Emerging Patient-Centered Concepts in Pain Among Adults with Chronic Kidney Disease, Maintenance Dialysis, and Kidney Transplant

Abstract

Patient reports of moderate to severe pain are common across the spectrum of chronic kidney disease. The synergistic effects of comorbid depression and anxiety can lead to maladaptive coping responses to pain, namely pain catastrophizing and illness-related post-traumatic stress disorder. If underlying depression and anxiety and associated maladaptive coping responses are not treated, patients can experience increased perception of pain, worsened disability, decreased quality of life, withdrawal from social activities, and increased morbidity and mortality. Meanwhile, interest in nonpharmacological treatments for pain that targets coping as well as comorbid anxiety and depression has been growing, particularly given the significant societal damage that has resulted from the opioid epidemic. Evidence--based, nonpharmacological treatments have shown promise in treating pain in areas outside of nephrology. Currently, little is known about these treatments’ effects among adults with CKD, and particularly end-stage kidney disease, when chronic pain can become debilitating. In this review, we examine patient-centered concepts related to pain that have received little attention in the nephrology literature. We also describe emerging areas of research, including omics technologies for biomarker discovery and advanced symptom clustering methods for symptom phenotyping, that may be useful to future kidney disease research and treatment.

Introduction

Pain is recognized as a debilitating symptom among adults with kidney disease. Among this population, pain has been most thoroughly characterized in those with end-stage kidney disease (ESKD) being treated with maintenance hemodialysis. Since the initial report by Binik et al. in 1982,¹ studies over the last four decades have indicated that between 50% and 80% of adults treated with hemodialysis report pain.² More recently, Brkovic, Burilovic & Puljak conducted a systematic review of 52 studies with 6,917 participants to understand the epidemiology of pain in people on hemodialysis, and found up to 82% of adult maintenance hemodialysis patients have acute pain and up to 92% experience chronic pain.³ Moreover, of those experiencing pain, at least 50% have chronic moderate to severe pain, making the burden of pain among hemodialysis patients similar to that recognized among patients with cancer.^4,5

Less is known about pain in adults with ESKD who are treated with peritoneal dialysis or transplantation. In a cross-sectional study of stable deceased-donor kidney transplant recipients, 62% reported pain and 67% reported more than one location of pain.⁶ While this prevalence of pain was similar to that among the maintenance hemodialysis patients in the study, the pain severity was less among the transplant recipients. Separately, a case-control study of kidney transplant patients found that the transplant recipients reported a lower intensity of chronic pain than that reported by their counterparts on maintenance hemodialysis, but a higher intensity than among healthy adults.⁷

While pain also appears to burden adults with earlier stages of CKD prior to dialysis (i.e., predialysis CKD or CKD stage 1-4),⁸ this population has not been widely studied, and the existing data is limited and conflicting. Among a cohort of over 1100 adults with CKD, the most common symptom reported by those with diagnoses of CKD stages 1–3 was bone and joint pain (86%).⁹ A survey from an outpatient clinic at a tertiary health care center in California found that nearly 73% of the adults with predialysis CKD, but only 9% of the adults without CKD, had experienced at least a 2-week duration of pain.¹⁰ Moreover, the prevalence of pain was higher among those with more severe CKD. In contrast, a report from an outpatient clinic at an academic medical center in Washington, DC, found that while 69% of predialysis CKD patients experienced pain,¹¹ this rate was no different than that found in patients without CKD, and the rate of pain did not vary by severity of CKD. These diverging findings likely are due to several factors, including differences in pain assessment tools, CKD severity and etiologies, and other cohort characteristics.

Types and Causes of Chronic Pain in CKD

The etiology and classification of pain in CKD has again been best characterized in adults with ESKD treated with maintenance hemodialysis. Acute and temporary pain may also be experienced frequently by maintenance hemodialysis patients in association with their recurring hemodialysis treatments. Sources of this type of pain include needle insertion and needle infiltration, muscle cramping from fluid shifts and removal, extremity pain related to vascular access, and a “washed out” feeling with substantial fatigue and headaches related to blood pressure changes that may persist for many hours after the hemodialysis treatment has ended.^12,13 On the other hand, chronic pain among maintenance hemodialysis patients has diverse etiologies that can include the cause of the disease itself (e.g., polycystic disease), complications of kidney disease (e.g., bone disease, neuropathy), or associated comorbidities (e.g., osteoarthritis, vascular disease, diabetes).^12,13

While small studies have found musculoskeletal pain to be the most common cause, accounting for up to 59% of chronic pain among maintenance hemodialysis patients, patients also frequently experience pain related to diabetic and nondiabetic neuropathy (40%) and multifactorial sources including vascular disease (20%).^3,14,15 The etiologies of pain among other populations of patients with kidney disease (e.g., ESKD patients treated with maintenance peritoneal dialysis, kidney transplant recipients, or predialysis kidney disease patients) are less well characterized. However, perhaps unsurprisingly, since each group exists along a trajectory of kidney disease, small studies have indicated that the causes of chronic pain are similar across groups, with musculoskeletal pain being the predominant cause.^6,10

A Conceptual Model for Pain

Theoretical and conceptual models have been found useful for guiding pain management research and clinical care in other patient populations. These frameworks serve as a foundation for research, standardizing concepts to increase the objectivity and generalizability of findings. The Loeser Model of Pain is a well-established framework used in pain research.

Loeser Model of Pain

The Loeser Model of Pain, initially postulated in the 1980s, has four layers or “onion rings” (Figure 1).¹⁶ These layers move outward from physical to behavioral factors, interact with one another, and, viewed as a whole, reflect the total experience of pain. It highlights that while pain neurobiology (the physical factors which initiated pain) is at the center, many other factors influence a person’s experience of pain, the meaning that is attached to pain, and how the body reacts to pain. Based on the biopsychosocial approach, this conceptual model explains that although pain is a nociceptive event, persistent pain leads to subsequent suffering and behavior changes that are shaped by external psychosocial and other environmental factors. The description of the model’s four layers that follows has been informed by more recent enhancements of the model (in 2013) by Butler and Moseley.¹⁷

Figure 1. Loeser’s conceptual model for pain in chronic kidney disease (nephropathy).

Abbreviations: PTSD, post-traumatic stress disorder.

Nociception

At the center of the model’s layers are the biological processes of pain, usually interpreted as the physiological factors of nociception (the initial trigger which may have caused the acute painful event). It’s also important to consider neurobiological mechanisms such as neuropathic pain and nociplastic pain in this realm. Since the model was initially proposed, researchers have gained a greater understanding of the neurobiology of pain. For example, an absence of nociception may be due to a failure of the nociceptive system to accurately interpret pain information. Or the core of the pain could be neuropathic or nociplastic: “pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain.”¹⁸

Pain (Sensory)

The next layer of the model adds the emotional activation of pain, including attitudes and beliefs regarding the experience of pain. Pain is not perceived in isolation. An important consideration about emotions is that these are based on subjective, internal past experiences which a person may deem to be relevant and important.

Suffering (Affective)

The next layer, suffering, can be described as the response to pain or the judgment of the pain experience. It refers to an individual’s personal experience of pain and what it means for them in their wider context. This response to pain is also affected by fear, anxiety, stress, and other psychological factors. As explained by Cassel, suffering occurs when a person judges pain as a threat, which can be either physical or psychological or both.¹⁹ During this judgment, the meaning of pain can be increased or decreased. For example, an ankle sprain after a basketball game often is experienced differently by someone who is on the winning team vs. someone who was on the losing team. The suffering experienced by that team member is augmented by the win or loss outcome of the game, which may increase or decrease the pain response.

Behavior

The outer layer is related to the individual’s behavioral response to the appraised experience, which is complex. Pain behaviors result from pain and suffering (the two middle layers) and encompass the things a person does or does not do in relation to the presence of the physiological and emotional/affective factors. Examples of pain behaviors include crying, grimacing, and limping. The behaviors themselves are observable by others and can be quantified. However, a person’s behavioral responses to pain can be based on childhood experiences and social learning as well as other contextual elements. Culture provides the context and is thus particularly important when understanding pain. People are a product of their social and cultural environment, and pain behavior is both learned and culturally mediated: people learn how to react or not react to pain. Some pain behavior messages in mainstream American culture, for example, include “Boys don’t cry” and “No pain, no gain” and “This won’t hurt a bit.”

The Loeser Model of Pain provides a way to understand both pain and the experience of pain and explains why it’s important to examine the multiple layers that influence pain.

Psychosocial Considerations in Pain Management for CKD

Pain, Depression, and Anxiety

The link between pain, depression, and anxiety in chronic disease, including CKD, is well-established.^20,21 However, the underlying psychological and biological mechanisms linking these debilitating symptoms are not yet clearly understood. Researchers in oncology have clearly established that pain, depression, and anxiety appear concurrently as a symptom cluster.²² The connection between pain, depression, and anxiety is especially apparent in individuals suffering from chronic pain.^18,19,23 The synergistic effects of these three symptoms can result in a vicious cycle where the anticipation of pain results in anxiety; the anxiety causes activation of the autonomic nervous system, resulting in muscle tension that increases the intensity of the pain; and the increased intensity and frequency of pain may increase depression. While perceived pain can affect the level of anxiety and depression experienced by an individual, increases in the levels of depression and anxiety have also been shown to increase the intensity of pain perception.²⁴ The synergistic effects of the pain-depression-anxiety symptom cluster can result in significant disability, decreased quality of life, and increased morbidity and mortality. Moreover, they result in maladaptive coping strategies that further feed the cycle of pain. Additionally, there have been growing calls in the nephrology community for more rigorous screening and treatment for depression among adults with CKD.^23,25,26

Pain Catastrophizing

Pain catastrophizing and illness-related post-traumatic stress disorder (PTSD, which will be discussed next) are two maladaptive coping strategies that are modifiable and can be targeted using nonpharmacological, patient-centered interventions. These coping strategies can also lead to or exacerbate anxiety and depression.

Pain catastrophizing is an negative cognitive and emotional response to an actual or perceived pain experience; it involves magnification, rumination, and feelings of hopelessness (Table 1).^27,28 Catastrophizing is believed to be a precursor of pain-related fear-avoidance behavior when the threat of pain causes an individual to catastrophize, this leads to fear of pain, avoidance of physical activity, and hypervigilance of pain monitoring.^27,29,30 Catastrophizing is considered to be among the most important psychological predictors of pain intensity and chronicity, mood, disability, quality of life, and health care resource utilization.^27,30,31 Moreover, catastrophizing has been shown to be an important mediator of the association between pain and depression.³²

Table 1.

Definitions and Constructs in Pain Catastrophizing

Construct	Definition	Examples28,108
Pain catastrophizing28	Broadly, a set of irrational exaggerated and negative cognitions, specifically pain-related worry and fear, arising from actual or perceived painful stimulation. Key to the concept is the individual’s inability to divert attention away from pain.	“I kept thinking I can’t stand this much longer; I want it to end."
Magnification108	To view or present a situation as considerably worse than it actually is.	“I worry that something serious may happen.” “I am afraid the pain will get worse.”
Rumination109	To dwell on the most extreme negative consequences of the pain experience.	“I can’t stop thinking about how much it hurts.” “I can’t seem to get it out of my mind.”
Hopelessness110	An emotion characterized by absence of hope or optimism accompanied by feelings that pain will never improve.	“It’s awful and I feel that it overwhelms me.” “The pain is terrible and will never get better.” “I feel I can’t go on.”

Pain catastrophizing centers around negative thoughts of future events and the inability to divert attention from anticipated pain experiences. Thus, treatment for catastrophizing focuses on distraction and mindfulness. While promising treatments exist—psychological approaches used to reduce pain catastrophizing include cognitive behavioral theory, acceptance and commitment therapy, and mindfulness-based strategies—most have resulted in small to moderate effects when pain catastrophizing is the outcome of interest.^30,31 To be clear, a recent meta-analysis demonstrated these psychological therapies, specifically acceptance and commitment therapy, have a strong effect on acceptance of pain.³³ It has been argued that when pain catastrophizing is the outcome of interest, absence of a common definition and a shared theoretical framework for this multifaceted construct complicates the interpretation of results and the identification of underlying mechanisms that drive changes in catastrophizing.^30,31,34 Nevertheless, pain catastrophizing represents an important and consistent pragmatic predictor of pain outcomes.³⁰

Research related to pain catastrophizing in CKD and associated treatments has been limited, and is entirely absent in the kidney transplantation literature.³⁵ Further clarification of construct definitions in the context of theory-guided clinical trials are needed generally. Given the multifactorial etiology of chronic pain and pain catastrophizing, leveraging the expertise of a multidisciplinary pain management team is essential to pain research and has been shown to be efficacious and cost-effective in treatment approaches to patients with chronic pain^27,36 Randomized controlled trials are needed and should include measures of pain catastrophizing as a predictor and potential mediator of pain in CKD. Further research is also needed to better characterize underlying biological mechanisms that drive the differential effects of pain catastrophizing on important clinical outcomes in CKD.

Chronic Pain and Post-Traumatic Stress Disorder/Event-Related Distress Comorbidity

Post-traumatic stress disorder is a type of psychiatric disorder that results from a traumatic life event. According to the National Center for PTSD, the prevalence of comorbid PTSD among individuals with chronic pain is estimated at 35%, while the prevalence of PTSD in the general population is 3.5%.^1,2 Illness-induced PSTD has been reported among adults who experience serious chronic illnesses, such as severe cardiovascular disease or cancer, who may perceive the illness experience as a traumatizing life event.^3,4 Commonly reported symptoms of PTSD include intrusive memories, avoidance behaviors, catastrophizing, being easily startled, and hypervigilance.^5,6 Individuals experiencing event-related distress that does not meet the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for PTSD diagnosis,⁷ may still experience PTSD-like symptoms that can negatively impact physical and emotional functioning and result in increased pain, depression and anxiety.^8,9 Regardless of the precipitating event, PTSD is strongly associated with the development of cardiovascular events,^10-13 and may contribute to the development and progression of kidney disease.

Chronic pain is a common feature of CKD, making it important for clinicians to understand the potential for synergistic effects of trauma associated with living with a chronic medical condition, the experience of chronic pain, and other stressful life events unrelated to an individual’s health. Prolonged exposure to pain, such as that experienced by people with CKD, can result in physical and psychological stress, depression, anxiety, and disability. In a comprehensive review of the interaction between chronic pain and PTSD, Kind & Otis (2019) noted individuals with comorbid pain and PTSD were more likely to experience more severe pain, depression, anxiety, disability, and increased opioid use compared to individuals with only one of these conditions.⁸

Few studies reported on PTSD or event-related distress in kidney disease. A study of people on hemodialysis in Germany reported a 17% lifetime prevalence of PTSD, regardless of the source of the traumatic event, and 10.4% lifetime prevalence with regard to hemodialysis.¹⁵ One study reported on event-related distress in a racially diverse population of non-dialysis dependent and dialysis dependent adults with ESKD, and found event-related distress, a similar but more broad category than PTSD, was associated with worse depressive symptoms and higher somatic and emotional burden, even after adjustment for age and gender.⁹ Another study in Louisiana observed 24% of people treated with hemodialysis reported PTSD symptoms following Hurricane Katrina, and blacks were nearly twice as likely to experience PTSD than whites.¹⁶ Siwakot, et al (2019), studied the association between a pretransplant history of PTSD among U.S. Veterans and posttransplant clinical outcomes and found no significant difference in mortality or graft function between those with PTSD and those without⁶ Finally, a recent study from South Korea observed 17.4% of people treated with hemodialysis who were in isolation due to the 2015 outbreak of Mediterranean Eastern Respiratory Disease (MERS Co-V-s) reported symptoms related to PTSD.¹⁷ Limitations to prior research include the use of screening instruments rather than diagnostic interviews. The Clinician Administered PTSD Scale (CAPS),¹⁸ a structured diagnostic interview, is the gold standard for making a diagnosis of PTSD, and a majority of the aforementioned studies used the Impact of Events Scale¹⁹ to measure distress. Additional research is needed to better understand the potential mechanisms of PTSD and chronic pain in CKD, and how these interactions relate to important clinical outcomes such as risk for cardiovascular outcomes and progression of kidney disease.

Social Support

Social support is generally recognized as the resources provided by others within an individual’s social network that lead the individual to feel themselves to be a loved and cared for member of a network of mutual obligations.⁵⁶ Members of the social network may include family, friends, peers, religious and social organizations, and health care professionals.^56,57

Self-reported disability among US adults with CKD is significant, even in early stages of the disease and particularly among the growing population of adults with CKD who are over 65 years of age.⁵⁸ As CKD progresses to ESKD, adults who are dependent on maintenance dialysis often find that adjusting to life on dialysis is a difficult challenge, one that threatens their social, occupational, and family roles as well as their concept of self.⁵⁹ Chronic pain associated with comorbidities, and the effects of the dialysis procedures themselves, results in a decreased ability to engage in usual physical and social activities. This in turn results in functional disability and withdrawal from social networks.^60,61 Among adults with ESKD, lack of perceived social support has been associated with increased morbidity and mortality and significantly impacts quality of life.²⁵

In a general patient population, providing services that address social factors, such as lack of transportation and resources for caregivers, can lead to lower health care utilization and costs.⁶² Including patients and members of their social support networks as part of care teams is increasingly recognized as an important component of patient-centered precision health.^63,64 However, there is to date limited knowledge of the psychological and biological mechanisms of perceived social support on chronic pain in CKD.

Recent evidence suggests that patients experiencing chronic pain who report higher levels of social support also experience less distress, less severe pain, and better functional status.⁶⁵ Holtzman et al. found that people with rheumatoid arthritis who reported having supportive families also reported significantly less pain intensity, less reliance on medication, and more activity with fewer limitations.⁶⁶ Less is known about the relationship between social support and chronic pain among people with CKD, however. Among adults treated with maintenance dialysis, Lora et al. observed that greater social support may help decrease comorbid stress associated with the illness, as well as depressive symptoms that often have a synergistic effect on pain perception.⁵⁶ Although research into the effects of perceived social support on chronic pain in CKD patients remains limited, links between perceived social support and depressive affect and quality of life are well-established.^57,61 Thus, perceived social support represents an important modifiable factor to include in future studies.

Age Considerations in Pain Management for CKD

Global advances in health and technology have led to improvements in socioeconomic development and life expectancy, resulting in a steady increase in the proportion of the global population aged 65 years and older.⁶⁷ The research literature has established that estimated glomerular filtration rate declines with age. As a result of these two trends, the number of people over the age of 65 who require CKD-related care has increased dramatically.⁶⁸ In the US, 50% of people with CKD are older than 70 years of age, and 40% of those with ESKD are 65 years and older.⁶⁹ Moreover, the number of people aged 65 and older who need maintenance dialysis continues to grow.⁶⁹

Older adults, meaning those aged 65 years and older, are also more likely to suffer from multiple comorbidities, such as diabetes, hypertension, or renovascular or cardiovascular disease—all of which are key contributors to the rising prevalence of CKD and disability among the aging population.⁶⁹ The general effects of aging also lead to people over 65 with CKD being more likely to experience musculoskeletal pain related to osteoarthritis and neuropathic pain associated with diabetes mellitus and peripheral vascular disease.^70,71 Not surprisingly, treatment for the growing population of adults with CKD over age 65 with multiple comorbidities comes at a significant financial cost. For example, Medicare beneficiaries with CKD make up 14% of the point prevalent aged Medicare population, but 25% of total expenditures.⁶⁹

Meanwhile, guidelines for pain management in those 65 and over with CKD are not yet well-established. Nonpharmacological management of pain using mindfulness-based therapies (e.g., cognitive behavioral therapy, acceptance and commitment therapy, meditation) and physical therapies (e.g., increasing physical activity, physical therapy) should be considered first-line treatment for pain (Box 1).⁷² Pharmacological management of pain among older adults, particularly with opioids, should be implemented with extreme caution. Older adults with CKD may be more prone to experiencing drug toxicities and serious adverse events such as effects on the central nervous system, hypotension, and respiratory depression due to impaired renal and liver function associated with aging.^70,71 Additionally, opioids can increase the risk of falls, a leading cause for injury and hospitalization among older adults. Further research is needed to better understand the complex interactions of pharmacological and nonpharmacological therapies in this growing CKD population.

Box 1. Nonpharmacological Treatments for Pain.

Physical Therapies

Application of heat/cold

Massage

Exercise/physical activity

Physical therapy

Acupuncture

Transcutaneous electrical nerve stimulation (TENS)

Psychological and Psychosocial therapies

Music therapy

Social support

Pain coping skills training (PCST)

Cognitive behavioral therapy (CBT)

Acceptance and commitment therapy (ACT)

Relaxation/guided imagery

Distraction therapy

Meditation

Spiritual care

Symptom Clustering and Symptom Science in CKD

While pain can present as an isolated symptom, pain in the context of chronic disease oftentimes occurs within a constellation of symptoms—also known as a symptom cluster.^73,74 Symptom clusters are defined as groups of two or more concurrent symptoms that are related to one another and are independent of other symptom clusters.⁷⁵ Symptom scientists in oncology were among the first to recognize the clinical importance of the concept of condition-specific symptom clusters.^76,77

Currently, two statistical approaches are used to determine symptom clusters: (1) variable-centered approaches, and (2) person-centered approaches. Variable-centered (de novo) approaches seek to identify correlations between individual symptoms. These correlations are usually ascertained from a symptom instrument that measures a broad range of physical and affective symptoms. Principal component analysis (PCA) and factor analysis are among the statistical methodologies most commonly used to conduct variable-centered clustering.⁷⁴ Qualitative methodologies, such as one-on-one interviews or focus groups, can also be used to identify symptom response patterns. An absence of standardized instruments to measure symptoms, as well as interpretation challenges related to heterogeneous clustering patterns, limits the clinical utility of this approach.^74,78

Person-centered (a priori) clustering approaches classify membership into symptom subgroups based on similar symptom response patterns. When using person-centered clustering, symptoms are determined based on empirical evidence and measured using standardized instruments such as the National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS). Person-centered clustering has emerged as a useful clinical tool for identifying subgroups of individuals that may be at greater risk of adverse clinical outcomes.²²

Pain has synergistic effects with other symptoms, such as fatigue, sleep disturbance, anxiety, and depression.^74,79 However, it can be difficult to disentangle the temporal relationship between pain and other comorbid symptoms as they often have a bidirectional relationship and appear as symptom clusters.⁸⁰ Understanding the shared underlying mechanisms of comorbid symptoms may lead to effective, targeted patient-centered treatments.⁸¹

During the second decade of the 21st century, a new area of research emerged: symptom science. Symptom science has been recognized by the NIH as a critical area of research for developing effective treatments to improve quality of life among people with chronic medical conditions.⁸² The goal of symptom science is to understand the molecular underpinnings of comorbid symptoms or symptom clusters using what are called omics approaches.⁸² Research into symptom clusters and their underlying biological mechanisms has now been pursued for several chronic medical conditions.^22,83 However, few studies have focused on symptom clusters in patients with CKD.^73,74,81 The NIH Symptom Science Model offers a framework for conducting symptom science research. A hypothetical model of the NIH Symptom Science Model in CKD is presented in Figure 2. Two recent reviews examined symptom clusters in adults with mild to moderate CKD and ESKD.^74,78 The symptoms that were studied the most included fatigue/sleep/energy, neuromuscular/pain, gastrointestinal, skin, and uremia. Symptoms such as fatigue, sexual dysfunction, and restless legs syndrome, as well as characteristics such as being female and having a diagnosis of diabetes, were associated with poorer quality of life.^79,84 Symptom clusters that included uremia were the clusters most often associated with increased risk of mortality.⁸⁵ In one study that compared symptom clusters of patients with advanced kidney disease and those of patients with advanced cancer, pain was more likely to be included in the phenotypes of patients with advanced kidney disease.⁷³

Figure 2. Theoretical application of NIH Symptom Science Model in chronic kidney disease.

Abbreviations: ACT, acceptance and commitment therapy; CBT, cognitive behavioral therapy; NIH, National Institutes of Health.

Future Directions for Research in CKD and Chronic Pain

Advances in technology and computing power have ushered in a revolution of health care innovation, with patient-centered precision health at its core. Several of these areas of innovation call for further attention in populations with CKD. First, randomized controlled clinical trials are needed to evaluate nonpharmacological strategies, including mindfulness/meditation, distraction, cognitive behavioral therapy, exercise, and physical therapy, to complement or replace opioid-based pharmacological pain treatment. Second, innovative research strategies using omics technologies (e.g., genomics, metabolomics, proteomics, microbiomics) can now be used to interrogate underlying biological mechanisms that may contribute to pain in CKD, due to recent technological advances and significant reductions in associated costs. Finally, advances in the statistical methods used for symptom phenotyping, specifically the use of latent models and machine learning algorithms, now provide significantly improved understanding of the complex interactions between pain and other comorbid symptoms and their associations with important patient outcomes. Here we provide some brief examples of these patient-centered interventions

Nonpharmacological Treatments for Pain

Given the devastating effects of the global opioid epidemic, there is a need for nonpharmacological treatment for pain. While little is known to date about the efficacy of nonpharmacological approaches to pain in CKD, strategies to complement or replace opioid-based pharmacological pain treatment, including mindfulness/meditation, distraction, cognitive behavioral therapies, exercise, and physical therapy (see Box 1), have demonstrated success in other chronic disease conditions.^29,34 The NIH’s Helping to End Addiction Long-term (HEAL) Initiative is an aggressive trans-agency effort to speed scientific solutions to stem the national opioid public health crisis. Under the auspices of the HEAL initiative, the National Institute of Diabetes and Digestive and Kidney Diseases developed the Hemodialysis Opioid Prescription Effort (HOPE) Consortium as a means of addressing opioid use within the US End-Stage Renal Disease hemodialysis program.⁸⁶ The HOPE Consortium focuses on rates of pain among adults treated with maintenance hemodialysis in the US and explores multimodal strategies and a combination of behavioral, cognitive, and medical interventions to reduce the number of chronic opioid prescriptions in this population. However, more research is needed with nonpharmacological treatments for pain among adults in earlier stages of CKD and after kidney transplantation.

Microbiomics, the Brain-Gut-Microbiome Axis, and Chronic Pain

The human body is host to trillions of symbiotic and pathologic microbial cells (microbiota), which make up the human microbiome. The millions of genes expressed by the thousands of microbial species⁸⁷ known as the metagenome, play a critical role in human physiological regulatory processes, including digesting, moderating local and systemic immune responses, synthesizing signaling molecules, and maintaining the structural integrity of the gut.⁸⁸ Improvements in our understanding of how the microbiome influences noncommunicable diseases such as CKD and chronic pain have led to an exponential growth in research exploring how the microbiome may be manipulated to improve human health.^89,90

Crosstalk between microbiota in the gut and sensory, inflammatory, and immune pathways in the central and peripheral nervous systems involved in the pain experience is complex.⁹¹ One potential mechanism to explain the relationship between CKD and chronic pain is the bidirectional communication pathway between the gut microbiome and the brain that is known as the brain-gut-microbiome axis (BGMA).^92,93 The BGMA is among the most studied microbiome pathways. Communication occurs via activation of the enteric nervous system, with the vagus nerve serving as the main channel. Microorganisms in the gut synthesize neurotransmitters and short-chain fatty acids (SCFAs), as well as neuroactive cytokines and chemokines, and these chemicals mediate central nervous system homeostasis via the vagal pathway or by crossing directly into the brain.⁹⁴

SCFAs are products of gut microbial fermentation that contribute to the maintenance of gut wall integrity and demonstrate neuroactivity through action in the central and peripheral nervous systems.^92,95 Microglia, specialized immune cells of the central nervous system, play an important role in the initiation and maintenance of chronic pain.⁸⁷ New evidence suggests that microbiota-derived SCFAs influence development and function of the microglia.^96,97 The gut microbiome was recently shown to be the primary determinant of pain sensitivity in a model of chemotherapy-induced peripheral neuropathy, where pain sensitivity was significantly correlated with the degree of microglial proliferation in the spinal cord.⁹⁸

The links between gut microbial community structure, SCFA production, and chronic pain in adults with CKD have not yet been explored and may serve as potential targets for randomized controlled trials focused on patient-centered interventions. Importantly, the microbiome is known to be amenable to patient-centered interventions including plant-based nutrition, supplementation with prebiotics and probiotics, increased physical activity, and stress reduction.^99-101

Metabolomics: Tryptophan Metabolism via the Kynurenine Pathway

The psychological stress associated with chronic disease and the proinflammatory state induced by accumulation of uremic toxins contribute to dysregulation of key biological pathways. Tryptophan metabolism via the kynurenine pathway is one such pathway. Tryptophan is an essential amino acid (i.e., one that must be acquired through diet). It is involved in multiple vital functions in human physiology, including structural and functional processes of the cell, protein biosynthesis, and immunoregulation.¹⁰² Tryptophan (Trp) is also a biochemical precursor to several important neuroactive compounds, including kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN), 5-hydroxytryptamine (5-HT, serotonin), and melatonin.

Currently, three enzymes are recognized as catalyzing tryptophan to kynurenine along the kynurenine pathway: tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO1), and indoleamine 2,3-dioxygenase (IDO2); less is known about the role of IDO2 than about the other two.¹⁰² TDO and IDO1 are the first rate-limiting step in the kynurenine pathway. Under physiological conditions, a majority of tryptophan is metabolized by TDO via the hepatic kynurenine pathway. The effect of tryptophan metabolism via the kynurenine pathway on psychoneurological symptoms (e.g., fatigue, pain, sleep disturbance, depression, anxiety) occurs as a result of two processes: (1) Under conditions of physiologic or psychological stress, IDO1 expression increases, promoting tryptophan degradation via the kynurenine pathway and resulting in deprivation of tryptophan hydroxylase (a precursor of 5-HT, serotonin) available for 5-HT biosynthesis via the serotonin pathway. (2) synthesis of neurotoxic metabolites (3-HK, QUIN) and neuroprotective metabolites (KYNA), which can cross the blood-brain barrier. Overexpression of IDO1 is systemic and leads to reduced production of serotonin, a key mediator of pain and depression.^102-106

Disruption of tryptophan metabolism has been observed in CKD^102,104,107 and may serve as an important biomarker in future research. Moreover, the gut microbiome, which plays an important role as a mediator of the kynurenine pathway via the BGMA (Figure 2), may also represent a target for future research into patient-centered interventions. Thus, including omics (see Table 2) into research designs for pain management in CKD may help identify novel biological targets for development of patient-centered interventions to reduce pain and other comorbid psychoneurological symptoms in people with CKD.

Table 2.

Omics Fields of Study and Definitions

Field of Study	Definition
Genomics	Genomics is the study of the full genetic complement of an organism (the genome). It employs recombinant DNA, DNA sequencing methods, and bioinformatics to sequence, assemble, and analyze the structure and function of genomes.
Metabolomics	Metabolomics refers to the systematic identification and quantification of the small molecule metabolic products (the metabolome) of a biological system (cell, tissue, organ, biological fluid, or organism) at a specific point in time. Mass spectrometry and NMR spectroscopy are the techniques most often used for metabolome profiling.
Transcriptomics	Genome-wide analysis of gene expression is the study of transcription at a genomic scale, also known as transcriptomics. Typically relying on data from microarrays or high throughput sequencing, it can determine what genes or transcript isoforms are enriched in a particular cell or tissue type, condition, disease, or phenotype.
Microbiomics	Microbiomics is the study of the microbiome. The microbiome comprises all of the genetic material within a microbiota (the entire collection of microorganisms in a specific niche, such as the human gut). This can also be referred to as the metagenome of the microbiota.
Epigenomics	Epigenomics is the systematic analysis of the global state of gene expression not attributable to mutational changes in the underlying DNA genome. An organism has multiple, cell type-specific epigenomes comprising epigenetic marks such as DNA methylation, histone modification, and specifically positioned nucleosomes.

All definitions obtained from Nature Research at https://www.nature.com.

Longitudinal Symptom Phenotyping

While advances have been made with regard to understanding symptom phenotypes and their underlying molecular underpinnings in a variety of chronic diseases, further research into symptom phenotyping in kidney disease is needed.^74,79 Specific areas for future research include (1) phenotyping symptoms across stages of kidney disease, including post kidney transplantation; (2) developing standardized multidimensional symptom instruments (e.g., severity, frequency, and duration) for measurement of symptoms associated with CKD; (3) examining the potential of shared underlying biological mechanisms of commonly reported symptom clusters by including omics biomarkers in study designs; and (4) exploring person-centered clustering methodologies, including structural equation modeling, latent class analysis, dynamic network modeling, and latent transition analysis,⁷⁴ to interrogate membership in symptom cluster subgroups and transitions in subgroup membership over time.

Conclusion

Theory-based interrogation of patient-centered factors that contribute to chronic pain among adults with CKD, and specifically the roles of pain catastrophizing, PTSD, and perceived social support, deserve further attention. Randomized controlled trials that employ longitudinal symptom phenotyping and the use of omics biomarkers to study potentially modifiable underlying biological mechanisms of chronic pain will expedite this field’s progression to a paradigm of patient-centered precision health in CKD.

Figure 3. The effects of the BGMA on regulatory pathways associated with pain experience.

Abbreviations: 3-HK, 3-hydroxykynurenine; ATCH, adrenocorticotropic hormone; BGMA, brain-gut-microbiome axis; CRH, corticotropin-releasing hormone; HPA: hypothalamus-pituitary-adrenal axis; IDO1, indoleamine 2,3-dioxygenase; KYN, kynurenine; QUIN, quinolinic acid.