RT-PCR, IHC C57BL/6 mice (UUO) C57BL/6 mice + cisplatin isolated TAL + WB Human kidneys afferent/efferent arteriole + RT-PCR Whole kidney + (↑) RT-PCR, WB Glm + (↑) IF kidney cortex − IHC Kidney cortex (interstitial, tubules, Glm) + IHC whole kidney + (↔) RT-PCR, WB PCT, DT, IC CD + IHC BV, Glm − IHC Frank Park, et al. Am J Physiol Renal Physiol. 2017 Nov 1; 313(5): F1124–F1132.

The CB1 receptor is overexpressed in experimental diabetes ND DM ND DM Barutta F, et al. Diabetes 2010;59(4):1046–1054 https://doi.org/10.2337/db09-1336

CB1 receptor expression is increased in multiple human nephropathies *P<0.05, **P<0.05, ***P<0.05 versus a control kidney Lola Lecru, et al. Kidney International (2015) 88, 72–84. doi:10.1038/ki.2015.63

CB1 Receptor Blockade (AM251) Ameliorates Albuminuria in Experimental Diabetic Nephropathy Nondiabetic Nondiabetic + Diabetic Diabetic + AM251 AM251 Body wt (g) 28.71 ± 1.13 29.41 ± 0.56 25.23 ± 0.84* 25.86 ± 0.69* Blood glucose 120 ± 5.81 104 ± 12.07 411 ± 36.07† 386 ± 36.64† (mg/dl) Glycated Hb 4.23 ± 0.05 4.40 ± 0.16 12.93 ± 0.32† 12.49 ± 0.24† (%) SBP (mmHg) 101 ± 3.30 98 ± 3.30 119 ± 10.50 118 ± 3.79 Kidney/BW 6.62 ± 0.03 6.46 ± 0.19 8.42 ± 0.99 7.34 ± 0.29 AER (μg/18 h) 33.4 37.5 336.6 153.1 (25.1–40.2) (12.6–126.4) (164.9–778.5)† (70.7–298.1)†‡ *P < 0.05 diabetic and diabetic + AM251 vs. nondiabetic and nondiabetic + AM251; †P < 0.001 diabetic and diabetic + AM251 vs. nondiabetic and nondiabetic + AM251; ‡P < 0.01 diabetic + AM251 vs. diabetic Barutta F, et al. Diabetes 2010;59(4):1046–1054 https://doi.org/10.2337/db09-1336

CB1 blockade abolished downregulation of nephrin, podocin, and ZO-1 protein expression in diabetic mice (ZO-1 = Zonula occludens-1) Barutta F, et al. Diabetes 2010;59(4):1046–1054 https://doi.org/10.2337/db09-1336

Cnr1 mRNA (encoding for CB1) expression in the renal cortex is increased after 8 days of unilateral ureteral obstruction (UUO) Lola Lecru, et al. Kidney International (2015) 88, 72–84. doi:10.1038/ki.2015.63

CB1 genetic disruption (Cnr1-/- ) reduce fibrosis during unilateral ureteral obstruction (UUO) Lola Lecru, et al. Kidney International (2015) 88, 72–84. doi:10.1038/ki.2015.63

CB1 blockade (Rimonabant) reduce fibrosis during unilateral ureteral obstruction (UUO) Lola Lecru, et al. Kidney International (2015) 88, 72–84. doi:10.1038/ki.2015.63

Summary of CB2 receptor in mammalian kidneys Animal Model Kidney Region/Cell Type Expression Technique Used to Measure Changes Sprague-Dawley Whole kidney Sprague-Dawley + STZ Whole kidney + RT-PCR, WB Sprague-Dawley + HFD Whole kidney + (↑) WB Wistar rat isolated TAL + (↓) WB C57BL/6 + STZ Glomerulus − WB Human Type 2 Diabetic Glomerulus + (↔) IF Human kidneys kidney cortex + (↓) IF − IHC Frank Park, et al. Am J Physiol Renal Physiol. 2017 Nov 1; 313(5): F1124–F1132.

CB2 receptor expression is decreased in human diabetic nephropathies ND DM Barutta G, et al. Diabetes 60:2386–2396, 2011

CB2 Receptor Agonist (AM1241) Ameliorates Albuminuria in Experimental Diabetic Nephropathy Body weight (g) ND ND+AM1241 DM DM+AM1241 BG (mg/dL) Glycated Hb (%) 28.80 ± 0.61 27.23 ± 0.43 24.92 ± 0.33* 24.83 ± 0.93* sBP (mmHg) 114 ± 5.44 111 ± 5.14 326 ± 16.41† 323 ± 41.10† KW/BW ratio 4.18 ± 0.35 4.00 ± 0.15 12.79 ± 0.35† 12.18 ± 1.10† 125 ± 6.83 119 ± 2.43 133 ± 3.16 132 ± 5.14 AER (μg/18 h) 5.81 ± 0.03 6.12 ± 0.08 7.25 ± 0.29‡ 6.83 ± 0.30‡ 78.8 71.9 315.4 162.9 (73.8–86.6) (69.5–79.6) (291.9–356.6)† (139.5–161.7)†§ *P < 0.01 DM and DM+AM1241 vs. ND and ND+AM1241. †P < 0.001 DM and DM+AM1241 vs. ND and ND+AM1241. ‡P < 0.05 DM and DM+AM1241 vs. ND. §P < 0.001 DM+AM1241 vs. DM. Barutta G, et al. Diabetes 60:2386–2396, 2011

Activation of the CB2 receptor by AM1241 prevented diabetes-induced downregulation of both nephrin and ZO-1. (Zonula occludens-1) Barutta G, et al. Diabetes 60:2386–2396, 2011

Carmona-Hidalgo B, et al. Pharmaceuticals 2021, 14(9), 863; https://doi.org/10.3390/ph14090863 Detrimental Effect of Cannabidiol on the Early Onset of Diabetic Nephropathy in Male Mice * p < 0.05, ** p < 0.01, *** p < 0.001 vs. vehicle-citrate buffer-treated mice (control).

CBD worsens STZ-induced renal lesions in glomerulus Carmona-Hidalgo B, et al. Pharmaceuticals 2021, 14(9), 863; https://doi.org/10.3390/ph14090863 ** p < 0.01, *** p < 0.001 vs (control) # p < 0.05, ## p < 0.01 vs. vehicle-STZ.

CBD worsens STZ-induced renal lesions in Tubule & Interstice Carmona-Hidalgo B, et al. Pharmaceuticals 2021, 14(9), 863; https://doi.org/10.3390/ph14090863 ** p < 0.01, *** p < 0.001 vs (control) # p < 0.05, ## p < 0.01 vs. vehicle-STZ.

Cannabinoids and the Kidney: Friend or Foe Endocannabinoid receptors in the kidney Cannabinoids for symptoms of kidney failure Synthetic cannabinoid induced AKI Cannabinoids in kidney transplantation

Potential mechanisms of action of cannabinoids in symptoms associated with kidney failure Hayley Worth, et al. CJASN 17: 911–921, 2022. doi: https://doi.org/10.2215/CJN.11560821

Summary of evidence for cannabinoid effect on symptoms associated with kidney failure Symptom Potential Mechanism Evidence in Study Details Evidence in Non-CKD Population Restless legs CB1 found throughout the Two case series CKD Population syndrome central nervous system Patients with RLS: (same center), Symptom relief with total n=18 Nil Cannabinoids modulate smoked marijuana or dopaminergic and GABAergic sublingual CBD Nonrandomized Hemodialysis patients: signaling study, n=21 uncontrolled Nil prospective study Pruritus Inhibition of TRPV1 Reduced Randomized, (n=21) found that an Patients with insomnia double-blinded, endocannabinoid- production of inflammatory associated with crossover containing emollient cytokines fibromyalgia: Nabilone trial, n=31 was effective superior to amitriptyline Insomnia THC has sedating properties, Nil possibly mitigated by CBD Hayley Worth, et al. CJASN 17: 911–921, 2022. doi: https://doi.org/10.2215/CJN.11560821

Summary of evidence for cannabinoid effect on symptoms associated with kidney failure Symptom Potential Mechanism Evidence in Study Details Evidence in Non-CKD Population CKD Pop. Anorexia Activation of central CB1, (a) Patients with HIV- (a) Four RCTs, Nil resulting in appetite stimulation associated cachexia and total n=204 (b) Two and shift of white and brown anorexia nervosa: Modest RCTs, total n=290 adipocytes to anabolic state efficacy with smoked cannabis and dronabinol (b) Patients with cancer-related anorexia: Mixed results Pain Actions on diverse range of Patients with chronic non- Two meta-analyses: Nil neuronal ion-channels and cancer pain and neuropathic 104 studies (47 RCTs, receptors, including α-3 glycine pain: Modest efficacy (69,78) 57observational), n=99 receptors, 5HT1a receptors, and 58; 16 double-blind TRPV1 RCTs, n=1750 Nausea Modulation of CB2 in the enteric Patients with CINV: Nabilone, Meta-analysis: 23 Nil nervous system, resulting in a dronabinol and THC:CBD RCTs, n=1359; one reduction of enterotoxin- modestly effective further RCT, n=81 mediated gut motility Potential action via central CB1 Hayley Worth, et al. CJASN 17: 911–921, 2022. doi: https://doi.org/10.2215/CJN.11560821

Cannabinoids and the Kidney: Friend or Foe Endocannabinoid receptors in the kidney Cannabinoids for symptoms of kidney failure Synthetic cannabinoid induced AKI Cannabinoids in kidney transplantation

Synthetic cannabinoids Alexandros Hebrew Pfizer John William Huffman Makriyannis University First generation AM-2201 HU-210 CP-47,497 JWH-018, JWH- AM-1235 073, JWH-015 JWH-030, JWH- 2502, JWH-176 Next generation XLR-11, PB-22, NPB-22, ADB-PINACA, AB-CHMINACA, MAB- CHMINACA, FUBIMICA Most common Spice, K2, herbal incense, Cloud 9, Mojo brand names Federica Barutta, et al. Kidney International (2018) 94, 252–258; https://doi.org/10.1016/j.kint.2018.01.024

Synthetic Cannabinoid induced AKI Author, year Age Sex Peak S.Cr Urine microscopy Renal biopsy Suspected Need (mg/dL) — mechanism of AKI RRT — Present case 21 M 7.9 Granular casts — ATN No — Srisung et al, 31 M 3.0 — Intrinsic AKI No 20151 5.7 — 32 M ATN Yes 31 M 3.5 — AIN with No eosinophiluria and ATN Bhanushali 20 M 13.7 3+ protein; trace ATN (tubular dilation, tubular ATN No et al, 20132 glucose; 6/10 epithelial cell vacuolization, 23 M 26 M WBC/HPF; occasional sloughing, and apical blebbing); 30 M muddy brown casts rare calcium oxalate crystals 15.2 2+ protein; 25 Mild ATN; few calcium oxalate ATN No ATN No RBC/HPF; occasional crystals granular casts 13.3 3+ protein; 26–50 ATN WBC/HPF; > 25 RBC/HPF; 3+ leukocyte esterase 3.2 Normal — ATN suspected No

Synthetic Cannabinoid induced AKI Author, year Age Sex Peak S.Cr Urine microscopy Renal biopsy Suspected Need (mg/dL) mechanism of AKI RRT Buser et al, 17 M 10.2 WBCs; RBCs; trace ATN with mild interstitial ATN and AIN No 20143 protein; 1+ eosinophils nephritis 15 M 7.8 Trace protein ATN (vacuolization of proximal ATN Yes tubular epithelial cells) with medullary peritubular capillaritis Kazory & 22 M 9.3 Proteinuria; WBCs; ATN (focal tubular atrophy and ATN No Aiyer, 20134 RBCs; trace ketones; flattened epithelium, loss of trace hemoglobin brush border, casts, vacuolization, and mitosis) Thornton et 26 M 7.7 1+ protein; trace blood — — No al, 20135 Ergül et al, 27 M 5.6 — — — Yes 20156 4.4 — — — Yes 24 M 21 M 2.9 — — — No Gudsoorkar 26 M 8.1 200 RBC/HPF initially; 5 — Intrinsic AKI Yes & Perez, RBC/HPF the next day; 20157 1+ proteinuria; no WBCs

Synthetic Cannabinoid induced AKI Author, year Age Sex Peak S.Cr Urine microscopy Renal biopsy Suspected Need (mg/dL) — mechanism of AKI RRT Rhabdomyolysis No Argamany et 27 M 13.9 2+ protein; 3+ blood — attributable to al, 20168 hyperemesis Sherpa et al, 45 M 3.1 — — No 20159 Sinangail et 42 M 4.3 + glucose; otherwise Diffuse inflammatory infiltrates ATN and acute al, 201610 normal with lymphocytic predominance tubulointerstitial affecting the cortex of the renal nephritis tubules and the interstitium with associated tubulitis

Synthetic Cannabinoid induced AKI Author, year Age Sex Peak S.Cr Urine microscopy Renal Suspected Need (mg/dL) biopsy mechanism of AKI RRT Centers for 19 M 5.2 WBCs; RBCs; RBC/granular casts 8 biopsies — 5 of Disease 15 M 6.8 WBCs; RBCs; RBC/granular casts; eosinophils performed; — 16 pts Control and 21 M 6.3 WBCs; RBCs; epithelial casts; granular casts 6 revealed — requir Prevention, 18 M 4.1 Hyaline casts; WBCs ATN and 3 — ed 201211 25 M 21.0 RBCs; proteinuria; eosinophils revealed — RRT 30 M 9.0 WBCs; RBCs; RBC/hyaline casts AIN — 18 M 6.6 WBCs; protein 30 — 33 M 3.3 — — 27 M 4.7 Small blood; protein 30 — 15 M 9.1 Protein trace — 26 M 7.7 Normal — 17 M 10.6 WBCs; RBCs; protein 2+; eosinophils 1+ — 18 M 9.6 Protein 2+; blood 3+; no RBCs — 18 M 5.5 Protein 1+ — 15 M 11.5 WBCs; RBCs — 15 M 6.2 WBCs; protein 1+ —

Synthetic Cannabinoid induced AKI Diagnosis by exclusion Mostly acute tubular necrosis, some acute interstitial nephritis underlying mechanism remains elusive contaminants, by products, interactions of mixed compounds, hyperemesis-induced dehydration direct deleterious effect

Cannabinoids and the Kidney: Friend or Foe Endocannabinoid receptors in the kidney Cannabinoids for symptoms of kidney failure Synthetic cannabinoid induced AKI Cannabinoids in kidney transplantation

Mauro Maccarrone, et al. Trends in Pharmacological Sciences, May 2015, Vol. 36, No. 5

Retrospective cohort studies examining the impact of marijuana on organ transplantation Author Organ Dates Patients Outcome measures Results Greenan et al. Kidney 2008–2013 1225 patients, 56 identified as active Impact of marijuana use in No significant 2016 marijuana users in the post-transplant post-transplant period on difference Ranney et al. 2009 period 1-year survival/graft failure Nickels et al. and graft function at 1 year 2007 Liver 1999–2007 1489 patients, 155 marijuana users Impact of marijuana use in No significant Mohite et al. 2017 identified in pre-transplant screening. pre-transplant period on difference Xu et al. 2010 43 marijuana users were listed and of patient survival those 23 received a transplant Liver 1994–2004 27 patients identified as polysubstance Impact of relapse on No significant users. Pre-transplant 20 were marijuana substance of abuse (*not difference users. In post-transplant period 8 only marijuana) on patient patients relapsed (5 on marijuana) survival Lung 2007–2013 302 total lung transplants, 19 were from Impact of marijuana use in No significant Heart marijuana users organ donor on survival rates difference of recipients and post- operative markers 1994–2007 997 total heart transplants, 79 were Impact of marijuana use in No significant from marijuana users organ donor on survival rates difference of recipients at 1 and 5 years Harinder Singh Rai and Gerald ScottWinder. Curr Psychiatry Rep (2017) 19: 91 DOI 10.1007/s11920-017-0843-1

Epidemiology of cannabis use and associated outcomes among KT recipients: A meta-analysis Study Country Study Year Sample Marijuana users Inclusion Follow Outcomes Confounder Quality of design size criteria up adjustment evidence (GRADE) Alhamad Australia Cohort 2019 52689 254 Medicare 3 years All cause graft failure, Recipient, donor, ⨁⨁⨁◯ et al (Pretransplant)– claims data for death censored graft transplant factors Moderate 55,897 KT recipients 0.5% 163 (Post- cannabis failure and death and propensity transplant) – dependence or score 3.2%Ftabhberi pSowoedleendCoehsotrtim201a9t9e19d pr40.8e3(%vMaarliejuannca e Saoebluff-srecepaonrtendab1iyseaur sBeiopsy proven a(c9ut5e %N/CA I 0.4%-20⨁.⨁5⨁%◯) ett hale use of cannabis vs no usealone) – 5.2% 45 use rejection, all cause Moderate (Marijuana and graft loss and death ⨁⨁⨁◯ all-cause allografttofbaacicloure (OR = 1.31, 95%ceCnIso0re.d7gr0af-t2lo.s4s 6) Greenan SwmedeonrtCaohloitrty20(1O6 R122=5 1s5.m56 o(24k.i,6n%g9))–54%.8%CSIe0lf-.re5p9or-te3d.912y)ear Graft failure, death EPTS and donor et al death-censored graftsucsrefeeoanridinrlguug re (ORan=d re1na.l7fu2nc,tio9n5%typCe I 1.13-2M.6od0er)ate Shrivasta USA Cohort 2015 1064 139 (13.1%) Self-reported NA Not reported Not applicable ⨁◯◯◯ va et al use or drug Very Low screening Pradeep K. Vaitla, et al. J Evid BasedMed. 2021;14:90–96.

Drugs Affected by Tetrahydrocannabinol (THC) and Cannabidiol (CBD) unknown CBD inhibits CYP 2D6, 2B6, and 2C19, and UGT 1A9 and 2B7 mechanism THC increases CBD increases levels of: CBD reduces levels of: levels of: Warfarin 2D6 substrates 2B6 substrates Dependent on 2D6 for Amitriptyline Nortriptyline Methadone activation Codeine Desipramine Flecainide UGT1A9 and UGT2B7 Tamoxifen Tramadol Haloperidol Risperidone substrates Partly dependent on 2C19 substrates Citalopram Mycophenolate 2C19 for activation Diazepam Escitalopram Dabigatran Clopidogrel Tacrolimus Voriconazole Mechanism unclear Warfarin Omeprazole Everolimus Sirolimus Hayley Worth, et al. CJASN 17: 911–921, 2022. doi: https://doi.org/10.2215/CJN.11560821

Drugs Affecting Tetrahydrocannabinol (THC) and Cannabidiol (CBD) Exposure Both THC and CBD are metabolized by CYP 3A4. CBD is also metabolized by 2C19 Increased levels of THC/CBD Reduced levels of THC/CBD Strong 3A4 inhibitors Clarithromycin Strong 3A4 inducers Carbamazepine Itraconazole Ketoconazole Posaconazole Phenytoin Rifampin (rifampicin)a Ritonavir Voriconazole Moderate 3A4 inducers Bosentan Moderate 3A4 inhibitors Amiodarone Dabrafenib Dexamethasone Rifabutin St. Cyclosporine Diltiazem Erythromycin John's wort Fluconazole Grapefruit juice Imatinib 2C19 inducers (CBD only) Apalutamide Verapamil Hayley Worth, et al. CJASN 17: 911–921, 2022. doi: https://doi.org/10.2215/CJN.11560821

Take Home Message CB1 receptor expression is increased in animal model of diabetic nephropathy and some human nephropathies. CB1 receptor antagonist reduces albuminuria and renal fibrosis in animal model. CB2 receptor expression is decreased in human diabetic nephropathies. CB2 receptor agonist ameliorates albuminuria in experimental diabetic nephropathy However, cannabidiol has detrimental effect of on the early onset of diabetic nephropathy in male mice

Take Home Message Cannabinoid effects on symptoms associated with kidney failure have been postulated from general population. Only an uncontrolled small prospective study in hemodialysis patients showed that an endocannabinoid-containing emollient was effective for pruritus. AKI has been associated with the use of synthetic cannabinoid No benefit of cannabinoid use in the outcome of organ transplantation

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