Opioids and the Kidney: A Compendium

Opioids are a class of medications used in pain management. Unfortunately, long-term use, overprescription, and illicit opioid use have led to one of the greatest threats to mankind: the opioid crisis. Accompanying the classical analgesic properties of opioids, opioids produce a myriad of effects including euphoria, immunosuppression, respiratory depression, and organ damage. It is essential to ascertain the physiological role of the opioid/opioid receptor axis to gain an in-depth understanding of the effects of opioid use. This knowledge will aid in the development of novel therapeutic interventions to combat the increasing mortality rate because of opioid misuse. This review describes the current knowledge of opioids, including the opioid epidemic and opioid/opioid receptor physiology. Furthermore, this review intricately relates opioid use to kidney damage, navigates kidney structure and physiology, and proposes potential ways to prevent opioid-induced kidney damage.


Introduction
Opioids are a popular class of drugs used for centuries both medically and recreationally.The poppy plant Papaver somniferum contains the primary active compounds used to produce naturally derived and synthetic analgesics. 1 For clarification, an opioid is any chemical compound not derived from plants and synthesized in a laboratory, in which more than 500 have been produced. 2Examples of opioids include the synthetic phenylpiperidines meperidine and fentanyl and the semisynthetic derivatives, oxycodone and hydromorphone 1,3 An opiate is a compound extracted directly from plant matter. 2Examples of opiates include the alkaloids morphine and codeine. 3,4For the remainder of this review, the term opioids will be used as a blanket term to describe both opioids and opiates.
Both opioids and opiates bind to opioid receptors. 4,5pioid receptors are conserved G protein-coupled receptors populated throughout the body, spanning the central and peripheral nervous systems, organs, and various cell types. 6Numerous G protein-coupled receptors are expressed in the kidneys as well. 7Multiple opioid receptors exist, and this review will discuss the three classical opioid receptors: kappa receptors (KORs), mu receptors (MORs), and delta receptors (DORs) and their function, location, and expression in the kidney. 6,8he primary rationale for opioid use is pain management. 1,4,5Chronic pain affects approximately 100 million adults in the United States. 9Medical opioid use for acute pain, end-of-life care, and cancer pain is invaluable for clinicians and patients. 10The pain relief benefits and euphoric properties of opioids make the drug also highly attractive for recreational use.Overprescription and recreational opioid use contribute to 91 deaths due to overdose per day in the United States. 9This pattern of use is responsible for the development of the opioid epidemic in the United States and across the world. 2,10pioid use can have injurious effects on organs in the body, including the kidney.This review describes opioid physiology in relation to kidney dysfunction.In addition, this mini-review provides ideas for novel therapeutic interventions to combat opioid-induced kidney damage.

Opioid Physiology Primary Physiologic Mechanism
2][13][14] Opioid receptors are widely distributed throughout the body and induce a myriad of effects.The primary effect of opioids is analgesia. 15he classical analgesic pathway of opioids leads to decreases in excitability and transmission of neuronal pain pathways. 4As an opioid binds to an opioid receptor, intracellular coupled G-proteins dissociate into their Ggb and Ga subunits. 3The Ggb subunit opens potassium channels and closes voltage gated calcium channels. 3The Ga subunit inhibits adenylate cyclase and decreases cyclic adenosine monophosphate levels. 3As a result, neuronal excitability decreases, as well as the discharge of pronociceptive neurotransmitters, creating the decreased sensation of pain (Figure 1). 3

Opioid Receptors
Rigorous research has been conducted to gain further understanding of the function and signaling pathways of opioid receptors.The three classical opioid receptors are delta (d), kappa (k), and mu (m) receptors (DORs, KORs, and MORs, respectively).The receptors are located across the central and peripheral nervous system, within different cell types, and throughout the body. 14ORs are most anatomically populated at the neocortex, olfactory bulb, nucleus accumbens, and amygdala. 14,16The primary function of DOR lies in their presynaptic location, where they block neurotransmitter release. 14Furthermore,  DOR can be found modulating neurotransmitter release in respiratory neurons, serving a purpose in respiratory pattern production. 14DOR activation also produces antidepressive effects. 14,17Studies have revealed an increase in anxiety and depression when the Oprd 1 gene (encoding gene for DORs) was knocked out in mice. 17ORs serve functions independent of other opioid receptors, including analgesia, diuresis, and brain reward function. 14,18KORs are coupled to calcium channels on presynaptic terminals and are found in the nucleus accumbens, claustrum, amygdala, hypothalamic nuclei, and, notably, podocytes in the kidney. 18KORs have a role in brain reward operation where activation produces dysphoria by inhibiting dopamine release in the striatum. 19KORs on presynaptic terminals coupled to calcium channels inhibit calcium current flow, thus inhibiting neurotransmitter (dopamine) release. 18KORs also serve a role in analgesia. 14inally, KOR activation produces analgesia and sedation independent of increases in respiratory depression and heart rate. 14This characteristic makes KOR an excellent target for therapeutic investigation.
MORs are the clinical target for prescribed opioids. 20The principal role of the MOR is analgesia. 20Located presynaptically and postsynaptically spanning the nervous system, MORs decrease neuronal calcium influx and increase neuronal potassium influx, mitigating neuronal transmission and alleviating pain. 21MORs are also located in brain reward circuits. 14In the brain reward pathway, MORs can be found in mesolimbic dopaminergic neurons, the nucleus accumbens, amygdala, hypothalamus, brainstem nuclei, and locus coeruleus. 22MORs in brain reward circuits are involved in pleasure, reward, reinforcement, and addictive states. 14,20

DOR, KOR, and MOR Expression in the Kidney
Studies have been conducted to identify and quantify opioid receptor gene expression in rodent and human kidneys.Conflicting evidence exists regarding opioid receptor gene expression in the human kidney.In one analysis, absolute quantitative RT-PCR detected no MOR gene expression, a small amount of mRNA KOR gene expression, and high DOR gene expression in the human kidney. 23nother in vitro analysis in human podocytes revealed high levels of MOR and KOR and almost no DOR gene expression. 24Confirmational immunofluorescence was performed on mouse kidneys, and the results aligned with the human RT-PCR findings in this study. 24RT-PCR performed in rat kidneys reported low levels of KOR and DOR gene expression and moderate levels of MOR gene expression. 25Work performed by our group revealed KOR expression in rat and human podocytes using immunohistochemistry and RT-PCR. 26

Nonanalgesic Mechanisms of Opioids
Opioids produce effects independent of analgesia.Opioids act on mood/reward pathways, depress respiration, and induce diuresis. 17,21,27In mood/reward pathways, the pleasure sensation of opioid use is a result of gammaaminobutyric acid (GABA) inhibition by MORs in neuronal reward pathways. 28GABA is the main neurotransmitter for inhibition in the central nervous system. 29Inhibition of GABA results in dopaminergic neuron hyperactivity in the nucleus accumbens and excess dopamine production. 28his produces the intense pleasure experience associated with opioid use. 28pioid-induced respiratory depression is the leading cause of all opioid-related deaths. 27The MORs located in the medulla are the principal receptors involved in respiratory depression. 27The medulla comprises a network of synchronized neurons responsible for producing breathing, delicate to opioid use. 27This network contains the preBötzinger complex. 27Studies show that disruptions of the preBötzinger complex can lead to respiratory failure. 27OR activation induces water diuresis via renal sympathetic nerve stimulation, decreasing antidiuretic hormone (ADH) action in the kidney and decreasing ADH release by the brain. 30In a study involving KOR agonists in normally hydrated rats, 2-Methoxymethyl-salvinorin, nalfurafine, and U50,488H, all increased free water clearance and urine volume compared with controls. 30In humans, administration of KOR agonists MR 2034, spiradoline, and MR 2033 increased urine volume output. 31The diuresis effect of KOR agonists/KOR activation has been studied in conditions where diuresis could serve therapeutic purposes. 30In rats with hypertension, one study confirmed that administration of the KOR agonist U50,488H produced declines in mean arterial pressure, decreased plasma ADH, and induced diuresis when compared with normotensive rats. 32Other opioid receptors play a role in diuresis.Administration of the central selective MOR agonist demorphin led to an increased diuresis and decreased sodium excretion without changing plasma flow, GFR, or the sympathetic outflow to the kidneys. 33OR agonist BW373U86 acutely increased diuresis and natriuresis through autonomic nervous system regulation. 34

Opioids and the Kidney Foundational Kidney Structure and Function
The kidneys are organs responsible for waste removal, urine production, BP regulation, and the maintenance of minerals, water, and salts. 35The functional unit of the kidney is the nephron, which comprises the glomerulus. 35,36The glomerulus is the main filtering unit of the kidney. 35The glomerular filtration barrier (GFB) is formed by three major cell types: podocytes, glomerular basement membrane (GBM), and the fenestrated endothelium (Figure 2A).

Podocyte Structure and Physiology
It is necessary to describe the cytoarchitecture and physiology of the podocyte because studies have linked opioid use to podocytopathy. 24,26Opioids can disrupt podocyte structure and function 26 (Figure 2B).8][39][40][41] Podocytes are atypical epithelial cells. 38,42The podocyte comprises three structures: foot processes, the cell body, and the extending processes. 43The cell body is oriented toward the Bowman's space.The extending processes continue from the cell body, which then divide into foot processes. 43oot processes intertwine with neighboring foot processes and the GBM, forming the end-stage of filtration slit diaphragm of the GFB. 42For proper adhesion and communication with the GBM, the slit diaphragm uses proteins including nephrin, synaptopodin, CD2AP, NEPH-1, ZO-1, and podocin. 44,45Podocyte effacement is an injurious consequence that can occur during a disruption in the anatomical actin cytoskeleton and support proteins forming the connection to the GBM. 46,47

Opioids and Kidney Pathology
Kidney damage is a dangerous side effect arising from chronic opioid use, and kidney disease has been shown to increase concurrently with opioid use. 48Novel medical approaches are needed to protect the kidney from opioidinduced insults.
Opioids are metabolized in the liver, and the kidneysensitive metabolites are processed through the kidney. 49hronic opioid use leads to the local and systemic accumulation of noxious metabolites. 50Prolonged opioid use and the toxic metabolite aggregation catalyze mechanisms leading to kidney damage, including increased BP, podocyte dysfunction, urinary retention, decreased renal blood flow and GFR, and sympathetic renal nerve stimulation (Figure 3). 50he increased sympathetic renal nerve stimulation by opioid misuse causes vasoconstriction, increased BP, decreased blood flow, and renal ischemia. 50,51Increased BP and decreased oxygen quantity occur at the glomerulus inducing glomerular damage and podocytopathy, leading to kidney dysfunction and increases in BP. 26 Work by our group has demonstrated that podocyte KOR activation opens transient receptor potential cation 6 (TRPC6) channels increasing calcium influx into the cell, causing podocyte dysfunction (Figure 2B). 26Our study used immortalized human podocytes, isolated human and rat glomeruli, and Dahl salt-sensitive rats.To observe calcium influx exclusivity by TRPC6, administration of SAR7334 (TRPC6 inhibitor) with BRL52537 (KOR agonist) showed complete inhibition of the BRL52538-induced calcium response in human podocytes, captured by radiometric confocal fluorescent microscopy. 26Dahl saltsensitive rats exhibited increased mean arterial pressure and microalbuminuria after chronic BRL52537 treatment.Podocytes isolated from hypertensive animals also exhibited a steady increase in total calcium influx following BRL52537 administration. 26Therefore, podocytopathy due to opioid use exacerbates the progression of hypertension and furthers kidney damage, ultimately leading to diseases, such as FSGS. 26urther evidence has been substantiated involving opioid use and podocytopathy.Morphine has been shown to induce podocyte effacement in mouse models and decrease slit diaphragm proteins in human podocytes in vitro. 24In this study, increased albuminuria was observed on highdose morphine administration in mice. 24Western blot of mouse kidney tissue lysates also showed declines in podocyte proteins nephrin and synaptopodin. 24These results were consistent with western blot analysis of human podocytes treated with 10 28 or 10 26 M morphine for 24 hours, which revealed declines in nephrin, synaptopodin, CD2AP, and podocin. 24linical studies in human patients investigating opioidinduced podocytopathy merit further investigation.Podocytopathy in human patient population can contribute to an array of diseases such as FSGS, nephrotic syndrome, and ESKD. 45Clinical insight into the degree of podocyte damage caused by opioid use could reveal mechanistic patterns and correlate to a number of kidney diseases.
In addition to podocytes, other glomerular cells can be affected by opioid misuse.Mesangial cells are responsible for the proper clearance of materials before the GFB, and over-proliferation of mesangial cells contributes to glomerulopathy. 38,52Morphine use has been shown to induce glomerulopathy via induction of mesangial cell proliferation. 44In this study, histopathology of morphinetreated kidneys revealed mesangial cell area increases and glomerular enlargement. 44n chronic opioid use, the anticholinergic character of various opioids on the MOR induces urinary retention. 50ere, sensory nervous function is inhibited, and the micturition reflex is impaired.The consequence of urinary retention is the generation of permanent renal scarring, due to prolonged high levels of reverse flow pressure. 51o mitigate the detrimental effects of opioid use described, attempts to establish safe opioid prescribing protocols have been made by the Center for Disease Control (CDC). 53,54However, the evolving nature of the opioid crisis makes setting a gold standard of care highly complex.5][56] If opioid therapy is needed, the CDC recommends beginning with a regimen of the lowest dose of instant-release opioids with the long-term goal of treatment cessation. 55he effects of chronic opioid use on the organs remain unknown and warrant further investigation and novel prescribing protocols.
Therapeutic modalities mitigating the detrimental effects of opioids on the kidney warrant further investigation.Novel approaches to mitigating kidney damage include the development of a bivalent or bifunctional medication targeting podocyte KOR.In addition, a compound capable of simultaneous administration with opioids could modulate podocyte KOR and TRPC6 channels.

Dialysis and Opioid Use
Chronic pain is a major concern in patients with ESKD.Approximately half of the patients receiving hemodialysis report chronic pain, and more than 60% of dialysis patients are prescribed, at minimum, one opioid per year. 57,58Of these prescriptions, 25% are higher doses than the recommended range. 59The most frequently prescribed opioids for hemodialysis patients from 2006 to 2010 were oxycodone and hydrocodone. 57Most notably, large analyses of opioid administration and patient outcomes remarkably confirmed a direct relationship between opioid use and mortality in dialysis patients. 57Furthermore, analyses have shown that chronic opioid use in the dialysis population generates many unfavorable side effects, leading to long-term hospitalizations and dialysis discontinuation. 57ialysis treatment and renal failure heavily alter drug pharmacokinetics and pharmacodynamics, increasing the likelihood of detrimental side effects. 59Poor renal clearance contributes to local and systemic toxic metabolite accumulation. 59Metabolite accumulation is further exacerbated by the reduced hepatic metabolic capabilities, including the effects of kidney failure on hepatic enzymes from thecytochrome P450 (CYP) superfamily. 59,60Patients with cytochrome P450 (CYP) polymorphism might have a significantly altered opioid concentration and could be at increased risk of drug interactions with CYP inducers or inhibitors. 61Excess accumulation of metabolites can lead to hypotension, central nervous system depression, seizures, respiration depression, and death in the hemodialysis population. 59Examples of medications with poor renal clearance in hemodialysis patients are fentanyl, methadone, morphine, and oxycodone. 59][64][65] CKD-associated pruritus (CKD-aP), a condition of itch lasting .6 weeks in patients with CKD without correlation to the level of uremia, is a common comorbidity in dialysis patients. 66,67Recently, the US Food and Drug Administration approved difelikefalin, a peripherally restricted and selective KOR agonist for moderate-to-severe CKD-aP. 68ajority of trials show significant improvement of the CKD-aP conditions; however, no studies reported analyses of kidney function during the treatment. 69,70Phase 3 clinical trials are currently underway for the safety and efficiency of difelikefalin in patients with CKD (Trial registration number NCT05342623).
Opioid analgesics in CKD should be adjusted to the degree of renal impairment at the onset and throughout treatment.Further research is needed regarding the safety and risk-benefit ratio of opioid administration in hemodialysis patients.Before initiating opioid treatment protocol, nonopioid therapeutics could be considered for pain management, including cognitive behavioral therapy, acetaminophen, topical nonsteroidal anti-inflammatories, and gabapentin. 57,59tential Strategies Targeting Podocyte KORs to Mitigate Kidney Damage Podocyte KORs are a potential therapeutic target for the prevention of opioid-induced kidney damage.Attenuating the detrimental effects of opioids is a state-of-the-art approach to the development of effective organ protection.Novel targeting strategies include the simultaneous administration of a KOR antagonist, locationally contained agonists, and the development of bivalent and bifunctional medications.

The Simultaneous Administration of KOR Antagonists
The synchronous administration of opioids and an effective KOR antagonist could concentration-dependently attenuate the rate of deleterious calcium influx at the TRPC6 channel on the podocyte, preserving podocyte viability.Promising KOR antagonists that warrant further investigation in their therapeutic potential to combat kidney disease are NMRA-140 (formerly BTRX-335140) and JNJ-67953964.
NMRA-140 is a novel and highly attractive KOR antagonist currently under clinical trial investigation because of its short-acting block of KOR and antidepressive function. 71,72Short-acting antagonists are beneficial in decreasing damaging proinflammatory signaling pathways, normally activated by long-lasting antagonists. 71he high KOR selectivity (8125 versus DOR, 138 versus MOR) reduces off-target side effects, and its short action time mimics traditional medications. 71,73Studies examining the potency of BTRX-335140 conclude high potency and positive measures of target engagement. 71The distinct properties of MNRA-140 afford the medication extensive examination in its protective role in opioid-induced kidney damage.
Another KOR antagonist of interest in the prevention of opioid-induced kidney damage is JNJ-67953964.JNJ-67953964 also boasts an advantageous short action time, is well tolerated for human use, and has a high KOR affinity. 74Studies have demonstrated improvements in depressive behavior on JNJ-67953964 administration. 75he unique characteristics of JNJ-67953964 affirm the medication as an excellent candidate for investigating its simultaneous use with opioids in mitigating opioid-induced kidney damage.

Locationally Contained Agonists
Recent progress has been made in structurally modifying KOR agonists to confine their location of action to designated locations in the body. 76In this approach, alterations to agonist structure could restrict agonist access to the podocyte.Ideally, this modality would induce analgesia while simultaneously serving a protective role in the kidney.

Bivalent and Bifunctional Medications
Bifunctional medications are drugs with a common core capable of acting on multiple targets. 14Bivalent medications structurally incorporate two pharmacophoric regions united by a liker, which permits dualpurpose action of the medication. 14A medication of these types could have both antagonist and antagonist properties.Supporting evidence has shown bivalent compounds with varying linker chain lengths exhibit increased selectivity and potency compared with their respective individual compounds. 77In the case of kidney protection, the theoretical compound could elicit KOR agonist analgesic effects at one pharmacophore while possessing a distinct pharmacophoric region functioning as a TRPC6 antagonist.In this case, calcium influx could be properly regulated on KOR agonist administration, preserving podocyte function.The efficacious design of novel bivalent and bifunctional medications could serve as breakthrough treatment options for kidney and other organ protection.
In conclusion, opioid misuse is a major threat to society.With prescription mishandling and illicit use surging, proper opioid legislative action and the accompanying detrimental physiological opioid effects require immediate attention.A comprehensive understanding of pain biology and opioid pharmacology could lead to the development of necessary deviations from the injurious classical use of opioids.Novel treatment options, including medications to be taken concurrently with opioids, bifunctional and bivalent medications, and locally contained opioid receptor agonists, need to be further elucidated.These modalities could prevent damage to opioid-induced kidney damage and reduce the incidence of deaths due to opioid use, combating the opioid epidemic.

Figure 1 .
Figure1.Fundamental opioid mechanism of action in analgesia.Opioid/opioid receptor binding induces GPCR dissociation into Ggb and Ga subunits.The Ggb subunit closes calcium channels and opens potassium channels.The Ga subunit decreases cAMP levels and inhibits adenylate cyclase.These actions lead to decreased discharge of pronociceptive neurotransmitters and decreased neuronal excitability, decreasing the sensation of pain.cAMP, cyclic adenosine monophosphate; GPCR, G protein-coupled receptor.

Figure 2 .
Figure 2. Proposed mechanism of glomerular injury through the kappa opioid receptors.(A) Components of the GFB.Three major cell types comprise the barrier: the fenestrated endothelium, GBM, and podocytes creating the ultrafiltration component of the nephron.(B) Podocytopathy due to opioid use.Opioids bind to kappa opioid receptors on podocytes.Binding results in TRPC6 channel activation and a significant increase in calcium influx.Increased amounts of calcium induce podocytopathy, leading to the progression of kidney disease and exacerbation of hypertension.GBM, glomerular basement membrane; GFB, glomerular filtration barrier; TRPC6, transient receptor potential cation 6.

Figure 3 .
Figure 3. Proposed mechanism of renal injury.(A) Opioid-induced mechanisms leading to kidney damage.Opioid use contributes to increases in BP, podocytopathy, decreases in renal blood flow and GFR, stimulation of the renal nerves, and urinary retention.(B) Roadmap of opioid-mediated mechanisms leading to kidney damage.Opioid use and poor renal clearance of opioid metabolites decrease GFR, contributing to local and systemic opioid toxicity and further kidney damage.Opioid use, along with age-related declines in renal function, also contributes to local and systemic opioid toxicity.

Disclosures A .
Staruschenko reports the following: Research Funding: Department of Veteran Affairs and National Institutes of Health; and Advisory or Leadership Role: Associate Editor: Scientific Reports; Editorial Board: American Journal of Physiology-Cell Physiology, BMC Nephrology, Kidney360, Deputy Editor; American Journal of Physiology-Renal Physiology; and Past Chair; American Heart Association, Council for the Kidney in Cardiovascular Disease.All remaining authors have nothing to disclose.

Table 1 .
Opioid receptor location, function, common agonists and antagonists, and endogenous peptides