Daniel Cukor, Ph.D.
James L. Levenson, M.D.
Deborah Rosenthal-Asher, Ph.D.
Paul L. Kimmel, M.D.
In this chapter, we cover psychiatric issues in chronic kidney disease (CKD) and end-stage renal disease (ESRD), including comorbid psychiatric disorders, social support, sexual dysfunction, treatment adherence, withdrawal from dialysis, renal psychiatric palliative care, psychotherapy and psychopharmacology (including psychiatric adverse effects of renal drugs), and drug interactions. Renal transplantation is also discussed in Chapter 29, “Organ Transplantation,” and Chapter 32, “Pediatrics,” and hemodialysis for toxic ingestions is covered in Chapter 35, “Medical Toxicology.” Electrolyte disorders are discussed in Chapter 21, “Endocrine and Metabolic Disorders.”
As the techniques of dialysis and transplantation have advanced, ESRD patients, including those with more severe illnesses and comorbidities, are living somewhat longer. Given that psychiatric disorders are widely prevalent among dialysis and renal transplant populations, mental health professionals can play a vital role in management, including intervention for mental health difficulties and promotion of compliance, as well as in palliative care for dying patients and those who wish to decline or discontinue dialysis.
Nephrology has recognized the need for psychiatric consultation since the initial development of kidney dialysis in the late 1960s and early 1970s. Nearly universal access to treatment in the United States followed passage of the 1972 End-Stage Renal Disease amendment to the Social Security Act, which provided federal subsidy for dialysis. Subsequently, the ESRD population has steadily grown, aged, and become more severely ill (United States Renal Data System 2016). Psychiatry’s potential role in the collaborative care of patients with renal disease is increasing.
Each year, approximately 100,000 Americans develop ESRD and more than 650,000 individuals are treated for ESRD (United States Renal Data System 2016). About 430,000 people are receiving maintenance dialysis, and 200,000 have a functioning kidney transplant. The number of patients starting renal replacement therapy in the United States had been growing by 5%–7% each year but is beginning to level off. In addition to the population with ESRD, an estimated 8 million individuals have earlier-stage CKD (United States Renal Data System 2016). The current annual cost of treating CKD is approximately $50 billion, and the Medicare expenditure is about $27 billion for hemodialysis and $4 billion for transplantation (United States Renal Data System 2016).
The major causes of renal failure are diabetes, hypertension, generalized arteriosclerosis, systemic lupus erythematosus, HIV infection, and primary renal diseases such as chronic glomerulonephritis, chronic interstitial nephritis, polycystic kidney disease, and other hereditary and congenital disorders. Diabetes is now found in almost half of ESRD cases. Patients with diabetes are especially likely to have increased morbidity because of its plethora of microvascular and macrovascular complications (Lea and Nicholas 2002).
Renal transplantation is the treatment of choice for many patients. If a transplant is successful, the patient’s survival (United States Renal Data System 2016) and quality of life (Franke et al. 2003; Kimmel and Patel 2006) are improved over what they would have been with maintenance dialysis. A major issue in transplantation is the shortage of donor organs. Transplanted kidneys may come from a living donor or through organ donation following death (long-term kidney survival is greater with living donors). More than two-thirds of kidneys transplanted in 2014 were from deceased donors. As of the end of 2014, the kidney transplant waiting list had nearly 90,000 dialysis patients who were candidates, with 83% awaiting their first transplant (United States Renal Data System 2016). Nearly 18,000 kidney transplants were performed in 2014 (United States Renal Data System 2016).
Peritoneal dialysis and hemodialysis are the two forms of dialysis. In peritoneal dialysis, dialysate fluid is introduced into and then removed from the peritoneal space through an indwelling catheter. The peritoneum serves as a semipermeable membrane, and fluid and wastes are removed together with dialysate. Peritoneal dialysis may be performed by a machine in the home at night (continuous cycling peritoneal dialysis [CCPD]) or manually at home four to six times per day (continuous ambulatory peritoneal dialysis [CAPD]). Only 7% of ESRD patients use peritoneal dialysis as the initial mode of renal replacement therapy (United States Renal Data System 2016). Hemodialysis may be conducted at the patient’s home but usually takes place at an outpatient dialysis unit for 3- to 4-hour sessions, typically three times per week. Home dialysis requires the participation of another person, who must be available to assist with 12–15 hours of weekly treatment. Although no studies have used random assignment to dialysis modalities, a study using patient surveys reported that those receiving peritoneal dialysis were more likely than those receiving hemodialysis to rate their care as excellent (Rubin et al. 2004).
In a study of 200,000 adult U.S. dialysis patients, almost 9% had been hospitalized with a comorbid psychiatric diagnosis (Kimmel et al. 1998b). Depression and other mood disorders were the most common diagnoses, followed by delirium and dementia. In a smaller study in an urban hemodialysis population, roughly 70% of the sample had at least one current DSM-IV (American Psychiatric Association 1994) Axis I diagnosis, as determined by the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) (Cukor et al. 2007). Depression and anxiety were the two most prevalent psychiatric disorders, followed by substance abuse and psychosis. A primary diagnosis of depression was more prevalent in ESRD patients than in patients with ischemic heart disease or cerebrovascular disease (Kimmel et al. 1998b).
Early studies of depression in ESRD reported prevalence rates ranging from 0% to 100%, reflecting widely variable definitions, criteria, and measurement methods (for a review, see Cukor et al. 2006). In the nephrology literature, there is a lack of clarity regarding the term depression and whether it refers to the affective symptom or the psychiatric disorder (Cohen 1996). In addition, the evaluation of depression is complicated by the fact that many of the somatic signs and symptoms of ESRD are very similar to signs of depression. For example, many uremic patients have diminished appetite, loss of energy, poor sleep (Losso et al. 2015), and diminished sexual interest (Kimmel 2002; Kimmel et al. 2007; Meyer and Hostetter 2007).
A variety of techniques have been used to improve the diagnostic accuracy of depression in patients with renal disease. Some ESRD research studies have relied exclusively on self-report instruments to determine symptom severity but have adjusted scoring of the measures to account for somatic complaints (Craven et al. 1988; Kimmel et al. 1993; Smith et al. 1985). Other studies (Cukor et al. 2007; Finkelstein and Finkelstein 2000; Hedayati et al. 2006; Watnick et al. 2003) have combined self-report measures with a structured diagnostic interview based on DSM-IV-TR (American Psychiatric Association 2000) criteria or have used multiple measurement points across time (Boulware et al. 2006; Cukor et al. 2008b; Kimmel et al. 2000). Although there has been much less study of depression in patients with CKD before initiation of dialysis, depression rates appear to be elevated in this population as well (Palmer et al. 2013).
Rigorous studies of depression self-report measures in ESRD patients have assessed these measures against structured diagnostic interviews (e.g., SCID-I) to determine optimal cutoff scores for diagnostic accuracy in ESRD. The Beck Depression Inventory (utilizing a cutoff of 14–15), the Patient Health Questionnaire–9 (PHQ-9) (utilizing scores ≥10), and the Center for Epidemiologic Studies Depression Scale (using scores ≥18) have all been used by studies to estimate the prevalence of major depressive disorder (MDD) in ESRD samples. However, despite their utilization of different instruments, studies have reported similar MDD prevalence rates, 20%–27% (Hedayati et al. 2006, 2009; Kimmel 2001; Kimmel et al. 1996, 1998a, 2000; Watnick et al. 2005).
Depression in patients with ESRD is a strong predictor of worse medical outcomes (Fan et al. 2014; Farrokhi et al. 2014). In a study examining the effect of depression on outcomes (time to death or hospitalization) in dialysis patients, Hedayati et al. (2008) found the diagnosis of MDD to be associated with a hazard ratio of 2.07 compared with nondepressed control subjects, after adjustment for other variables. Kimmel et al. (2000) found that tracking multiple measurements of depression produced a more robust association with mortality than did tracking any single measurement in hemodialysis patients. Similarly, Boulware et al. (2006) demonstrated that associations with outcomes existed with multiple measurements of depression that did not exist with baseline data. Cukor et al. (2008b) reassessed SCID-diagnosed depressed and anxious ESRD patients after 16 months and noted a variety of clinical trajectories. A persistent course of depression was associated with significantly lower quality of life and more reported health problems compared with intermittent depression. These data suggest that a single measure of depression at a specific point in time might not be as meaningful as assessment of depression over a longer time span.
Despite the high prevalence of depression in dialysis patients and frequent prescription of antidepressants, there has been little study of the effectiveness of these medications. A 2016 Cochrane review identified only four small clinical trials examining the efficacy of antidepressant in ESRD patients, and rated the evidence as limited and inconclusive (Palmer et al. 2016). A larger trial of sertraline yielded negative findings (Friedli et al. 2017). The utility of antidepressants may be limited by low acceptance rates among hemodialysis patients (Atalay et al. 2010; Friedli et al. 2017; Pena et al. 2017).
In addition to pharmacotherapy, psychotherapy is an appropriate intervention for depressed ESRD patients, with cognitive-behavioral therapy (CBT) receiving the most scientific attention. Both individual (Cukor et al. 2014) and group psychotherapy interventions (Duarte et al. 2009) have been associated with significant improvement of depression in hemodialysis patients in small-scale randomized trials. Despite the significant challenges of studying depression in ESRD populations, including recruitment, screening, outcome measurement, confounding treatment, and overall low acceptance of interventions (Hackett and Jardine 2017), larger-scale rigorous trials investigating interventions for depression are currently under way (Hedayati et al. 2016).
Anxiety is a complicating comorbid diagnosis for many medical illnesses and often co-occurs with depression in ESRD populations (Cohen et al. 2016; Cukor et al. 2007, 2008a, 2008b). There is relatively little anxiety research specific to ESRD patients, but it appears that an anxiety diagnosis is associated with diminished quality of life (Cukor et al. 2008a, 2013; Sareen et al. 2006). One early study (Nichols and Springford 1984) found that about one-third of hemodialysis patients experienced episodes of moderate anxiety during their first year of dialysis treatment. In a study that assessed psychiatric diagnoses in a sample of 70 predominately African American ESRD patients, about 45% had at least one anxiety disorder. The most common diagnoses identified were phobias and panic disorder (Cukor et al. 2008a). The prevalence of panic disorder was much higher in ESRD patients than in community samples, a finding that may be related to hypervigilance to bodily sensations associated with hemodialysis or fears about the outcome of ESRD treatment.
Posttraumatic stress symptoms related to dialysis experiences, serious medical events, or other traumas are also common among hemodialysis patients (Tagay et al. 2007). Phobias for needles or the sight of blood are common in the general population (see Chapter 10, “Anxiety Disorders”), and such phobias are among the most frequently reported reasons that hemodialysis patients choose self-care treatment instead of in-center dialysis (McLaughlin et al. 2003). There are no published clinical trials of psychopharmacology or psychotherapy for anxiety in patients with ESRD and very few case reports regarding anxiety in this population (Cohen et al. 2016).
Substance use disorders, such as cocaine or heroin dependence or chronic overuse of nonsteroidal anti-inflammatory drugs (NSAIDs), can lead to CKD (Jaffe and Kimmel 2006; Norris et al. 2001). Substance use may also result in HIV infection, which can secondarily cause renal failure (Kimmel et al. 2003). In a sample of 145 hemodialysis patients, Hegde et al. (2000) found that 28% had difficulty with chronic alcoholism. Those who abused alcohol had poorer nutrition than nonabusers, as demonstrated by serum albumin measurements (Hegde et al. 2000). Another study found cocaine users to be less compliant with dialysis attendance than nonusers (Obialo et al. 2008). There is a high and variable rate of prescription opioid use in dialysis centers (Wyne et al. 2011), which may be of particular concern in the context of the current opioid epidemic. Chronic opioid prescription was found to be associated with greater risk of death, discontinuation of dialysis, and hospitalization in U.S. dialysis patients (Kimmel et al. 2017). Although additional research is needed regarding substance use disorders and dialysis, substance abuse should be taken seriously and addressed with specialist care.
To function well, dialysis units depend on the ability of their staff to provide appropriate patient care. There has been an increase in the number of reported disruptive patients within dialysis units (Hashmi and Moss 2008), with verbal aggression being the most prevalent behavior (Jones et al. 2014). Disruption on the unit may affect the individual, as in the case of noncompliance with treatment. A patient’s disruptive behavior may also affect other patients receiving dialysis therapy. A disruptive patient may harm others by coming late to appointments, thus disrupting dialysis scheduling for others, or by threatening the staff (Hashmi and Moss 2008).
The decision to withhold dialysis treatment from a disruptive patient must be carefully considered. Although all patients should be treated equally and with respect, the welfare of a disruptive patient must be balanced against the welfare of health care personnel and other patients. If disruptive behavior affects only the patient him- or herself, the individual should not be refused dialysis treatment. For example, treatment cannot be denied to a patient who is noncompliant with his or her medical regimen but continues to want dialysis. However, in the case of a disruptive patient who continually shows up late to appointments and does not abide by rules of the unit, moving the individual to a different shift or unit might be considered (Hashmi and Moss 2008). Verbal or physical abuse on the unit should not be tolerated, and the welfare of staff and other patients should not be compromised.
Suggested strategies for dealing with disruptive patients include attempting to first create a calm environment, approaching the patient directly about his or her behavior, using reflective listening techniques to help the patient feel understood, attempting to understand the reasons for the patient’s responses and behavior, outlining specific goals the patient can pursue in treatment, educating the patient about consequences that may result from his or her behavior (ideally through a behavioral contract), and making a referral to a skilled team member such as a psychologist or social worker (Goldman 2008; Hashmi and Moss 2008; Sukolsky 2004). Two helpful resources addressing dialysis-related disruptive behavior and conflict resolution are the Renal Physicians Association/American Society of Nephrology’s “Clinical Practice Guideline on Shared Decision-Making in the Appropriate Initiation of and Withdrawal From Dialysis” (Galla and The Renal Physicians Association and the American Society of Nephrology 2000) and the Decreasing Dialysis Patient–Provider Conflict (DPC) project (for a review, see Goldman 2008).
The extent to which CKD represents a unique risk factor for dementia (Deckers et al. 2017) and the cognitive impact of hemodialysis are still unclear (Lin et al. 2015); however, cognitive impairment is prevalent in ESRD (Murray et al. 2006). A recent meta-analysis found that hemodialysis patients perform more poorly across cognitive domains compared with the general population, especially on measurements of orientation and attention (O’Lone et al. 2016). Cognitive impairment has been associated with increased mortality in hemodialysis patients (Drew et al. 2015; Griva et al. 2010), with impairment in cognitive abilities potentially impacting decision making and adherence to treatment (Kurella Tamura and Yaffe 2011).
Cognitive impairment in this population may be related to uremia, various medical comorbidities (e.g., electrolyte disturbances, severe malnutrition, impaired metabolism, cerebrovascular disease), or adverse effects of treatment. Uremia is a clinical syndrome resulting from profound loss of renal function and has been associated with cognitive impairment, including difficulty with concentration, memory, and intellectual functioning (Pliskin et al. 1996; Souheaver et al. 1982; Williams et al. 2004). Signs and symptoms of uremia vary considerably, with severity presumably dependent on both the degree of renal failure and the speed with which renal function is lost. Central nervous system symptoms may begin with mild cognitive dysfunction, fatigue, and headache, progressing to hypoactive delirium and, if untreated, coma. Restless legs syndrome, muscle cramps, and sleep disorders are also common in uremic patients (see Chapter 14, “Sleep Disorders”). Other common symptoms include pruritus, anorexia, nausea, and vomiting (Haddy et al. 2008; Meyer and Hostetter 2007; Weisbord et al. 2003). Anemia is also a potential risk factor for impaired cognitive functioning in those with kidney disease (Pereira et al. 2005). A reduction in oxygen due to anemia may result in impaired cognitive function, especially in individuals with neurological or cerebrovascular diseases (Johnson et al. 1990). Depression itself may also be etiologically related to the cognitive deficits (Dong et al. 2016).
The relationship between degree of cognitive impairment and CKD stage is unclear. Kurella et al. (2004) measured cognitive functioning in 80 CKD patients not receiving dialysis and 80 ESRD patients receiving hemodialysis treatment. The authors found a relationship between stage of CKD and degree of cognitive impairment on measures of mental status, executive functioning, and verbal memory. Another study (Elias et al. 2009) also found an association between CKD severity and presence of cognitive impairment. In this study, CKD patients with lower renal function, as well as those with higher serum creatinine levels, showed performance decrements on measures of visuospatial processing, attention, and planning. More recently, Kurella Tamura et al. (2017) examined dialysis initiation and cognitive functioning in 212 patients with advanced CKD. Although there was no change in global cognitive functioning, the study found an association between dialysis initiation and reduced performance on tests of executive functioning. Additionally, patients with advanced CKD who transitioned to dialysis demonstrated poorer executive functioning compared with those who did not initiate dialysis. This study raises the possibility that dialysis treatment itself may negatively affect executive functioning.
Dementia has been identified as a mortality risk factor in ESRD. Hypertension and diabetes, both highly prevalent among ESRD patients, are risk factors for the development of dementia (Saczynski et al. 2008; Semplicini et al. 2006). One large study of hemodialysis patients (Kurella et al. 2006) found a dementia prevalence of 4% in the overall sample. Compared with those without dementia, patients diagnosed with dementia had a higher risk of death (relative risk (RR)=1.48; 95% confidence interval (CI)=1.32–1.66) and were twice as likely (RR=2.01; 95% CI=1.57–2.57) to withdraw from dialysis treatment. Consistent with findings in the general population, older age, black race, lower education, and presence of diabetes or cerebrovascular disease were found to be related to dementia risk in ESRD patients.
Maintaining an optimal level of cognitive function is important for quality of life and is a prerequisite for successful adaptation to dialysis. Further studies are needed to help elucidate the relationships among CKD, dialysis, and cognitive functioning in order to identify and minimize risk factors and develop management and intervention techniques to help decrease the impact cognitive impairment has on this population.
ESRD patients can receive social support from family, friends, and individuals on the dialysis unit (e.g., physicians, social workers, nurses, other patients). Increased levels of social support may positively influence outcomes through various mechanisms, including decreased depression, increased patient perception of quality of life, increased access to health care, increased patient adherence to prescribed therapies, and beneficial physiological effects on the immune system (Cohen et al. 2007b). Higher levels of perceived social support are thought to have a positive influence on health outcomes, utilization of health care services, and treatment compliance. Previous research has demonstrated that social support is related to improved health outcomes and lower mortality in ESRD patients (Cohen et al. 2007b; Kimmel et al. 1998a; Untas et al. 2011).
The impact of hemodialysis on both male and female sexual functioning is well documented (Levy and Cohen 2001) but often not discussed with patients. One study found that 43% of ESRD patients reported having a decreased interest in sex, and 47% reported trouble getting aroused (Abdel-Kader et al. 2009). Data show that women with ESRD often have decreased sexual desire but do not necessarily identify it as sexual dysfunction (Mor et al. 2014). A meta-analysis found that depression, older age, and diabetes were consistently associated with higher levels of sexual dysfunction (Navaneethan et al. 2010). The relative roles of physical dysfunction, medical illness, medication effects, and psychological function in inducing sexual dysfunction in CKD patients have not been determined. The first line of treatment for erectile dysfunction is typically sildenafil, which appears to be safe in ESRD patients who do not have contraindications to treatment (Palmer 2003), as well as effective (Turk et al. 2010). (See also Chapter 15, “Sexual Dysfunctions.”)
Clinical and behavioral indices of adherence in dialysis patients include dialysis attendance, interdialytic weight gain, and medication adherence. Lack of adherence to treatment regimens is believed to be a common cause of inadequate dialysis and poor outcome (Kaveh and Kimmel 2001). Many factors may contribute to nonadherence, including depression, anxiety, cognitive dysfunction, personality traits, the doctor–patient relationship, and financial difficulties. The rate of nonadherence among dialysis patients varies by country as well (Bleyer et al. 1999; Hecking et al. 2004). Common noncompliant behaviors include shortening or missing dialysis sessions and engaging in dietary and medication indiscretions. According to self-reports, 12% of dialysis patients miss one peritoneal dialysis exchange per week, and 5% skip two to three exchanges per week (United States Renal Data System 2016). To maintain optimal health, ESRD patients must adhere to their prescribed treatments. Patients are prescribed regimens for their medications, diet, fluid intake, exercise, medical appointments, and dialysis attendance. Measures of behavioral compliance are clinically meaningful and associated with hard outcomes (Kimmel et al. 1995, 1998a; Leggat 2005). A study that examined medication adherence in ESRD found that 37% of hemodialysis patients reported less-than-perfect adherence to the medication regimen and that increased depressive affect was associated with decreased medication adherence (Cukor et al. 2009). Because adherence was self-reported, the data may be an overestimation of the actual level of adherence, demonstrating the great need for addressing this issue in this population. Similarly, a study looking at 286 patients found depressive symptoms to be associated with missing and shortening dialysis treatment sessions (Weisbord et al. 2014). Another study found that the median daily pill burden of an ESRD cohort was 19. In one-quarter of subjects, it exceeded 25 pills per day. Phosphate binders accounted for about one-half of the daily pill burden, and 62% of the participants were noncompliant with the prescribed phosphate binder therapy (Chiu et al. 2009). A systematic review of studies of adherence to prescribed oral medications in adult chronic hemodialysis patients found that more than half of the included studies reported nonadherence rates of 50% or more, with a mean of 67% (Schmid et al. 2009).
A variety of interventions targeting adherence in ESRD have been studied. Some of these interventions are educational in nature, attempting to increase knowledge of the importance of adherence and the consequences of noncompliance. However, the efficacy of educational interventions that target adherence is questionable. One study found that the hemodialysis patients who demonstrated better knowledge about the importance of monitoring phosphorus levels in their dietary regimens were less compliant, as measured by biomarkers and interdialytic weight gain (Durose et al. 2004). Other interventions have included CBT, motivational interviewing, relaxation training, social skills training, self-monitoring, and behavioral reinforcement to increase adherence (Nozaki et al. 2005; Sharp et al. 2005b; Tsay et al. 2005). A small randomized controlled trial of CBT demonstrated an increase in fluid adherence (as measured by interdialytic weight gain) at 10 weeks postbaseline (Sharp et al. 2005a). Another small study (Christensen et al. 2002) compared levels of adherence in hemodialysis patients who participated in a 7-week behavioral self-regulation intervention and matched control hemodialysis patients. The study showed that the intervention patients had higher adherence (as measured by interdialytic weight gain) 8 weeks after completing the intervention compared with the control patients. A more recent similar study did not demonstrate improvement in the behavioral self-regulation group over a placebo support control condition (Howren et al. 2016). A pilot study designed to improve immunosuppressant medication adherence in kidney transplant recipients that utilized a brief intervention based on motivational interviewing and CBT also demonstrated efficacy (Cukor et al. 2017). In a study that was targeting depression (Cukor et al. 2014), patients receiving CBT showed improvements in mood as well as in fluid compliance (as measured by interdialytic weight gain). These studies suggest the potential value of implementing interventions to target adherence, but the studies to date have been small and of short duration and have had bias-prone study designs (Sharp et al. 2005b).
Withdrawal from dialysis can be viewed as part of the life cycle of the ESRD patient and part of the dying process. In the United States, dialysis withdrawal has been more common among women and older patients and less common among African American and Asian patients, with significant regional variation (Gessert et al. 2013; Kurella Tamura et al. 2010; Munshi et al. 2001). Cognitive impairment has also been associated with the decision to withdraw (Chater et al. 2006). Patients who begin dialysis with high depression scores are more likely to withdraw within the first year of treatment (Lacson et al. 2012).
The topic of dialysis withdrawal is commonly approached in the assessment of patient quality of life versus quantity of life (Hackett and Watnick 2007). Reasons for the decisions of individuals who choose not to initiate or continue dialysis have included concerns about being a burden to family members and mistrust of medical treatment (Ashby et al. 2005). However, withdrawal from dialysis may often be appropriate for a dialysis patient who is failing to thrive or is suffering. Many patients and families choose this option because it allows for a quicker death and the end of suffering (Cohen and Germain 2005; Cohen et al. 2003). The median time to death after stopping dialysis is 7–8 days (O’Connor et al. 2013), and dialysis termination usually does not cause pain or discomfort (Cohen et al. 2000). Withdrawal typically results in lethargy progressing to coma and death. Psychiatrists can assist with determinations of patient capacity and the potential influence of depression or other psychosocial factors. One study that controlled for biomarkers and age found depression to be a unique predictor of withdrawal from dialysis treatment (McDade-Montez et al. 2006). The decision to withdraw from dialysis is complex, and a patient’s decision to discontinue does not necessarily constitute suicide. Ideally, the decision should be made when the patient is not in the midst of severe depression, so that the appropriate course is clear (Russ et al. 2007).
With the goal of providing better end-of-life care for this very ill population, Cohen et al. (2005) have advocated that attention be focused on the following issues:
Early frank discussions concerning prognosis and goals of care—Ideally, these discussions should include the family and should begin when options for care are discussed. The possibility of not starting dialysis, especially if the burdens of dialysis might outweigh the benefits, should be considered. Patients should also know that they have the option of stopping dialysis if their quality of life diminishes. Written advance directives can help focus the discussion, and do-not-resuscitate orders should be strongly considered when cardiopulmonary resuscitation is likely to be futile (Moss 2000).
Attention to symptoms at all stages of the disease process—Patients with ESRD have a high burden of symptoms related to dialysis and their comorbid conditions (Cohen and Germain 2005; Weisbord et al. 2008).
Early hospice referrals—Such referrals can take place in the hospital, home, nursing home, or inpatient hospice unit. All patients who terminate dialysis should be offered referral to hospice.
Maximal palliative care at the end of life—This care includes aggressive pain control, spiritual and emotional support, and attention to the patient’s terminal treatment preferences and goals. Utmost sensitivity is needed in making decisions about withholding or discontinuing care, attending to cultural biases, countertransference, and other complicating factors (Moss 1998, 2000).
Newer models of renal palliative care emphasize integration of dialysis and hospice services (Moss 2017) and specialized training in end-of-life issues for nephrologists (Bristowe et al. 2014). There has also been recent acknowledgment of the systemic barriers in place that prevent adequate renal palliative care from reaching all patients (Grubbs et al. 2014; Tamura and Meier 2013). While the logistics of the incorporation of palliative care vary widely across medical settings, the psychiatrist is often an integral member of the team required to initiate, develop, and then execute a care plan.
Among the selective serotonin reuptake inhibitors (SSRIs), citalopram, escitalopram, and sertraline would be expected to have the fewest potential interactions with other medications taken by patients with renal impairment. Paroxetine clearance is reduced in patients with renal insufficiency (Doyle et al. 1989). Some evidence suggests that dosage adjustments may not be needed for citalopram (Spigset et al. 2000) and fluoxetine (Finkelstein and Finkelstein 2000) in patients with renal insufficiency.
While the longest experience has been with the tricyclic antidepressants (TCAs), ESRD patients, especially those with diabetes, are often more sensitive to their side effects. Hydroxylated metabolites of TCAs may be markedly elevated in patients with ESRD and responsible for some TCA side effects. Nortriptyline and desipramine are the preferred TCAs in renal failure because they are less likely to cause anticholinergic effects or orthostatic hypotension than other TCAs (Gillman 2007).
Limited data are available on the use of newer antidepressants in patients with renal failure. The half-life of venlafaxine is prolonged in renal insufficiency; its clearance is reduced by over 50% in patients undergoing dialysis (Troy et al. 1994). Desvenlafaxine undergoes significant renal elimination, so dosage reduction is required in moderate to severe renal impairment. Because antidepressants are typically metabolized by the liver and those metabolites are excreted by the kidney, it seems prudent to initially reduce the dose for all antidepressants to minimize the potential accumulation of active metabolites (Cohen et al. 2007a). However, ordinary dosages are frequently required in ESRD patients and are usually well tolerated (Dev et al. 2014).
A recent, well-designed randomized controlled trial by Hedayati et al. (2017) compared the SSRI sertraline against placebo in the pharmacological treatment of depressed patients with CKD but not ESRD. Despite having a high rate of medication adherence and no greater than usual amounts of side effects, patients treated with sertraline had no detectable differences in outcome compared with patients treated with placebo. The reason for this surprising finding may have to do with the role of the placebo effect in behavioral trials (Walther et al. 2017), or it may be related to the overall moderate level of depression in the study sample and the questionable utility of SSRIs for mild to moderate depression (Cukor and Kimmel 2018).
Antipsychotics typically do not depend on renal elimination, with the exception of paliperidone, which is largely excreted unchanged in urine and thus requires dosage reduction in patients with renal insufficiency (Vermeir et al. 2008). As with TCAs, adverse effects of antipsychotics may be amplified by medical comorbidities such as diabetes, hyperlipidemia, and cerebrovascular disease in ESRD patients.
No clinical trials of pharmacotherapy for anxiety in ESRD patients have been published. The preferred benzodiazepines are those with inactive metabolites (e.g., lorazepam, oxazepam). Even so, the half-lives of lorazepam and oxazepam may rise significantly in patients with ESRD, and dosage reduction may be required. Other benzodiazepines with inactive metabolites include clonazepam and temazepam, but less is known about changes in their half-lives in ESRD. SSRIs are typically the first line of treatment for anxiety in ESRD patients, particularly given the high comorbidity of depression (Cohen et al. 2016).
Lithium is almost entirely excreted by the kidneys. It is contraindicated in patients with acute renal failure. Some clinicians consider lithium to be relatively contraindicated in patients with stable renal insufficiency. If used, lithium should be conservatively dosed while monitoring renal function frequently. Despite these cautions and lithium’s possible nephrotoxicity (discussed under “Renal Effects of Psychotropics” later in this chapter), there are some bipolar patients who do not respond to or tolerate the alternative mood stabilizers. For these patients, lithium is the only effective drug. Lithium is completely dialyzed and may be given safely as a single oral dose (300–600 mg) following hemodialysis treatment. Lithium levels should not be checked until at least 2–3 hours after dialysis because re-equilibration from tissue stores occurs in the immediate postdialysis period. The dose of gabapentin, pregabalin, lithium, and topiramate should be modified on the basis of creatinine clearance (Levenson and Owen 2017).
While the data are limited, dosage adjustment of donepezil and rivastigmine is probably unnecessary. Galantamine should be used cautiously in patients with moderate renal insufficiency and is not recommended in patients with severe renal insufficiency. Memantine requires dosage reduction in patients with severe renal insufficiency (Levenson and Owen 2017).
Dopaminergic therapy (i.e., levodopa or the dopamine receptor agonists pramipexole, ropinirole, and rotigotine) has been recommended as first-line treatment for restless legs syndrome, based on studies in the general population. However, data supporting use of dopamine agonists in individuals with ESRD are very limited, as are data for alternative therapies (e.g., gabapentin, clonazepam, opioids) (Gopaluni et al. 2016).
The syndrome of inappropriate antidiuretic hormone secretion (SIADH), resulting in hyponatremia, may be caused by many psychotropic drugs, especially carbamazepine and oxcarbazepine, but also SSRIs, TCAs, and antipsychotics. Hypernatremia due to nephrogenic diabetes insipidus (NDI) may be caused by lithium through inhibition of renal tubular water reabsorption. Most patients receiving lithium have polydipsia and polyuria, reflecting NDI. Adverse effects of lithium-induced NDI vary from mild polyuria to hyperosmolar coma. Amiloride is considered the treatment of choice for lithium-induced NDI, but NDI also has been treated with NSAIDs, thiazides, and sodium restriction (Grünfeld and Rossier 2009).
The effect of lithium on renal function is controversial, with variable results from recent retrospective and cohort studies (for a review, see Levenson and Owen 2017). Progression to ESRD in patients taking lithium is rare (0.2%–0.7%) and typically requires use for many years (Presne et al. 2003). One meta-analysis concluded that any lithium-induced effect on renal function is quantitatively small and probably clinically insignificant (Paul et al. 2009). A population-based study in Sweden found that renal failure was rare but did occur in patients being treated with lithium (Bendz et al. 2010). However, a larger nationwide Danish study found that maintenance treatment with lithium was associated with an increased rate of CKD, but not an increased rate of ESRD (Kessing et al. 2015). The authors concluded that associations between use of lithium and CKD may be at least partly attributable to bias. Other factors besides lithium use that may contribute to such changes include age, episodes of lithium toxicity, other medications (NSAIDs, substance abuse), and the presence of comorbid disorders (e.g., hypertension, diabetes). Lithium nephrotoxicity is not strongly dose related (Freeman and Freeman 2006). Other psychiatric drugs have not been reported to be associated with kidney injury, except for one recent retrospective study that found moderate (but small absolute) increased risks of acute kidney injury with some, but not all, antipsychotics, with greater risk with atypical than typical antipsychotics (Jiang et al. 2017).
Drugs with significant anticholinergic activity, such as TCAs and antipsychotics (both low-potency typical agents and atypical agents), frequently cause urinary retention. Less commonly, urinary retention has been reported to occur with SSRIs, serotonin–norepinephrine reuptake inhibitors, and bupropion. Urinary incontinence and other lower-urinary-tract side effects are very common with clozapine (Jeong et al. 2008). Sexual side effects of psychotropic drugs are reviewed in Chapter 15, “Sexual Dysfunctions.”
Anticholinergic agents commonly used to treat overactive bladder are associated with psychiatric adverse effects, including cognitive impairment, confusion, fatigue and psychosis. Cumulative use of strong anticholinergics, including bladder antimuscarinics, is associated with an increase in incident dementia (Gray et al. 2015). Thiazide diuretics are a common cause of hyponatremia, which when severe can cause lethargy, stupor, confusion, psychosis, irritability, and seizures. The risk may be increased further if the patient is also taking a psychotropic drug that causes hyponatremia, such as an SSRI or carbamazepine. Psychiatric adverse effects of other medications frequently used to treat patients with renal disease are covered elsewhere in this book—corticosteroids for autoimmune nephritis (Chapter 24, “Rheumatology”), antihypertensives (Chapter 17, “Heart Disease”), and immunosuppressants after renal transplantation (Chapter 29, “Organ Transplantation”).
A number of pharmacodynamic and pharmacokinetic drug interactions frequently occur between drugs prescribed for renal and urological disorders and psychotropic drugs. Anticholinergic side effects may be increased if anticholinergic psychotropic drugs are given to patients taking urinary antispasmodics. Like other anticholinergics, antispasmodics may block the benefits of cholinesterase inhibitors. As noted in the previous section, the hyponatremic effects of thiazide diuretics may be enhanced in combination with oxcarbazepine and carbamazepine, and to a lesser degree with SSRIs, TCAs, and antipsychotics.
Diuretics variably affect lithium excretion, depending on the type of diuretic and the volume status of the patient. Thiazide diuretics may reduce lithium excretion, resulting in increased lithium levels. Acute administration of loop diuretics (e.g., furosemide, ethacrynic acid, bumetanide) increases lithium excretion, causing a drop in lithium levels, but with chronic use, compensatory changes leave lithium levels somewhat unpredictable but usually not significantly changed. Carbonic anhydrase inhibitors (e.g., acetazolamide) and osmotic diuretics (e.g., mannitol) reduce lithium levels (Levenson and Owen 2017). Potassium-sparing diuretics (e.g., amiloride, triamterene, spironolactone) may increase lithium excretion. Furosemide and amiloride are considered to have the least effects on lithium excretion (Levenson and Owen 2017).
The psychosocial needs of the renal patient are becoming more clearly defined and valued by Centers for Medicare & Medicaid Services guidelines and dialysis care teams. The psychiatric presentation of patients with chronic kidney disease and end-stage renal disease are varied, but depression and anxiety seem to be paramount. More research is needed to identify safe and efficacious treatments in this population and to examine possible confluent mechanisms in patients with comorbid psychiatric difficulty and renal dysfunction. Kidney patients, especially in the advanced stages of the disease, are particularly susceptible to isolation and sexual dysfunction, conditions not often discussed with the medical team. There are multilayered reasons why some kidney patients are nonadherent to treatment recommendations and consider withdrawal from dialysis, and a thorough understanding of the biopsychosocial universe of the patient is often necessary to understand their behavior. The psychiatrist should be an integral member of the treatment team.
Abdel-Kader K, Unruh ML, Weisbord SD: Symptom burden, depression, and quality of life in chronic and end-stage kidney disease. Clin J Am Soc Nephrol 4(6):1057–1064, 2009 19423570
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Revised. Washington, DC, American Psychiatric Association, 1994
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000
Ashby M, op’t Hoog C, Kellehear A, et al: Renal dialysis abatement: lessons from a social study. Palliat Med 19(5):389–396, 2005 16111062
Atalay H, Solak Y, Biyik M, et al: Sertraline treatment is associated with an improvement in depression and health-related quality of life in chronic peritoneal dialysis patients. Int Urol Nephrol 42(2):527–536, 2010 19953347
Bendz H, Schön S, Attman PO, et al: Renal failure occurs in chronic lithium treatment but is uncommon. Kidney Int 77(3):219–224, 2010 19940841
Bleyer AJ, Hylander B, Sudo H, et al: An international study of patient compliance with hemodialysis. JAMA 281(13):1211–1213, 1999 10199431
Bristowe K, Shepherd K, Bryan L, et al: The development and piloting of the REnal specific Advanced Communication Training (REACT) programme to improve Advance Care Planning for renal patients. Palliat Med 28(4):360–366, 2014 24201135
Boulware LE, Liu Y, Fink NE, et al: Temporal relation among depression symptoms, cardiovascular disease events, and mortality in end-stage renal disease: contribution of reverse causality. Clin J Am Soc Nephrol 1(3):496–504, 2006 17699251
Chater S, Davison SN, Germain MJ, et al: Withdrawal from dialysis: a palliative care perspective. Clin Nephrol 66(5):364–372, 2006 17140166
Chiu YW, Teitelbaum I, Misra M, et al: Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients. Clin J Am Soc Nephrol 4(6):1089–1096, 2009 19423571
Christensen AJ, Moran PJ, Wiebe JS, et al: Effect of a behavioral self-regulation intervention on patient adherence in hemodialysis. Health Psychol 21(4):393–397, 2002 12090682
Cohen L: Renal disease (Chapter 25: Internal Medicine and Medical Subspecialties), in The American Psychiatric Press Textbook of Consultation-Liaison Psychiatry. Edited by Rundell JR, Wise MG. Washington, DC, American Psychiatric Press, 1996, pp 573–578
Cohen LM, Germain MJ: The psychiatric landscape of withdrawal. Semin Dial 18(2):147–153, 2005 15771660
Cohen LM, Germain M, Poppel DM, et al: Dialysis discontinuation and palliative care. Am J Kidney Dis 36(1):140–144, 2000 10873883
Cohen LM, Germain MJ, Poppel DM: Practical considerations in dialysis withdrawal: “to have that option is a blessing.” JAMA 289(16):2113–2119, 2003 12709469
Cohen LM, Levy NB, Tessier EG, et al: Renal disease, in The American Psychiatric Publishing Textbook of Psychosomatic Medicine. Edited by Levenson JL. Washington, DC, American Psychiatric Publishing, 2005, pp 483–493
Cohen SD, Norris L, Acquaviva K, et al: Screening, diagnosis, and treatment of depression in patients with end-stage renal disease. Clin J Am Soc Nephrol 2(6):1332–1342, 2007a 17942763
Cohen SD, Sharma T, Acquaviva K, et al: Social support and chronic kidney disease: an update. Adv Chronic Kidney Dis 14(4):335–344, 2007b 17904500
Cohen SD, Cukor D, Kimmel PL: Anxiety in patients treated with hemodialysis. Clin J Am Soc Nephrol 11(12):2250–2255, 2016 27660303
Craven JL, Rodin GM, Littlefield C: The Beck Depression Inventory as a screening device for major depression in renal dialysis patients. Int J Psychiatry Med 18(4):365–374, 1988 3235282
Cukor D, Kimmel PL: Treatment of depression in CKD patients with an SSRI: why things don’t always turn out as you expect. Clin J Am Soc Nephrol April 13, 2018 [Epub ahead of print] 29653958
Cukor D, Peterson RA, Cohen SD, et al: Depression in end-stage renal disease hemodialysis patients. Nat Clin Pract Nephrol 2(12):678–687, 2006 17124525
Cukor D, Coplan J, Brown C, et al: Depression and anxiety in urban hemodialysis patients. Clin J Am Soc Nephrol 2(3):484–490, 2007 17699455
Cukor D, Coplan J, Brown C, et al: Anxiety disorders in adults treated by hemodialysis: a single-center study. Am J Kidney Dis 52(1):128–136, 2008a 18440682
Cukor D, Coplan J, Brown C, et al: Course of depression and anxiety diagnosis in patients treated with hemodialysis: a 16-month follow-up. Clin J Am Soc Nephrol 3(6):1752–1758, 2008b 18684897
Cukor D, Rosenthal DS, Jindal RM, et al: Depression is an important contributor to low medication adherence in hemodialyzed patients and transplant recipients. Kidney Int 75(11):1223–1229, 2009 19242502
Cukor D, Ver Halen N, Fruchter Y: Anxiety and quality of life in ESRD. Semin Dial 26(3):265–268, 2013 23432416
Cukor D, Ver Halen N, Asher DR, et al: Psychosocial intervention improves depression, quality of life, and fluid adherence in hemodialysis. J Am Soc Nephrol 25(1):196–206, 2014 24115478
Cukor D, Ver Halen N, Pencille M, et al: A pilot randomized controlled trial to promote immunosuppressant adherence in adult kidney transplant recipients. Nephron 135(1):6–14, 2017 28049201
Deckers K, Camerino I, van Boxtel MP, et al: Dementia risk in renal dysfunction: a systematic review and meta-analysis of prospective studies. Neurology 88(2):198–208, 2017 27974647
Dev V, Dixon SN, Fleet JL, et al: Higher anti-depressant dose and major adverse outcomes in moderate chronic kidney disease: a retrospective population-based study. BMC Nephrol 15:79, 2014 24884589
Dong J, Pi HC, Xiong ZY, et al: Depression and cognitive impairment in peritoneal dialysis: a multicenter cross-sectional study. Am J Kidney Dis 67(1):111–118, 2016 26255306
Doyle GD, Laher M, Kelly JG, et al: The pharmacokinetics of paroxetine in renal impairment. Acta Psychiatr Scand Suppl 350:89–90, 1989 2530798
Drew DA, Weiner DE, Tighiouart H, et al: Cognitive function and all-cause mortality in maintenance hemodialysis patients. Am J Kidney Dis 65(2):303–311, 2015 25240262
Duarte PS, Miyazaki MC, Blay SL, et al: Cognitive-behavioral group therapy is an effective treatment for major depression in hemodialysis patients. Kidney Int 76(4):414–421, 2009 19455196
Durose CL, Holdsworth M, Watson V, et al: Knowledge of dietary restrictions and the medical consequences of noncompliance by patients on hemodialysis are not predictive of dietary compliance. J Am Diet Assoc 104(1):35–41, 2004 14702581
Elias MF, Elias PK, Seliger SL, et al: Chronic kidney disease, creatinine and cognitive functioning. Nephrol Dial Transplant 24(8):2446–2452, 2009 19297357
Fan L, Sarnak MJ, Tighiouart H, et al: Depression and all-cause mortality in hemodialysis patients. Am J Nephrol 40(1):12–18, 2014 24969267
Farrokhi F, Abedi N, Beyene J, et al: Association between depression and mortality in patients receiving long-term dialysis: a systematic review and meta-analysis. Am J Kidney Dis 63(4):623–635, 2014 24183836
Finkelstein FO, Finkelstein SH: Depression in chronic dialysis patients: assessment and treatment. Nephrol Dial Transplant 15(12):1911–1913, 2000 11096130
Franke GH, Reimer J, Philipp T, et al: Aspects of quality of life through end-stage renal disease. Qual Life Res 12(2):103–115, 2003 12639058
Freeman MP, Freeman SA: Lithium: clinical considerations in internal medicine. Am J Med 119(6):478–481, 2006 16750958
Friedli K, Guirguis A, Almond M, et al: Sertraline versus placebo in patients with major depressive disorder undergoing hemodialysis: a randomized, controlled feasibility trial. Clin J Am Soc Nephrol 12(2):280–286, 2017 28126706
Galla JH; The Renal Physicians Association and the American Society of Nephrology: Clinical practice guideline on shared decision-making in the appropriate initiation of and withdrawal from dialysis. J Am Soc Nephrol 11(7):1340–1342, 2000 10864592
Gessert CE, Haller IV, Johnson BP: Regional variation in care at the end of life: discontinuation of dialysis. BMC Geriatr 13:39, 2013 23635315
Gillman PK: Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol 151(6):737–748, 2007 17471183
Goldman RS: Medical director responsibilities regarding disruptive behavior in the dialysis center—leading effective conflict resolution. Semin Dial 21(3):245–249, 2008 18533968
Gopaluni S, Sherif M, Ahmadouk NA: Interventions for chronic kidney disease-associated restless legs syndrome. Cochrane Database Syst Rev (11):CD010690, 2016 27819409
Gray SL, Anderson ML, Dublin S, et al: Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med 175(3):401–407, 2015 25621434
Griva K, Stygall J, Hankins M, et al: Cognitive impairment and 7-year mortality in dialysis patients. Am J Kidney Dis 56(4):693–703, 2010 20800327
Grubbs V, Moss AH, Cohen LM, et al; Dialysis Advisory Group of the American Society of Nephrology: A palliative approach to dialysis care: a patient-centered transition to the end of life. J Am Soc Nephrol 9(12):2203–2209, 2014 25104274
Grünfeld JP, Rossier BC: Lithium nephrotoxicity revisited. Nat Rev Nephrol 5(5):270–276, 2009 19384328
Hackett AS, Jardine MJ: We need to talk about depression and dialysis: but what questions should we ask, and does anyone know the answers? Clin J Am Soc Nephrol 12(2):222–224, 2017 28126705
Hackett AS, Watnick SG: Withdrawal from dialysis in end-stage renal disease: medical, social, and psychological issues. Semin Dial 20(1):86–90, 2007 17244129
Haddy FJ, Meyer TW, Hostetter TH: Uremia. N Engl J Med 358(1):95, author reply 95, 2008 18172186
Hashmi A, Moss AH: Treating difficult or disruptive dialysis patients: practical strategies based on ethical principles. Nat Clin Pract Nephrol 4(9):515–520, 2008 18612329
Hecking E, Bragg-Gresham JL, Rayner HC, et al: Haemodialysis prescription, adherence and nutritional indicators in five European countries: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 19(1):100–107, 2004 14671045
Hedayati SS, Bosworth HB, Kuchibhatla M, et al: The predictive value of self-report scales compared with physician diagnosis of depression in hemodialysis patients. Kidney Int 69(9):1662–1668, 2006 16598203
Hedayati SS, Bosworth HB, Briley LP, et al: Death or hospitalization of patients on chronic hemodialysis is associated with a physician-based diagnosis of depression. Kidney Int 74(7):930–936, 2008 18580856
Hedayati SS, Minhajuddin AT, Toto RD, et al: Prevalence of major depressive episode in CKD. Am J Kidney Dis 54(3):424–432, 2009 19493599
Hedayati SS, Daniel DM, Cohen S, et al: Rationale and design of a trial of sertraline vs. cognitive behavioral therapy for end-stage renal disease patients with depression (ASCEND). Contemp Clin Trials 47:1–11, 2016 26621218
Hedayati SS, Gregg LP, Carmody T, et al: Effect of sertraline on depressive symptoms in patients with chronic kidney disease without dialysis dependence: the CAST randomized clinical trial. JAMA 318(19):1876–1890, 2017 29101402
Hegde A, Veis JH, Seidman A, et al: High prevalence of alcoholism in dialysis patients. Am J Kidney Dis 35(6):1039–1043, 2000 10845814
Howren MB, Kellerman QD, Hillis SL, et al: Effect of a behavioral self-regulation intervention on patient adherence to fluid-intake restrictions in hemodialysis: a randomized controlled trial. Ann Behav Med 50(2):167–176, 2016 26631085
Jaffe JA, Kimmel PL: Chronic nephropathies of cocaine and heroin abuse: a critical review. Clin J Am Soc Nephrol 1(4):655–667, 2006 17699270
Jeong SH, Kim JH, Ahn YM, et al: A 2-year prospective follow-up study of lower urinary tract symptoms in patients treated with clozapine. J Clin Psychopharmacol 28(6):618–624, 2008 19011429
Jiang Y, McCombs JS, Park SH: A retrospective cohort study of acute kidney injury risk associated with antipsychotics. CNS Drugs 31(4):319–326, 2017 28290080
Johnson WJ, McCarthy JT, Yanagihara T, et al: Effects of recombinant human erythropoietin on cerebral and cutaneous blood flow and on blood coagulability. Kidney Int 38(5):919–924, 1990 2266676
Jones J, Nijman H, Ross J, et al: Aggression on haemodialysis units: a mixed method study. J Ren Care 40(3):180–193, 2014 25042357
Kaveh K, Kimmel PL: Compliance in hemodialysis patients: multidimensional measures in search of a gold standard. Am J Kidney Dis 37(2):244–266, 2001 11157365
Kessing LV, Gerds TA, Feldt-Rasmussen B, et al: Use of lithium and anticonvulsants and the rate of chronic kidney disease: a nationwide population-based study. JAMA Psychiatry 72(12):1182–1191, 2015 26535805
Kimmel PL: Psychosocial factors in dialysis patients. Kidney Int 59(4):1599–1613, 2001 11260433
Kimmel PL: Depression in patients with chronic renal disease: what we know and what we need to know. J Psychosom Res 53(4):951–956, 2002 12377308
Kimmel PL, Patel SS: Quality of life in patients with chronic kidney disease: focus on end-stage renal disease treated with hemodialysis. Semin Nephrol 26(1):68–79, 2006 16412831
Kimmel PL, Weihs K, Peterson RA: Survival in hemodialysis patients: the role of depression. J Am Soc Nephrol 4(1):12–27, 1993 8400064
Kimmel PL, Peterson RA, Weihs KL, et al: Behavioral compliance with dialysis prescription in hemodialysis patients. J Am Soc Nephrol 5(10):1826–1834, 1995 7787151
Kimmel PL, Peterson RA, Weihs KL, et al: Psychologic functioning, quality of life, and behavioral compliance in patients beginning hemodialysis. J Am Soc Nephrol 7(10):2152–2159, 1996 8915975
Kimmel PL, Peterson RA, Weihs KL, et al: Psychosocial factors, behavioral compliance and survival in urban hemodialysis patients. Kidney Int 54(1):245–254, 1998a 9648085
Kimmel PL, Thamer M, Richard CM, et al: Psychiatric illness in patients with end-stage renal disease. Am J Med 105(3):214–221, 1998b 9753024
Kimmel PL, Peterson RA, Weihs KL, et al: Multiple measurements of depression predict mortality in a longitudinal study of chronic hemodialysis outpatients. Kidney Int 57(5):2093–2098, 2000 10792629
Kimmel PL, Barisoni L, Kopp JB: Pathogenesis and treatment of HIV-associated renal diseases: lessons from clinical and animal studies, molecular pathologic correlations, and genetic investigations. Ann Intern Med 139(3):214–226, 2003 12899589
Kimmel PL, Cukor D, Cohen SD, et al: Depression in end-stage renal disease patients: a critical review. Adv Chronic Kidney Dis 14(4):328–334, 2007 17904499
Kimmel PL, Fwu C, Abbot KC, et al: Opioid prescription, morbidity, and mortality of United States dialysis patients. J Am Soc Nephrol 28(12):3658–3670, 2017 28935654
Kurella M, Chertow GM, Luan J, et al: Cognitive impairment in chronic kidney disease. J Am Geriatr Soc 52(11):1863–1869, 2004 15507063
Kurella M, Mapes DL, Port FK, et al: Correlates and outcomes of dementia among dialysis patients: the Dialysis Outcomes and Practice Patterns Study. Nephrol Dial Transplant 21(9):2543–2548, 2006 16751655
Kurella Tamura M, Yaffe K: Dementia and cognitive impairment in ESRD: diagnostic and therapeutic strategies. Kidney Int 79(1):14–22, 2011 20861818
Kurella Tamura M, Goldstein MK, Pérez-Stable EJ: Preferences for dialysis withdrawal and engagement in advance care planning within a diverse sample of dialysis patients. Nephrol Dial Transplant 25(1):237–242, 2010 19734137
Kurella Tamura M, Vittinghoff E, Hsu CY, et al; CRIC Study Investigators: Loss of executive function after dialysis initiation in adults with chronic kidney disease. Kidney Int 91(4):948–953, 2017 28139292
Lacson E Jr, Li NC, Guerra-Dean S, et al: Depressive symptoms associate with high mortality risk and dialysis withdrawal in incident hemodialysis patients. Nephrol Dial Transplant 27(7):2921–2928, 2012 22273670
Lea JP, Nicholas SB: Diabetes mellitus and hypertension: key risk factors for kidney disease. J Natl Med Assoc 94 (8 suppl):7S–15S, 2002 12152917
Leggat JE Jr: Adherence with dialysis: a focus on mortality risk. Semin Dial 18(2):137–141, 2005 15771658
Levenson JL, Owen JA: Renal and urological disorders, in Clinical Manual of Psychopharmacology in the Medically Ill, 2nd Edition. Edited by Levenson JL, Ferrando SJ. Arlington, VA, American Psychiatric Publishing, 2017, pp 195–232
Levy NB, Cohen LM (eds): Central and peripheral nervous systems in uremia, in Textbook of Nephrology, 4th Edition. Edited by Massry SG, Glassock R. Philadelphia, PA, Williams & Wilkins, 2001, pp 1279–1282
Lin YT, Wu PHJ, Kuo MC, et al: Comparison of dementia risk between end stage renal disease patients with hemodialysis and peritoneal dialysis—a population based study. Sci Rep 5:8224, 2015 25703589
Losso RL, Minhoto GR, Riella MC: Sleep disorders in patients with end-stage renal disease undergoing dialysis: comparison between hemodialysis, continuous ambulatory peritoneal dialysis and automated peritoneal dialysis. Int Urol Nephrol 47(2):369–375, 2015 25358390
McDade-Montez EA, Christensen AJ, Cvengros JA, et al: The role of depression symptoms in dialysis withdrawal. Health Psychol 25(2):198–204, 2006 16569111
McLaughlin K, Manns B, Mortis G, et al: Why patients with ESRD do not select self-care dialysis as a treatment option. Am J Kidney Dis 41(2):380–385, 2003 12552500
Meyer TW, Hostetter TH: Uremia. N Engl J Med 357(13):1316–1325, 2007 17898101
Mor MK, Sevick MA, Shields AM, et al: Sexual function, activity, and satisfaction among women receiving maintenance hemodialysis. Clin J Am Soc Nephrol 9(1):128–134, 2014 24357510
Moss AH: “At least we do not feel guilty”: Managing conflict with families over dialysis discontinuation. Am J Kidney Dis 31(5):868–883, 1998 9590203
Moss AH: A new clinical practice guideline on initiation and withdrawal of dialysis that makes explicit the role of palliative medicine. J Palliat Med 3(3):253–260, 2000 15859665
Moss AH: Integrating supportive care principles into dialysis decision making: a primer for palliative medicine providers. J Pain Symptom Manage 53(3):656.e1–662.e1, 2017 28065700
Munshi SK, Vijayakumar N, Taub NA, et al: Outcome of renal replacement therapy in the very elderly. Nephrol Dial Transplant 16(1):128–133, 2001 11209006
Murray AM, Tupper DE, Knopman DS, et al: Cognitive impairment in hemodialysis patients is common. Neurology 67(2):216–223, 2006 16864811
Navaneethan SD, Vecchio M, Johnson DW, et al: Prevalence and correlates of self-reported sexual dysfunction in CKD: a meta-analysis of observational studies. Am J Kidney Dis 56(4):670–685, 2010 20801572
Nichols KA, Springford V: The psycho-social stressors associated with survival by dialysis. Behav Res Ther 22(5):563–574, 1984 6508707
Norris KC, Thornhill-Joynes M, Robinson C, et al: Cocaine use, hypertension, and end-stage renal disease. Am J Kidney Dis 38(3):523–528, 2001 11532684
Nozaki C, Oka M, Chaboyer W: The effects of a cognitive behavioural therapy programme for self-care on haemodialysis patients. Int J Nurs Pract 11(5):228–236, 2005 16109047
Obialo CI, Bashir K, Goring S, et al: Dialysis “no-shows” on Saturdays: implications of the weekly hemodialysis schedules on nonadherence and outcomes. J Natl Med Assoc 100(4):412–419, 2008 18481480
O’Connor NR, Dougherty M, Harris PS, et al: Survival after dialysis discontinuation and hospice enrollment for ESRD. Clin J Am Soc Nephrol 8(12):2117–2122, 2013 24202133
O’Lone E, Connors M, Masson P, et al: Cognition in people with end-stage kidney disease treated with hemodialysis: a systematic review and meta-analysis. Am J Kidney Dis 67(6):925–935, 2016 26919914
Palmer BF: Sexual dysfunction in men and women with chronic kidney disease and end-stage kidney disease. Adv Ren Replace Ther 10(1):48–60, 2003 12616463
Palmer S, Vecchio M, Craig JC, et al: Prevalence of depression in chronic kidney disease: systematic review and meta-analysis of observational studies. Kidney Int 84(1):179–191, 2013 23486521
Palmer SC, Natale P, Ruospo M, et al: Antidepressants for treating depression in adults with end-stage kidney disease treated with dialysis. Cochrane Database Syst Rev (5):CD004541, 2016 27210414
Paul R, Minay J, Cardwell C, et al: Meta-analysis of the effects of lithium usage on serum creatinine levels. J Psychopharmacol 24(10):1425–1431, 2009 19395432
Pena J, Mor M, Tohme F, et al: Acceptance of anti-depressant treatment by patients on hemodialysis and their renal providers. Clin J Am Soc Nephrol 12:298–303, 2017 28126707
Pereira AA, Weiner DE, Scott T, et al: Cognitive function in dialysis patients. Am J Kidney Dis 45(3):448–462, 2005 15754267
Pliskin NH, Yurk HM, Ho LT, et al: Neurocognitive function in chronic hemodialysis patients. Kidney Int 49(5):1435–1440, 1996 8731111
Presne C, Fakhouri F, Noël LH, et al: Lithium-induced nephropathy: rate of progression and prognostic factors. Kidney Int 64(2):585–592, 2003 12846754
Rubin HR, Fink NE, Plantinga LC, et al: Patient ratings of dialysis care with peritoneal dialysis vs hemodialysis. JAMA 291(6):697–703, 2004 14871912
Russ AJ, Shim JK, Kaufman SR: The value of “life at any cost”: talk about stopping kidney dialysis. Soc Sci Med 64(11):2236–2247, 2007 17418924
Saczynski JS, Jónsdóttir MK, Garcia ME, et al: Cognitive impairment: an increasingly important complication of type 2 diabetes: the age, gene/environment susceptibility—Reykjavik study. Am J Epidemiol 168(10):1132–1139, 2008 18836152
Sareen J, Jacobi F, Cox BJ, et al: Disability and poor quality of life associated with comorbid anxiety disorders and physical conditions. Arch Intern Med 166(19):2109–2116, 2006 17060541
Schmid H, Hartmann B, Schiffl H: Adherence to prescribed oral medication in adult patients undergoing chronic hemodialysis: a critical review of the literature. Eur J Med Res 14(5):185–190, 2009 19541573
Semplicini A, Amodio P, Leonetti G, et al: Diagnostic tools for the study of vascular cognitive dysfunction in hypertension and antihypertensive drug research. Pharmacol Ther 109(1–2):274–283, 2006 16202453
Sharp J, Wild MR, Gumley AI, et al: A cognitive behavioral group approach to enhance adherence to hemodialysis fluid restrictions: a randomized controlled trial. Am J Kidney Dis 45(6):1046–1057, 2005a 15957134
Sharp J, Wild MR, Gumley AI: A systematic review of psychological interventions for the treatment of nonadherence to fluid-intake restrictions in people receiving hemodialysis. Am J Kidney Dis 45(1):15–27, 2005b 15696440
Smith MD, Hong BA, Robson AM: Diagnosis of depression in patients with end-stage renal disease. Comparative analysis. Am J Med 79(2):160–166, 1985 3895906
Souheaver GT, Ryan JJ, DeWolfe AS: Neuropsychological patterns in uremia. J Clin Psychol 38(3):490–496, 1982 7050178
Spigset O, Hägg S, Stegmayr B, et al: Citalopram pharmacokinetics in patients with chronic renal failure and the effect of haemodialysis. Eur J Clin Pharmacol 56(9–10):699–703, 2000 11214779
Sukolsky A: Patients who try our patience. Am J Kidney Dis 44(5):893–901, 2004 15492956
Tagay S, Kribben A, Hohenstein A, et al: Posttraumatic stress disorder in hemodialysis patients. Am J Kidney Dis 50(4):594–601, 2007 17900459
Tamura MK, Meier DE: Five policies to promote palliative care for patients with ESRD. Clin J Am Soc Nephrol 8(10):1783–1790, 2013 2374400
Troy SM, Schultz RW, Parker VD, et al: The effect of renal disease on the disposition of venlafaxine. Clin Pharmacol Ther 56(1):14–21, 1994 8033490
Tsay SL, Lee YC, Lee YC: Effects of an adaptation training programme for patients with end-stage renal disease. J Adv Nurs 50(1):39–46, 2005 15788064
Turk S, Solak Y, Kan S, et al: Effects of sildenafil and vardenafil on erectile dysfunction and health-related quality of life in haemodialysis patients: a prospective randomized crossover study. Nephrol Dial Transplant 25(11):3729–3733, 2010 20466680
United States Renal Data System: USRDS 2015 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2016
Untas A, Thumma J, Rascle N, et al: The associations of social support and other psychosocial factors with mortality and quality of life in the dialysis outcomes and practice patterns study. Clin J Am Soc Nephrol 6(1):142–152, 2011 20966121
Vermeir M, Naessens I, Remmerie B, et al: Absorption, metabolism, and excretion of paliperidone, a new monoaminergic antagonist, in humans. Drug Metab Dispos 36(4):769–779, 2008 18227146
Walther CP, Shah AA, Winkelmayer WC: Treating depression in patients with advanced CKD: beyond the generalizability frontier. JAMA 318(19):1873–1874, 2017 29101401
Watnick S, Kirwin P, Mahnensmith R, et al: The prevalence and treatment of depression among patients starting dialysis. Am J Kidney Dis 41(1):105–110, 2003 12500227
Watnick S, Wang PL, Demadura T, et al: Validation of 2 depression screening tools in dialysis patients. Am J Kidney Dis 46(5):919–924, 2005 16253733
Weisbord SD, Carmody SS, Bruns FJ, et al: Symptom burden, quality of life, advance care planning and the potential value of palliative care in severely ill haemodialysis patients. Nephrol Dial Transplant 18(7):1345–1352, 2003 12808172
Weisbord SD, Bossola M, Fried LF, et al: Cultural comparison of symptoms in patients on maintenance hemodialysis. Hemodial Int 12(4):434–440, 2008 19090866
Weisbord SD, Mor MK, Sevick MA, et al: Associations of depressive symptoms and pain with dialysis adherence, health resource utilization, and mortality in patients receiving chronic hemodialysis. Clin J Am Soc Nephrol 9(9):1594–1602, 2014 25081360
Williams MA, Sklar AH, Burright RG, et al: Temporal effects of dialysis on cognitive functioning in patients with ESRD. Am J Kidney Dis 43(4):705–711, 2004 15042548
Wyne A, Rai R, Cuerden M, et al: Opioid and benzodiazepine use in end-stage renal disease: a systematic review. Clin J Am Soc Nephrol 6(2):326–333, 2011 21071517