Depression and Neurocognitive Function in Chronic Kidney Disease


While living with CKD poses many of the same psychological challenges as many other chronic illnesses, the high treatment burden, chronicity, and unique physiological demands of the illness expose patients to a substantive and rather unique set of biopsychosocial demands. The most common and most studied psychiatric presentation is depression. While there is still much to be learned about the etiology, sequelae, and best treatment options, the high rates of the disorder necessitate increased clinical and scientific attention. In addition to depression, impaired neurocognitive functioning is a primary concern in patients with CKD. There are multiple proposed etiologies and many observed types of impairment. The impairment appears to vary across cognitive domains and in severity, but is quite prevalent with estimates as high as 60% of CKD patients demonstrating significant impairment. Case material is presented to highlight the richness and complexity of these presentations.


Depression, neurocognitive, psychiatry, psychosocial


  • Outline

  • Part I.Depression in Chronic Kidney Disease, 237

  • Etiology of Depression, 237

  • Epidemiology of Depression, 238

  • Differentiating Depression from Medical Illness, 239

  • Prevalence, 239

  • Sequelae of Depression, 240

    • Suicide, 240

    • Malnutrition, 240

    • Treatment Compliance, 240

    • Social Support, 240

    • Immunological Response, 240

    • Mortality, 241

    • Marital Issues, 241

  • Comorbidities of Depression, 241

    • Substance Use, 241

    • Anxiety Disorders, 242

    • Dementia/Delirium, 242

  • Treatment of Depression, 242

    • Psychotherapeutic Options, 242

    • Pharmacotherapy, 242

  • Case Presentation, 243

  • Summary of Depression in Chronic Kidney Disease, 243

  • Part II.Neurocognitive Function in Chronic Kidney Disease, 244

  • Etiology of Neurocognitive Impairment, 244

  • Prevalence of Neurocognitive Impairment, 247

  • Neurocognitive Functioning after Transplantation, 248

  • Sequelae of Neurocognitive Impairment, 248

  • Treatment of Neurocognitive Impairment, 249

  • Case Presentation, 249

  • Summary of Neurocognitive Function in Chronic Kidney Disease, 249

A biopsychosocial perspective on patients with renal disease compels the clinician to consider the context and take the patient’s reactions into account. Although the psychological landscape of renal disease is, in some ways, similar to other chronic health conditions, it also represents a novel combination of physical, emotional, and social changes. The high treatment burden, chronicity, and course are all unique, and patients respond to these demands in a variety of ways based on personality, psychological functioning, social context, resources, and personal experience. Stress and the response to stress may be key in determining the ability of the patient to cope with and adapt to the challenges of illness and its treatment. The scientific literature, heretofore, has focused on the two most common psychiatric challenges to the patient with renal disease: depression and neurocognitive impairment.

Depression in Chronic Kidney Disease

Etiology of Depression

Depression has long been identified as the primary mental health issue for patients with chronic kidney disease (CKD) and specifically end-stage renal disease (ESRD). It is unclear what etiological factors contribute to the increased vulnerability to depression, but understanding the biological, psychological, and social context in which the depression develops is essential. The biopsychosocial model proposes that various etiological factors play roles in establishing vulnerability to depression. The diathesis-stress model posits that depression results when preexisting vulnerability is activated by stressful life events. This predisposition can be either genetic, implying an interaction of nature and nurture, or cognitive, involving a lasting influence of attitudes and beliefs formed in childhood, or perhaps both.

Several biological theories for vulnerability to depression have been proposed, including a monoamine hypothesis, abnormalities in neurogenesis, known side effects of commonly prescribed medications for ESRD or common comorbid illnesses, an overactive hypothalamic-pituitary-adrenal (HPA) axis, hormonal dysregulation, as well as certain vitamin deficiencies. Although all these theories have a substantial basis, none have emerged as a singular explanation for the increased biological vulnerability. At core of these theories is the concept of stress and the ability to achieve stability through change, or “allostasis.” McEwen and Stellar developed the construct of allostatic load to express the vulnerability to disease that continuous physiological and psychological demand creates. The stress response of the CKD or ESRD patient may be impaired or overwhelmed due to the biochemical milieu created by renal disease or by the broad range of psychosocial threats the ESRD patient encounters. The expressed psychological reaction can be viewed as the combination of the biological and psychosocial threats in the context of the patient’s resources to cope with these increased demands.

Another way to conceptualize the psychological vulnerability to depression may be through noxious learning experiences. Beck and colleagues developed the cognitive model of depression in which he proposed three concepts as the hallmarks of depression: a triad of negative thoughts that comprise a negative bias about oneself, one’s world, and one’s future; distorted information processing and recurrent patterns of depressive thinking; and distorted cognitive schema. These patterns of maladaptive thinking often begin in childhood or adolescence and serve as a risk factor for the future development of the full depressive syndrome.

What these theories share in common is predicated on the acknowledgment that life on dialysis for patients with ESRD is demanding. Although kidney disease shares similarities with other chronic disorders, there may be other substantial losses associated with ESRD, beyond the loss of kidney function. Patients can undergo profound changes in role functioning, work status, autonomy, intimate relationships, and body image. The treatment burden of hemodialysis (HD) is also demanding. The weekly time demand is substantial and lifelong, without successful transplantation. Patients with ESRD report fatigue, pain, sexual dysfunction, gastrointestinal symptoms (nausea, vomiting, and anorexia), dermatological changes, and appetite changes. These ongoing challenges of living with ESRD can serve as the trigger that interacts with the person’s previous vulnerabilities and induce depression. There are a variety of psychological pathways in which the challenges of ESRD can affect a person. It is possible that patients with ESRD are put into a state of “learned helplessness” because treatment options are limited, and they are forced indefinitely to remain in their difficult situations with little hope for improvement or control over their outcomes. Threats to the patient’s autonomy and control as a result of the demanding course of treatment can serve as the precipitating stressor for a depressive episode.

The onset of depressive symptoms and depression can also be associated with changes in interpersonal factors, including strained or critical personal relationships. Patients with ESRD may experience changes in social role functioning, relationships with a spouse or adult children as a result of the transition to a caregiving or care-needing role, the death of a significant other, or the availability or quality of social relationships with friends because of their own health-related life events. These types of change have been associated with late-life depression.

One new integrative theory of depression, the social signal transduction theory of depression, posits that life stressors, particularly ones that involve interpersonal threat initiate a cascade of neural, physiological, molecular, and genomic processes that lead to the development and maintenance of depression. The stress response is not specific but initiates survival mechanisms in which proinflammatory cytokines upregulate components of the immune system, which then can lead to profound changes in behavior, which can be essential in the face of immediate physical threat, but maladaptive in the chronic state or in the context of prolonged social stress.

Epidemiology of Depression

The precise definition of depression as a construct, mood state, or a clinical syndrome is difficult because the feelings of sadness and hopelessness are ubiquitous and are not unique to depression or even any specific mental health problem. The Diagnostic and Statistical Manual of Mental Disorders ( DSM ) defines depression by the presence of specific symptoms in the absence of a range of other symptoms presenting for a specified duration. The hallmark symptoms of depression are low mood and loss of interest or pleasure in formerly enjoyable activities. In the fifth edition of the DSM ( DSM-V ), mood disorders with depression are divided into unipolar and bipolar depression. The latter includes a manic component. The most common form of depression is major depressive disorder, characterized by the presence of a major depressive episode in the absence of mania. The hallmark features of a depressive episode must occur during the same 2-week period but are often difficult to distinguish from the common symptoms of uremia ( Table 16.1 ).

TABLE 16.1

Symptom Overlap Between Criteria for a Major Depressive Episode and Uremia

DSM-V Major Depressive Episode Uremia
Depressed mood Irritability, cognitive changes, encephalopathy, drug effects
Decreased interest in activities Decreased libido, cognitive dysfunction
Weight change Anorexia, edema, cachexia, volume overload
Sleep changes Insomnia, sleep apnea
Psychomotor agitation Encephalopathy
Fatigue Fatigue, anemia
Diminished ability to concentrate Cognitive dysfunction, malaise
Feelings of worthlessness
Thoughts of death/suicide

DSM , Diagnostic and Statistical Manual of Mental Disorders.

To diagnose a major depressive episode, the clinician must determine whether the depressed mood has been of a significant intensity for a 2-week duration. The clinician should explicitly inquire about each of the symptoms in Table 16.1 and then must use his or her clinical judgment to determine whether the symptoms meet the criteria. A major depressive episode represents a significant change in the patient’s functioning. Other diagnoses, such as chronic depression or an adjustment disorder, may be more appropriate for more-chronic or less-severe presentations.

Differentiating Depression from Medical Illness

The task of distinguishing depression from subclinical mood dysregulation is made more complex by the overlap of the symptoms of depression and advanced CKD. The clinician must pay careful attention to the etiology, nature, and timing of the presentation, because there is considerable overlap between the somatic symptoms of depression and those of uremia. The depressive symptoms of psychomotor agitation or retardation, decreased appetite or weight change, sleep disturbance, and aches and pains are often difficult to distinguish from the uremic symptoms of encephalopathy, anorexia, day/night reversal, and neuropathy, respectively, adding to the difficulty of making an accurate diagnosis (see Tables 16.1 and 16.2 ).

TABLE 16.2

Beck Depression Inventory-II Items With Somatic Items Italicized

  • 1.


  • 12.

    Loss of interest

  • 2.


  • 13.


  • 3.

    Past failure

  • 14.


  • 4.

    Loss of pleasure

  • 15.

    Loss of energy

  • 5.

    Guilty feelings

  • 16.

    Changes in sleep

  • 6.

    Punishment feelings

  • 17.


  • 7.


  • 18.

    Changes in appetite

  • 8.


  • 19.

    Concentration difficulty

  • 9.

    Suicidal thoughts or wishes

  • 20.

    Tiredness or fatigue

  • 10.


  • 21.

    Loss of interest in sex

  • 11.



The difficulty in defining and identifying depression has led to challenges in its standard measurement. There is still no universal standard for the most appropriate screening technique. Different studies in patients with CKD use the Beck Depression Inventory (BDI), the Hamilton Depression Rating Scale (HAM-D), The Patient Health Questionnaire (PHQ), the Zung Self-Rating Depression Scale, subscales from the SF-36, and questions from the Kidney Disease Quality of Life (KDQOL) Instrument. To provide a validating clinical diagnosis, researchers have used the Structured Clinical Interview for the DSM-IV (SCID), the Diagnostic Interview Schedule (DIS), or the Primary Care Evaluation of Mental Disorders (PRIME-MD). The field still needs to achieve consensus regarding the appropriate screening and diagnostic tools for the broad population of patients with ESRD. Furthermore, there is an urgent need to precisely identify appropriate screening measures’ cutoff scores that have meaningful prognostic value in varying ESRD samples.

A few studies have begun this task by validating the BDI against structured psychiatric interviews to determine meaningful cutoff scores for ESRD populations. In a sample of 99 white HD patients, Craven and colleagues found a 45.4% prevalence of depression using the BDI cutoff score of 10, but found a BDI score of 15 or greater had better sensitivity and specificity for the diagnosis of depressive disorders in dialysis patients when the DIS was used as the criterion. Watnick and colleagues validated the BDI and the PHQ-9 against the SCID as depression assessment tools in an ethnically diverse dialysis population in several dialysis centers. Twenty-six percent of the sample were diagnosed with a depressive disorder. The optimal BDI cutoff value that maximized sensitivity and specificity was 16, whereas the optimal cutoff for the PHQ was 10. Hedayati and colleagues compared the BDI and the Center for Epidemiological Studies Depression Scale (CES-D) to the SCID. The prevalence of depression was 27% in their sample of 98 ethnically diverse patients. About one-quarter of the subjects were veterans. A BDI cutoff score of 14 and a CES-D score of 18 had the most predictive value. These studies indicate there is agreement between the BDI and clinician administered diagnostic tools, and a BDI score of 14 to 16 suggests the presence of a depressive disorder.

Other studies report varying rates of depression, depending on the sample population and the measurement tool. A study of mostly white patients starting home dialysis in the Midwest United States found the prevalence of depression to be 18% using diagnostic criteria. Kimmel and colleagues studied primarily African American patients with ESRD in HD centers in Washington, D.C. About one-half of the patients scored greater than 10 on the BDI. When the more conservative cutoff of 15 was used, about 25% of the patients screened positive. In their sample of primarily African Americans in Brooklyn, New York, Cukor and colleagues found that more than 70% of HD patients had a psychiatric diagnosis by the SCID, and 29% of the sample had a current depressive disorder.

To develop an accurate picture of depression in patients with chronic medical illnesses, such as CKD, it is possible that longitudinal assessments provide valuable information. As a follow-up study, Cukor and colleagues reassessed subjects 16 months later, and three different clinical pathways emerged. About one-half of the patients did not have a psychiatric diagnosis at either baseline or follow-up, 21% had a variable or intermittent course, and 11% had a persistent course, with depression diagnoses at both evaluations. The persistent course of depression was associated with significantly lower quality of life and more reported health problems. Kimmel and colleagues and Boulware and colleagues demonstrated that associations with outcomes existed with multiple measurements of depression that did not exist with baseline data. These data suggest a single measure of depression at a specific time might not be as meaningful as measuring depression over the course of a time span.

Beyond the timing of the assessment, the demographics of the patient need to be taken into account. Specifically, the patient’s gender and race need to be evaluated. In community samples, women have higher rates of depression and present for treatment more frequently. It is unknown whether this pattern holds true in the US ESRD population. Race and age have been identified as factors in the likelihood of depression developing in patients with diabetes, a primary cause of ESRD. Ethnicity has been associated with a variety of barriers to care, leading to mental health disparities. There is some evidence in the ESRD literature that quality of life, perceptions of religious support, and quality of social support vary according to race and might contribute to depression. One study compared 78 black and 82 white HD patients, and found no differences in their levels of depressive affect. They did, however, find a stronger emphasis on religion/spirituality as a coping tool within a group of black patients. As the new Medicare QIP requirement to screen for depression goes into effect, the provider community will need to decide the appropriate measures, frequency, and follow-up for depression evaluation.

Sequelae of Depression

Patients with ESRD who are also depressed are at risk for consequences that extend beyond disordered mood. Depression can affect the course of disease progression through direct and indirect pathways.


The most acute danger that depression presents is the increased risk of suicide. Patients with ESRD may be particularly at risk because they can commit suicide through passive means, by no longer receiving dialysis or by manipulating a functional vascular access site. This makes suicide in this population readily available and complicates assessment and intervention strategies. Increased levels of depression have been associated with higher levels of suicidality. Patients with ESRD had an 84% increased rate of suicide compared with the general US population. Important risk factors for suicide in the ESRD population include a previous history of mental illness, recent hospitalization, age greater than 75 years, male gender, white or Asian race, and alcohol or drug dependence. Because of the increased prevalence and the relative ease with which patients with ESRD can commit suicide, screening for depression and suicidal ideation should be an essential part of the treatment plan in depressed patients with ESRD.


A possible route through which depression could influence the course of ESRD is malnutrition. Some exploratory studies have found negative correlations between BDI scores and serum albumin levels, protein catabolic rate, and nutritional status scores in small samples, whereas others have not. The reasons for these disparate findings remain unclear, but may be related to differences in composition of the study samples, cultural and socioeconomic factors, or treatment conditions. The causal pathways between increased depressive affect and decreased appetite or nutrition have not yet been determined but may be bidirectional. Careful longitudinal or interventional studies will be needed to establish causal relationships.

Treatment Compliance

Another route through which depression can exert an influence on ESRD outcomes is through impairing treatment compliance. Better adherence to the HD prescription has been associated with improved survival. Studies have indicated a relationship between depressive affect and laboratory and behavioral markers of poor compliance in dialysis patients. Decreased behavioral compliance with the dialysis prescription correlated with increased depressive affect is prevalent HD patients. Initial findings suggest that successful treatment of depression may, at least temporarily, be associated with improved fluid compliance.

Social Support

Patients with depression may be more likely to feel less connected to their existing relationships and isolated from social connections. In chronic illness, this can lead to deleterious consequences. Several studies have shown an association between survival and perception of social support in patients with ESRD of different ethnic backgrounds. McClellan and colleagues used a prospective design and demonstrated that social support predicted survival of HD patients. Christensen and colleagues showed that a social support indicator, measured by family cohesion, predicted survival in HD patients. The result of these studies remain tentative, because the effects of medical and treatment parameters were not controlled. Kimmel and colleagues showed increased perception of social support, measured by the Multidimensional Scale of Perceived Social Support, predicted survival even when variation in age, severity of comorbid illness, serum albumin concentration, dialysis membrane type, and study site were controlled. In an analysis of the Dialysis Outcomes and Practice Patterns Study (DOPPS) on over 30,000 patients from a multinational sample, higher mortality rates were found among patients reporting less social support. Lower levels of perceived family support were also associated with decreased adherence to fluid and weight gain recommendations. It is unclear to what extent the quality of one’s social support is mutable and whether interventions designed to promote social support will have an effect on other outcomes such as mood, adherence, and survival.

Immunological Response

Depression may affect the course of ESRD through its impact on immunological factors and inflammation. Stress has long been linked to the dysregulation of the HPA axis, and depression has long been associated with abnormal glucocorticoid metabolism in healthy people. The precise mechanisms through which depression may modulate the immune system are still unclear, but one proposed theory is that depression increases cytokine activity, which may disrupt the HPA axis by impairing negative feedback of circulating corticosteroids.

There is also some evidence that inflammatory biomarkers, such as proinflammatory cytokines and C-reactive protein, are dysregulated and predict outcome in patients with ESRD. In one small study, there was an association between genetic predisposition to produce low levels of interleukin (IL)-10 (A/A genotype for the IL-10—1082 polymorphism) and increased chance of depression. The reasons for the increased risk of chronic inflammation in ESRD are complex; however, it has been suggested that a proinflammatory state is intrinsic to ESRD and is related to the higher-than-expected rates of cardiovascular disease and other causes of increased mortality in this population. Antiinflammatory agents may be a new frontier in treating depression in comorbid medical illnesses.


There has been a great deal of scientific discussion regarding the association between depression and mortality in patients with ESRD. Some initial studies in ESRD patients found associations between depressive affect and mortality. However, these studies were preliminary and used comparisons of means between groups of deceased and surviving patients, without accounting for confounding medical and demographic factors. Other studies have been unable to detect simple associations between depression or depressive affect and survival in patients with ESRD. The Dialysis Outcomes and Practice Patterns Study, an observational study on a large multinational sample, has provided information regarding screening questions related to depressive affect and survival in patients with ESRD treated with HD. They used statements from the KDQOL regarding depressive affect and found that those who answered affirmatively to having more frequently experienced depressive affect had a higher risk of mortality, withdrawal from dialysis therapy, and hospitalization. Despite the nature of their nonstandard assessment, the study findings seem to indicate a robust relationship between depressive affect and medical sequelae. One prospective longitudinal study found that when subjects were divided by affect severity based on a single depression score, those with severe depressive affect had significantly shorter time to death. Kimmel and colleagues were initially unable to demonstrate a relationship between increased level of baseline depressive affect and mortality in a sample of almost 300 HD patients. They did report associations between the perception of increased burden of illness and mortality and between the perception of a high level of social support and improved survival. The group subsequently performed longitudinal assessments of the study population, evaluating BDI scores up to six times over a period of 20 months to 5 years (mean 38.6 months). The data were analyzed using Cox regression models to predict the length of survival. They found that an increased level of depressive affect over time was associated with an increased risk of mortality, even when the analysis was controlled for medical parameters. Boulware and colleagues generated similar results when they evaluated baseline and longitudinal data from the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) study, a large cohort of incident patients starting dialysis. They determined that levels of depressive affect, measured by non-validated mood questions from the SF-36, at the beginning of the study were not associated with increased overall mortality. However, similar to Kimmel’s findings, using several different time-dependent analyses, the investigators demonstrated that persistently higher levels of depressive affect over time were associated with increased risk of death and cardiovascular events in both adjusted and unadjusted analyses.

There is also evidence that the repeated measurement of a depression diagnosis is more informative than cross-sectional assessments. Patients with ESRD who were depressed at two diagnostic interviews, spaced 16 months apart, exhibited correlations with lower quality of life and more reported health problems. Although the limited study duration prevented these results from being extended directly to mortality, it appears that a persistent course of depression represents an increased risk of morbidity and mortality for patients with ESRD treated with HD.

Hedayati and colleagues reported on time to death or hospitalization in an ESRD sample. They found a hazard ratio of about 2 for patients with ESRD with depression, compared with patients with ESRD without depression. A metaanalysis concluded that the conflicting research reports are likely due to the use of different depression scales and the ability of the studies to meaningfully correct for illness variables, but that there appears to be need to elucidate the mechanisms underscoring such relationships.

Marital Issues

Depressed ESRD patients may be at particular risk for marital difficulty. In addition to the typical strain that the development of a chronic illness places on a couple, the depressed patient could feel more easily overwhelmed and can be perceived as not being invested in the relationship. Role changes can be profound because spouses can now become caregivers or wage earners, which may promote further depression or resentment. There have been only a few studies that assess marital relationships in patients with ESRD, with one study reporting that greater than 50% of couples that included a patient with ESRD experienced marital discord. In a study of Indian HD patients and their spouses, marital discord was reported in about one-third of the sample, which had a strong relationship to either individual’s depression. Marital support and conflict may also be associated with the degree to which a patient adheres to the dialysis prescription.

Comorbidities of Depression

Depression often presents with other common coexistent psychiatric conditions. It is important to carefully evaluate each presenting patient for the co-occurrence of these other conditions.

Substance Use

All ESRD patients should be carefully screened for substance abuse because of the potentially nephrotoxic effects of some illicit drugs. Patients with depression are often unsure regarding how to effectively cope with their mood and may turn to drugs or alcohol to “self-medicate”. One study found that in a sample of 145 HD patients, 28% were judged to have a problem with chronic alcohol abuse. The study further found that the alcoholic group had poorer nutritional markers than the nonalcoholics.

Little is known about the effect of intravenous drug use on dialysis or vascular access; however, active substance abuse should be considered an acute situation, and coordination of care with addiction specialists should be undertaken. In a systematic review of opioid and benzodiazepine use, the authors found wide variability between centers, due to varying assessment techniques. They concluded that more precision in substance research and overall, more attention is required to further elucidate rates of substance use, the reasons for use and the consequences of use/over use. Recent findings suggest prescription of opioid medication in ESRD dialysis patients is common and associated with increased morbidity and mortality.

Anxiety Disorders

Anxiety is a complicating comorbid diagnosis for many patients with medical illness. Anxiety often occurs with depression in ESRD populations. Anxiety is consistently ranked as a major cause of years lost to disability in the United States. There is relatively little anxiety research specific to ESRD patients, but it appears that an anxiety diagnosis exerts a powerful negative effect on quality of life. Compound depression and anxiety might represent a clinical entity that has a synergistic, negative effect on patients’ perception of quality of life. One must consider that anxious patients can have characteristics on a spectrum from the more classic worried and withdrawn to agitated or angry.

When disruptive behavior presents in ESRD patients, it is important to try to understand the cause of the patient’s distress and to explore whether stress and anxiety may lead to undesirable outcomes. Similarly, excessive anxiety might lead to somatic vigilance, a discomfort with changes in bodily sensations. This may be particularly important to evaluate in patients who often prematurely end dialysis sessions because pain or discomfort might be a concomitant of anxiety.


Neurocognitive disorders are common in patients with ESRD. Depression can be a precipitant for neurocognitive decline, and the evaluation of any patient who reports a change in his or her mental acuity should include screening for depression. Withdrawal from dialysis is relatively common, especially in elderly patients or patients who fail to thrive, and the physician should try to determine the patient’s wishes before the patient’s mood and mental status may compromise his or her ability to provide a meaningful directive. A full discussion of neurocognitive changes in ESRD is in the following section.

Treatment of Depression

The difficulties in identifying and assessing depression should not serve as barriers to the successful treatment of depression. Although there has been relatively little clinical research on the treatment of depression in ESRD patients, the literature that does exist has been encouraging. The main treatment options for depression include psychotherapy and pharmacotherapy.

Psychotherapeutic Options

There are several forms of psychotherapies (cognitive-behavioral, interpersonal, supportive, group therapy) that have demonstrated consistent and substantial efficacy in the treatment of depression in general populations, which may well be effective tools for patients with ESRD as well. In comparison to pharmacological interventions, psychotherapy has the advantage of few deleterious side effects, frequently introducing benefits such as improved sleep, improved interpersonal relationships, and improved regimen compliance. However, a significant disadvantage is that therapy typically requires the patient to be motivated to change. The first step in wanting to change is acknowledging the presence of a problem. Denial, an unconscious mental operation that allows the person to avoid facing harsh realities, is a considerable obstacle. Incorporating a mental health evaluation as a standard of care is one strategy to reduce barriers to psychological care and to minimize patients’ resistance to psychotherapeutic interventions. In addition, referring clinicians should explain their biopsychosocial conceptualization of disease and how treating psychological components is essential for good medical care.

There is an insufficient amount of literature on psychotherapeutic intervention in HD populations, but there is increasing interest in psychotherapeutic interventions for ESRD patients treated with HD. There is increasing literature indicating that psychosocial interventions, such as cognitive behavioral therapy, are effective for treating depression. In two small randomized controlled trials (RCTs) cognitive-behavioral therapy was shown to be effective in reducing depression when administered in both individual and group formats. Although this initial evidence is encouraging, larger scale trials are needed, and some are underway.


In today’s healthcare environment, nephrologists have, in many ways, become primary care providers for ESRD patients and often find themselves prescribing medications usually prescribed in primary care or other settings. When considering a psychotropic medication for patients with ESRD, it is important for nephrologists to balance their familiarity with the pharmacokinetics of psychotropic agents against the probability of the patient accepting a psychiatric referral, attending the appointment, and following through on the recommendations. Nephrologists must be aware of whether a drug is cleared through renal or hepatic metabolism and whether the drug clearance is affected by HD or peritoneal dialysis (PD). Most psychotropic medications are protein-bound, lipid soluble, penetrate the blood–brain barrier, and are cleared by the liver, with the notable exception of lithium. Protein binding may be impaired in ESRD, which can affect drug metabolism. Therefore, to reduce the potential for overdosing, consideration should be given to the reduction of the initial dose of psychotropic medications in this patient population. Clinical responses should be carefully monitored as doses are increased, and drug levels should be obtained if available.

Antidepressants have a potentially essential role in treating unipolar depression in patients with ESRD, with selective serotonin reuptake inhibitors (SSRIs) being the first line of pharmacological treatment. Tricyclic antidepressants (TCAs) and SSRIs are typically cleared by the liver, and therefore require only a minimal dose adjustment in patients without liver disease. For patients with ESRD, the initial dose of an SSRI is often one-half to two-thirds the usual dose. Typically, treatment with SSRIs should be continued for at least 4 to 6 weeks before deciding whether there has been a therapeutic benefit. If improvement is not achieved after 3 to 4 months, then consideration should be given to switching to another antidepressant. Establishing an appropriate antidepressant regimen may involve trial and error. The nephrologist and patient should expect that adjustments will need to be made to identify the optimal medication and dosing.

There is some evidence that SSRIs are effective in the treatment of depression in patients with ESRD. An early study found a treatment advantage in 12 depressed patients with ESRD treated with the SSRI fluoxetine over those given a placebo. Wuerth and colleagues found that depressive symptoms were markedly ameliorated in PD patients who completed a 12-week course of treatment with sertraline, bupropion, or nefazodone, despite low rates of compliance overall. Researchers in Korea found that fluoxetine significantly reduced HAM-D scores in patients with ESRD.

For a variety of reasons, SSRIs are the preferred medication for the treatment of ESRD patients with depression. SSRIs typically cause fewer anticholinergic symptoms than TCAs, are not associated with cardiac conduction abnormalities, and are less lethal in large doses compared with TCAs, which are lethal in large doses and can be used in suicide attempts. An additional benefit of SSRIs in this patient population is that they may reduce postural hypotension, presumably through effects on vascular tone. Fluoxetine, the first available SSRI, is the best-studied drug in this family. Other medications in this family include paroxetine, sertraline, and citalopram.

Venlafaxine and bupropion hydrochloride are examples of a different class of antidepressants called selective norepinephrine reuptake inhibitors (SNRIs). The SNRIs should be used with caution in ESRD patients because these drugs are primarily cleared by the kidneys. Bupropion has active metabolites that are almost completely excreted through the kidney. These may accumulate in dialysis patients, predisposing them to developing seizures.

Monoamine oxidase inhibitors (MAOs) have numerous side effects and should be avoided if possible in ESRD patients because of their potential to cause hypotension. All medications carry the risk of adverse effects, and patients’ regimens need to be carefully selected and then closely monitored. If the nephrologist does not believe that the regimen is sufficiently improving the depression, or he or she is not comfortable with the multiple iterations that are often required in gaining efficacy from antidepressants, a psychiatric consultation is warranted.

The literature has highlighted the challenges in having patients effectively accept an SSRI prescription at the dialysis center. Wuerth and colleagues documented some of the barriers to patient acceptance, but data from two studies emphasize the significant role of the patient’s willingness to take the medication. Successfully prescribing a medication for depression includes appropriate diagnosis, appropriate selection of an agent and dose, as well as patient education regarding the need for and potential benefits and harms of the intervention choice.

Case Presentation

A 63-year-old African American man with diabetes recently transferred into an HD center. He was employed as a bus driver and approaching retirement, and, after 6 months on dialysis, he had to stop working because of a disability. The patient was married to his second wife, who was many years younger. The majority of his friends and social interactions were centered at his job with the Transit Authority.

The nutritionist was concerned over the change in the patient’s dietary compliance and excessive interdialytic weight gain. The patient dismissed the dietician’s attempts at intervention, and a psychological consult was obtained. The psychologist found that the patient had been functioning quite well before stopping work, and then a chain of events transpired that developed into a vicious circle, promoting greater depression and poorer health ( Fig. 16.1 ). The patient confided that, since he began dialysis, he had been experiencing erectile difficulty. This, coupled with his discontinuation of work, had him feeling like he was “less of a man.” He began avoiding conversations with his wife during the day and ceased sleeping alongside her at night. He also was less social with his friends at work.

FIG. 16.1

Proposed map of interaction between depression and ESRD.

The psychologist proposed an intervention that included family sessions to promote open communication, a referral to discuss the use of sildenafil, and “behavioral activation,” a series of exercises designed to enable the patient to reengage in pleasurable activities despite his lack of desire. Simultaneously, the patient’s beliefs about what it means to “be a man” were challenged. After some time, he was able to redefine his role from being a “provider” to that of a “partner.” After 6 months of treatment, the patient was enjoying a modified lifestyle with his wife and friends that provided them with satisfaction and fulfillment. The patient’s medication and diet compliance improved.

Summary of Depression in Chronic Kidney Disease

Depression has a multifaceted etiology that can interact with the substantial burden of ESRD. The true prevalence rates for depression are difficult to establish because of the overlap of depressive and uremic symptoms. The rate of depression in pre-ESRD CKD patients is not well known, and whether depression rates increase with the progression through CKD stages is also unclear. Using a clinician-administered, semistructured interview, the rates for a diagnosis of depression in ESRD patients treated with HD appear to be 20% to 30%. ESRD patients report elevated levels of depressive affect at a rate approaching 40%. Longitudinal assessment of depression has revealed stronger associations with outcomes. Depression’s deleterious effects may extend to higher rates of poorer nutrition, poorer treatment compliance, decreased social support, and mortality. It is also possible that depression is associated with changes in immunological or inflammatory responses. Depression may be comorbid with substance abuse, anxiety disorders, or dementia, which complicates treatment. The literature on treatment of depression in the setting of ESRD is still developing, but both psychotherapy and psychopharmacological strategies appear to be efficacious. The initial dose of an SSRI in patients on HD is typically one-half to two-thirds the usual dose for patients with ESRD. Great care should be extended in engaging the patient as partner in depression care; otherwise, the likelihood that he or she will take medications as directed is greatly reduced. Cognitive-behavioral therapy shows promise as a possible first-line treatment for depression at the dialysis center, but larger clinical trials are needed.

Neurocognitive Function in Chronic Kidney Disease

Etiology of Neurocognitive Impairment

Cognitive impairment poses many challenges to the CKD or ESRD patient, their caregivers, and their families. Depending on the severity of impairment, activities of daily living, such as ability to manage medications or even driving to medical appointments may become unsafe. Remembering to take one’s medication or even attend dialysis sessions may become problematic. The burden of impairment often falls on those who take on caregiving responsibilities, and the stress of witnessing a loved one undergo cognitive decline can be devastating.

The assessment of neurocognitive functioning is a vital part of the comprehensive care of the CKD patient. Aside from the impact on activities of daily life, cognitive dysfunction can be associated with disease progression and affect the likelihood of adherence to the medical regimen, or it can serve as a gross measure of adjustment. Tables 16.3 and 16.4 provide, respectively, lists of cognitive domains and tests that can be used in the evaluation of cognition. Cognitive impairment can range from subtle, with only minor impairment in a circumscribed domain, to gross diffuse dysfunction. Major neurocognitive disorder, or “dementia,” is used when there is a decline in cognitive functioning in one or more areas of cognition that affects independence in daily activities, such as remembering to pay bills and managing medication. If the cognitive decline is transient and abrupt, and there is a change in attention or awareness, the impairment is referred to as delirium . Delirium may occur with a concurrent neurocognitive disorder. The most common type of dementia is Alzheimer disease. Alzheimer disease can be progressive and, in advanced stages, result in profound impairment in memory and language and visuoperceptual ability. Another common cause of dementia is vascular neurocognitive disorder, which is often characterized by significant impairment in executive functioning.

Feb 24, 2019 | Posted by in NEPHROLOGY | Comments Off on Depression and Neurocognitive Function in Chronic Kidney Disease
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