The Dialysis and Kidney Transplant Patient 19

The pertinence of this area can best be understood by noting that in the United States alone there are over 80,000 people who develop renal failure each year, about 325,000 people who are on some form of dialysis, and over 100,000 who have functioning kidney transplants (United States Renal Data System, 2005).

Further, more so than many other chronic medical illnesses, this is an area of great need for psychiatric input, both in the evaluation of candidates for treat- ment as well as of the recipients of transplants (Reichsman and Levy, 1972).

Like other areas of consultation-liaison (CL) work, a good working relationship with the directors of the treatment services is crucial to one’s acceptance by med- ical and other professional staff (Levenson and Glocheski, 1991). “Acceptance”

not only means having one’s recommendations seriously considered, as are those of other consultants, but also being seen as part of the treatment team (Cohen, 1996).

Irrespective of what they may have been taught in medical school, transplant sur- geons and nephrologists, similarly to other medical practitioners, vary greatly in their consideration of the behavioral aspects of illness. Therefore, the degree to which the CL psychiatrist can be involved in patient management varies greatly (Levy and Wynbrandt, 1975).

Organ substitution and transplantation are at the cutting edge of medicine (Surman, 1989). Kidney failure was the earliest vital organ system treated by these means. Therefore, in its longevity it is the area with the largest amount of research and behavioral literature. Yet, there is still a dearth of systemic, well-designed behavioral studies, and none involving several institutions.

19

The Dialysis and Kidney Transplant Patient

Norman B. Levy and Adam Mirot

CONTENTS

19.1 Dialysis . . . 206

19.1.1 Forms of Treatment and Their Stresses . . . 206

19.1.2 Psychiatric Complications and Their Treatment . . . 206

19.1.3 Pharmacology of Renal Failure. . . 208

19.1.4 Withdrawal from Dialysis . . . 210

19.2 Palliative Care . . . 212

19.2.1 General Issues in Renal Palliative Care . . . 212

19.2.2 Psychiatric Aspects of Renal Palliative Care . . . 213

19.3 Renal Transplantation . . . 214

205

This chapter discusses the major stresses associated with renal failure and its various forms of treatment, as well as the psychiatric morbidity it causes and what the CL psychiatrist can do to ameliorate and in some cases cure these problems.

19.1 Dialysis

19.1.1 Forms of Treatment and Their Stresses

Dialysis utilizes osmosis through a semipermeable membrane to transfer body wastes to a substitute excretory system. In hemodialysis, blood is brought out- side the body through a dialyzer in which dialysate fluid is separated from blood by a membrane and the purified blood is returned to the individual. In peri- toneal dialysis, the semipermeable membrane is the peritoneal lining. Dialysate fluid is introduced into the peritoneal space through an abdominal catheter where it remains, and the fluid is removed and discarded. The ionic concentra- tion of dialysate fluid is crucial. Since the direction of osmosis is from higher ionic concentration to the lesser, dialysate fluid must set at the ideal ionic con- centration of substances. For example, if the ionic concentration of potassium in the dialysate fluid is lower than what is normal in blood, then less potassium will be eliminated than should be removed, and if the dialysate has lower potas- sium than normal, then too much potassium will be removed from the patient’s blood (Parker, 1992).

What makes dialysis unique is the utter dependence of patients on this treat- ment, lest they die. This is particularly stressful for the very independent patient.

This stress may be minimized by the selection of a modality that fosters inde- pendence such as continuous ambulatory peritoneal dialysis (CAPD), self-care center dialysis, and home hemodialysis. All forms of dialysis are associated with the stress of adherence to a very constrained diet that is low in sodium, potas- sium, protein, phosphates, and fluids. Renal transplantation enables a greater independence and a freer diet, but, as will be seen later in this chapter, involves the stress of the possibility of organ rejection and the need to be on immuno- suppressive medications with their side effects for the rest of one’s life (Levy et al., 2006).

19.1.2 Psychiatric Complications and Their Treatment 19.1.2.1 Delirium

As in the case of other chronic medical illnesses, delirium may occur as a

result of medical complications including electrolyte imbalance. In addition,

since dialysis is an intermittent process, unlike normal function in which the kid-

neys are working every second of every day, the period prior to a dialysis run is

one in which the patient is usually mildly to moderately azotemic and therefore

may be in a mild to moderate delirium. After a dialysis run, most patients find

themselves mildly affected by a disequilibrium syndrome, a state caused by the

relatively rapid change in fluid and electrolytes. As to treatment of delirium,

the usually minor events mentioned above respond to the passage of time and

require no special therapy. An issue here is the importance of the liaison psy-

chiatrist’s being vigilant as to the presence of delirium that is often overlooked

in its early phases by medical practitioners and may be a sign of serious medical

illness (Lipowski, 1980). Its presence needs to be called to the attention of staff so that its cause can be investigated and treated.

19.1.2.2 Depression and Suicide

Depression as well as anxiety have been called the most common complications of medical/surgical illnesses (Levy, 1989). Aside from endogenous depression, the exogenous form of this disorder is usually heralded by a loss that is real, threat- ened, or fantasized. Patients with renal failure, especially those on dialysis, sus- tain many such losses. Most never return to their prior work, household, or school activities. The loss of a job is a major event in that it not only results in a loss of income, but it usually is associated with a loss of self-esteem as well as a loss of the sense of masculinity in men and femininity in women. In addition, patients on dialysis have a loss of personal freedom, a loss of independence, a reduction in their life expectancy, and a loss of their healthy appearance in that their complexion appears almost sun-tanned but it is not a healthy looking brown. Because the avenue of access to the circulatory system involves the surgi- cal creation of arteriovenous fistulas, both the scars of these procedures as well as the often snake-like bulging caused by the arterialization of the venous system also compromises their appearance. The medical regimen of these patients entails restrictions in their diet and requires restraint in their fluid intake.

Early behavioral observations of these patients seemed to show a higher inci- dence of suicide than in either the general population or those with other chronic medical conditions. Abram and his colleagues (1971) published their survey of the existing dialysis centers’ incidence of suicide in their patients. They concluded that suicide was 500 times more common in these patients than in the general population. But because the statistics on suicide in the general population lack precision and are underreported, Abram and colleagues speculated that the actual number is much higher. Without even considering withdrawal from dialy- sis as suicide, the reason for many suicides must include both the issue of depres- sion and the fact that dialysis patients have ready access to an avenue of death.

When one compares the incidence of death in the line of duty among New York City police officers with their suicide rate, one finds suicide far exceeds line- of-duty death every year, except for 2001 when the World Trade Center disaster resulted in an unusually high number of police deaths. Similarly, people who have ready access to their demise such as physicians and other health professions have a high incidence of suicide. Perhaps this too explains the higher rate in dialysis patients, who need only miss a few runs and overindulge in potassium-rich food to attain their death.

There are several treatment options for depression (Kimmel, 2002).

Unfortunately, as with patients with other illnesses, depressed renal patients tend as a group to be resistant to talking therapies (Reichsman and Levy, 1972). This is often rationalized, again as in the case of other medical illnesses, by the statement,

“If you were on dialysis with all its handicaps, wouldn’t you be depressed too?” An occasional more insightful patient may be suitable for individual or group therapy.

Many, if not most, depressed dialysis patients are willing to entertain the possibil- ity of being on antidepressant medications, as is discussed later in this chapter.

19.1.2.3 Anxiety

Anxiety is another common psychiatric complication of dialysis (Kimmel, 2002).

Since anxiety is a protective mechanism to the threat of insult to the body, there

are many reasons for dialysis patients to be anxious. The procedure itself is a

rather dramatic one in which the patients’ blood is removed from their bodies, cleansed, and returned. In this process there are many opportunities for mishaps, even exsanguination. Many people are very anxious awaiting the results of blood and other testing. Changes in staff and in procedures are usually anxiety producing. The treatment of anxiety is usually entirely pharmacological, and is discussed later in this chapter.

19.1.2.4 Noncompliant and Aggressive Behavior

This is the most vexing psychiatric problem facing the nephrology staff.

To understand why noncompliant behavior seems to be so commonplace, one needs to understand two factors: the skewing of the population that develops renal failure, and how patients handle chronic illness. Diabetes and hypertension patients who are noncompliant with treatment are prone to kidney failure, as are patients with addictive disorders. Therefore, renal failure patients are not a cross section of the general population; rather, this illness is more prevalent in the noncompliant and, to a degree, in antisocial people. Also, patients with chronic medical illnesses often fail to stick to their diets or to comp[ly with other aspects of their medical management.

The management of noncompliant patients is difficult because of the nature of the problem. It is important to help patients understand that failure to adhere to the medical regimen can result in repeated hospitalization and a decrease in life expectancy. When noncompliance involves missing dialysis runs and aggres- sive behavior, it is important for staff to maintain minimal tolerance for it.

Again, early on, it is important for the staff to make clear that any aggressive behavior that affects the safety of staff and other patients will be treated as a police matter. Further, chronic offenders and patients who repeatedly miss dialysis runs may be transferred to other units.

19.1.2.5 Sexual Dysfunction

In a symposium of the American Psychiatric Association in 1972, Belding Scribner, an early pioneer in treating chronic renal failure, observed that one third of men on dialysis were totally impotent, one third were partially impo- tent, and one third did not have an impotence problem (Levy et al., 1974). This led to a few studies, most of which were conducted by questionnaires, that essen- tially showed that Scribner was almost correct. When women were asked about their sexual functioning, a significant group, but fewer than the men, reported sexual dysfunction, in particular, a decrease in libido and a decrease in orgasm.

Renal transplant patients also have similar problems with sexual functioning, but at a much lower degree than dialysis patients (Levy, 1973).

There are several treatment options for these disorders. Since depression is often closely associated with sexual dysfunction, its relief can reduce and even cure sexual dysfunction in a significant number of these patients. Masters and Johnson’s (1970) techniques have been used with success in selected patients. In men, the use of agents that increase the release of nitric oxide in the corpus cavernosum of the penis such as sildenafil (Viagra) and similar medications have been a godsend to many patients (Cohen et al., 2005b).

19.1.3 Pharmacology of Renal Failure

The term pharmacokinetics refers to the factors affecting the passage of pharma-

ceuticals in the body, from their entry to their excretion (Callaghan et al., 1999).

The term absorption refers to how much of the drug actually enters the body.

Except in rare cases of gastroparesis or gastrointestinal edema, both of which are associated with slower absorption, patients with renal failure do not have any significant change in absorption as compared with those with normal kid- ney function. Once the drug is absorbed, the next issue is drug distribution, which refers to the concentration of the agent in body tissues. The distribution is increased in the cachetic patient and decreased in the edematous. Protein binding refers to the ability of the body to bind the drug to body protein, in par- ticular albumin. The free, unbound portion of the drug is that which is thera- peutically active. Renal failure patients have a significantly diminished ability to bind pharmaceuticals to body protein, thereby making more of the drug available for both therapy and toxicity. Since virtually all medications, with the exception of lithium, that are prescribed by psychiatrists have a high degree of protein binding, the general rule is that one should not prescribe for renal fail- ure patients more than three fifths of the maximum dose given to those with normal kidney function. Fortunately, the major organ for drug metabolism is the liver (again, with the exception of lithium), which eliminates metabolites in bile, making drug excretion an issue only in those few drugs such as lithium that are excreted in the urine.

Most drugs that are prescribed by psychiatrists are fat soluble, pass the blood–brain barrier, are metabolized by the liver, and are excreted by the bowel.

It is important that the issue of using a lower maximum dose for renal failure patients than those with normal renal function be kept in mind in the following descriptions of medications.

Antidepressants may be used judicially in these patients since neither renal failure nor dialysis affects dosing, except as mentioned above (Kennedy et al., 1989). One must keep in mind that the major handicap in the use of tricyclic medications is the potential issue of overdose in a population with a high inci- dence of suicide. For this reason and because they are less anticholinergic, the selective serotonin reuptake inhibitor (SSRIs) are often favored in these patients.

There is less data concerning antipsychotics. One should keep in mind the issue of QT prolongation as one would in patients with normal renal function.

There is a host of potential side effects of clozapine, including a relatively high incidence of pericarditis. Aside from the data recently released in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) studies (Lieberman et al., 2005), there is some further advantage in the use of the typical as opposed to the atypical or second-generation antipsychotics in renal patients because there is a longer track record of use for the older medications.

The benzodiazapines are among the most commonly used pharmaceuticals in all of medicine because they rate among the safest in the benefit/risk ratio.

Lorazepam, which is removed by the kidney in those with normal renal func- tion, reverts to hepatic metabolism with excretion in bile in kidney failure, and therefore may be used in these patients (Lam et al., 1997).

Concerning the mood stabilizers, lithium is a unique medication, especially in

its use in patients with renal failure. Because it is dialyzable and removed entirely

by the kidney, it may be given as a single dose after each dialysis run. It will be

maintained at about the same concentration in the body because its avenue of

excretion is blocked by renal failure. When dialysis is given, lithium’s small mol-

ecule passes through the semipermeable membrane and is eliminated. There is

less data concerning the use of the antiseizure medicines, chief of which is

valproate. Experience has shown that they may be used in patients with renal failure (Levy, 2000).

19.1.4 Withdrawal from Dialysis

Consulting psychiatrists may be asked to provide perspective and advice to nephrologists about patients who wish to discontinue dialysis, particularly in cases in which the treating physician is not comfortable with the patient’s decision. The willful rejection of life-prolonging treatment is an emotionally laden issue, and cognitive dissonance between patient and physician may manifest itself in asser- tions of patient psychopathology or in questions about the patient’s capacity to make this decision.

The survival curve for end-stage renal disease (ESRD) (chronic kidney disease stage 5) patients on chronic dialysis is not encouraging (Cohen et al., 2006). Of patient deaths, at least a fifth are due to voluntary dialysis discontinuation, and existing data point to a steady increase in this proportion (Cohen et al., 1997;

Renal Physicians Association, 2000). The stage of illness at which any particular patient reaches a threshold for continuing dialysis is highly individual, and is fur- ther influenced by culture, religion, and family. The Renal Physicians Association (RPA) deems it appropriate to withhold or withdraw dialysis at the direct request of acute renal failure or ESRD patient with decision-making capacity (Renal Physicians Association, 2000). This guideline is also extended to incapacitated patients who have previously refused dialysis in oral or written directives, or whose legal agents refuse dialysis on their behalf (Cohen et al., 1997).

In early studies on ESRD, voluntary cessation of dialysis was indiscriminately labeled as being a type of suicide (Abram et al., 1971). However, a more rea- sonable distinction in the psychiatric literature between pathologically driven suicide and rational treatment termination has since been recognized. Rational motives for a patient to refuse dialysis are legion. If they are not transplant can- didates, chronic dialysis patients suffer significant discomfort, inconvenience, and progressive functional disability, in return for which they may sometimes expect a limited prolongation of life on the edge of uremia. Standard palliative measures offer incomplete relief of physical symptoms, and may add their own side effects to the overall burden of care. The risks and injuries attendant to chronic dialysis may eventually outweigh the perceived benefits. In such a cir- cumstance, withdrawal from dialysis is appropriate and permits the facilitation of a “good death,” with comfort, dignity, and brevity (Cohen et al., 2003).

Patients may also refuse dialysis for reasons that are pathological. As elsewhere described, there are an impressive array of psychiatric disorders found in the chronic dialysis/ESRD population including, most commonly, depressive and anxiety spectrum disorders, followed by delirium and dementia (Kimmel et al., 1993). Dialysis-dependent patients can consciously or unconsciously take their own lives with ease by missing treatments, engaging in dietary indiscretions, and ignoring fluid restrictions.

Consulting psychiatrists are commonly asked to help distinguish pathologic

from benign motives in patients refusing dialysis and to guide physicians strug-

gling with the decision of whether to honor or challenge these refusals. In

approaching this task the most important initial judgment made by the psychi-

atrist is how stringent a test to apply for capacity. It is helpful that the nephrol-

ogy community has provided national guidelines identifying a number of

patient conditions appropriate for discontinuing dialysis (Cohen et al., 2003;

Moss, 2001). These conditions include patients with severe, irreversible demen- tia; patients with permanent unconsciousness; patients with disabling, end-stage lung, liver, heart, or neoplastic disease; patients with chronic, unremitting pain that will only be prolonged by dialysis; and hospitalized patients with multiple organ system failure persisting after 3 days of intensive therapy. It may be inferred that in these situations a low standard for dialysis refusal capacity is also appropriate.

At the same time, the national guidelines also identify as appropriate for dialysis discontinuation patients with “severe mental disability” who are uncooperative with the dialysis procedure, not interactive, or combative. From the consulting psy- chiatrist’s point of view, it is potentially more troublesome to assign a low capacity standard for dialysis refusal to these patients, as they may include individuals with psychoses or affective disorders. It is important to recall that psychiatric illness in and of itself cannot be equated with incapacity, and that existential, spiritual, or developmental struggles at the end of life should not be unnecessarily labeled as pathologic. Ambivalence and even anguish about relinquishing life-prolonging treatment is to be expected, and may also be found in those parties most intimately involved in the patient’s life and care. Nevertheless, severe psychiatric disorders can be incapacitating and should be ruled out in cases of life-threatening non- compliance and early dialysis termination. Major depression, particularly when complicated by psychosis, can readily interfere with an individual’s ability to retain, weigh, and cognitively process information and should be considered in clinically suspect dialysis refusals (Cohen et al., 2003). There are instances in which it is appropriate and necessary to defer dialysis discontinuation while treating comorbid psychiatric illness (Cohen et al., 2003).

In screening for psychopathology and in setting capacity standards, it is also helpful to refer to the degree to which patients’ decisions are culturally endorsed and supported by family and loved ones. This is not to say that an individual patient’s decision must be popular; rather, it is to say that to the degree a decision to terminate dialysis conflicts with a patient’s traditional values and imperils social bonds, suspicion of a capacity-altering mental illness should be heightened. In such cases, a more exacting examination of the patient’s information processing and reasoning is appropriate.

The concept of shared decision making in end-of-life care is emphasized in the American College of Physicians-American Society of Internal Medicine (ACP-ASIM) Consensus Panel report (Karlawish et al., 1999; Lo et al., 1999).

Often the need for a capacity determination is itself an indication of failure in a process that should ideally build consensus among stakeholders, including the patient, family, physicians, and other significant caregivers (Cohen et al., 2003).

A number of potential sources of conflict are listed in the RPA guideline, including miscommunication or misunderstanding about the patient’s prog- nosis, differences in participant values, and interpersonal and individual issues.

From the psychiatric perspective, reframing a capacity consultation to focus on

restoring dialogue between participants may be a more helpful intervention than

seemingly vindicating one or another party. In true emergencies, RPA guidelines

suggest continuing dialysis while allowing conflict resolution to proceed, with

the consent of the patient or legal designate. The psychiatric consultant may be

called upon to provide a temporizing capacity determination if such consent is

withheld. This being said, the RPA/American Society of Nephrologists (ASN)

shared decision-making guidelines recognize that there are limits to conflict resolution, and that patients may have the right to unilaterally refuse dialysis.

Once a decision is made to withhold or terminate dialysis, it can be antici- pated that lethargy, coma, and death will ensue within a mean time of 8 days (Cohen et al., 2006). It has been traditionally taught that uremic deaths are gen- tle. However, more recent retrospective, family-derived data describe severe pain in a preponderance of dying ESRD patients during the last week of life (Cohen et al., 2005a). This highlights the fact that psychiatric consultation does not nec- essarily end with the withdrawal of dialysis. The termination of life-prolonging treatment provides an opportunity for the psychiatric consultant to help smooth the transition of the patient’s care to a primary goal of palliation.

19.2 Palliative Care

Patients with ESRD are defined by a glomerular filtration rate (GFR) of less than 15 cc/minute and are considered to be in need of dialysis or renal transplant. These patients are increasingly elderly, entering ESRD at a median age of 65 (Cohen et al., 2006). They routinely suffer from multiple comorbidities, including a num- ber of diseases predisposing them to vascular occlusive events. Diabetes, hyperten- sion, and peripheral vascular disease are common, and myocardial infarctions and congestive heart failure occur with more than five times the frequency of the gen- eral Medicare population (Cohen et al., 2006; United States Renal Data System, 2002). In addition, psychiatric syndromes and diseases of bone, skin and joints are frequently found. To this substantial comorbidity is added the systemic effects of uremia itself, along with symptoms referable to treatment.

19.2.1 General Issues in Renal Palliative Care

End-stage renal disease patients live with protracted somatic discomfort. As a group, patients suffer an average of 10.5 symptoms at any given time, including most prominently fatigue, pruritus, pain, cramps, sleep disruption, anorexia, and constipation (Merkus et al., 1999; Valderrqabano et al., 2001; Weisbord et al., 2003).

Sexual dysfunction is also common and is discussed elsewhere in this chapter.

Palliative remedies are available for most symptoms, but are limited in efficacy and tolerability. Issues of comfort and palliation have a direct impact on the course of intercurrent psychiatric conditions. Consulting psychiatrists should be aware of common issues in renal palliative care and should tailor interventions to add to patient comfort during life-prolonging treatment, as well as during the dying process.

In terms of fatigue, psychotropic medications should be reviewed in order to minimize those with potential for contributing to sedation, anergia, and abulia.

A psychostimulant like methylphenidate may be used symptomatically (Cohen et al., 2006); the role of newer agents like modafinil remains to be investigated.

Pain is reported by 50% to 63% of dialysis patients (Cohen et al., 2006;

Merkus et al., 1999), and may be even more prevalent among those who are

dying (Cohen et al., 2005a). Opioids are the mainstay of treatment for pain in

this population, and there is extensive literature to guide the nephrologist in the

choice and dosing of agents. It should be noted that a psychotomimetic poten-

tial has been noted with mixed agonist-antagonist analgesics (butorphanol,

nalbuphine, pentazocine) and of N-methyl-

-aspartate (NMDA) antagonists in renal failure patients (Inturrissi, 2002). Adjuvant psychotropics are often added for management of neuropathic pain, especially tricyclics like amitriptyline and anticonvulsants like gabapentin. Although enterically metabolized, the usual caveats apply about the use of tricyclics in elderly patients and in those vulner- able to delirium, constipation, and seizure. The common comorbidity of renal failure and cardiac disease is also something to consider when prescribing tri- cyclics as adjuvants in dialysis patients as well as their potential for a lethal outcome in overdose in this high suicide population. It should be noted that among tricyclics desipramine is 70% renally excreted; the drug and its 2-hydroxy metabolite can accumulate in renal failure and are not removed by dialysis.

About half of protriptyline’s elimination is by a slow renal excretion; it is also nondialyzable. Gabapentin is commonly prescribed in neuropathies. It is excreted unchanged in the urine; dosage must be adjusted downward for creatinine clear- ance, and supplemental posthemodialysis doses must be given. Blood levels of carbamazepine and valproic acid need to be monitored. Carbamazepine is sub- stantially dependent on renal excretion. Despite little dependence of the drug on renal elimination, free valproic acid levels can be elevated in renal failure.

Duloxetine has come into play as a treatment for diabetic neuropathy. However, it is dependent on renal elimination and is contraindicated in renal failure.

Sleep disruption is reported by 50% to 90% of patients (Cohen et al., 2006;

Walker et al., 1995), and a high incidence of formal sleep disorders, including restless legs syndrome, periodic leg movements disorder, and sleep apnea has been documented (Cohen et al., 2006; Kimmel et al., 1997). The efficacy of stan- dard treatments for insomnia in uremic patients is not clear (Pieta et al., 1998).

There is also additional risk in uremic patients of precipitating neuropsychiatric side effects with medications (Pieta et al., 1998; Sloand et al., 2004). Treatment of insom- nia with sedative hypnotics can be considered if sleep apnea is not present. These may include standard doses of zolpidem, temazepam, flurazepam, and trazodone.

In dialysis patients, particularly those with cardiac disease, it is worth noting that trazodone may contribute to hypotension and that trazodone-associated arrhyth- mias have been reported (James and Mendelson, 2004). Triazolam at low doses is also considered a renal hypnotic. Its potential for inducing rebound insomnia, anterograde amnesia, and behavioral disinhibition is likely no greater than that of other benzodiazepines (Mendelson and Jain, 1995; Rothschild, 1992). However, the potential for contributing to delirium is significant.

Anorexia is found in 25% to 48% of chronic dialysis patients (Merkus et al., 1999). Depression should be investigated in malnourished patients (Cohen et al., 2006) and treated if present. Medications contributing to dry mouth and constipa- tion, particularly those with anticholinergic properties, should be reduced or elim- inated if possible. In the treatment of depression accompanied by anorexia, side effect profiles of psychotropic agents like mirtazapine can be used to advantage.

19.2.2 Psychiatric Aspects of Renal Palliative Care

Psychiatric treatment is an essential aspect of palliative care for the dying ure- mic patient. Psychotherapeutic interventions in the hospice setting are generally supportive, directed at helping the patient and loved ones make the best use of the remaining time before the advent of terminal uremia and loss of awareness.

Life review, expressions of love and devotion, and the specific addressing of

“unfinished business” between patient and family may all have necessary roles in the leave-taking process. As the patient’s window of lucidity closes, the clini- cian at bedside will often direct increased attention to the bereaved survivors.

Pharmacotherapy in the final week of life is symptom-driven, targeting changes in mental status potentially disruptive to the comfort and dignity of the patient. When terminal delirium is accompanied by agitation, haloperidol is the mainstay psychotropic (Neely et al., 2000), as it is hepatically metabolized, and has inactive metabolites. It may be used at 0.5 to 1 mg po/SQ/IM/IV hourly, titrating to effect (Neely et al., 2000). Akathisia, dystonia, and parkinsonism can be dealt with by using diphenhydramine 25 to 50 mg IV q 4 to 6 hours in the usual manner (Neely et al., 2000), although the use of this agent will likely hasten cognitive decline. Haloperidol and benzodiazepines can be employed in the short period of postdialysis palliation to quell intercurrent anxiety, affec- tive lability, and sleep disturbance. As always, the consulting psychiatrist should be alert for paradoxical disinhibition and accelerated confusion when using benzodiazepines in the neuropsychiatrically compromised patient.

It should be noted that the postdialysis dying process involves role transition for the caregivers, as well as for the patient and loved ones. Doctors, nurses, and ancillary staff may be susceptible to feelings of helplessness and profes- sional inadequacy in the context of death, particularly if the relationship with the patient has deepened over time. Psychiatric consultation during this criti- cal period also includes maintaining an awareness of distress experienced by members of the renal team and responding supportively to it.

19.3 Renal Transplantation

The selection process for potentially eligible patients and living donors includes psychosocial assessment, often employing instruments capable of highlighting those candidates meriting more complete examination by a transplant team psy- chiatrist (DiMartini et al., 2005). There are at least a couple of general trans- plant screening instruments available, including the Psychosocial Assessment of Candidates for Transplantation (PACT) and the Transplant Evaluation Rating Scale (TERS) (DiMartini et al., 2005; Olbrisch et al., 1989; Twillman et al., 1993).

The psychiatric consultant assesses potential donors and recipients with regard to their psychiatric histories, coping styles, available systems of support, motivations for candidacy, and decisional capacity (Cohen et al., 2006). The psychiatrist is asked to assure the team that candidates and donors are capable of informed consent to renal transplant and that organ donation itself is altru- istic and not coerced. The consulting psychiatrist is also expected to identify behavioral “red flags” likely to impact on patient survival. When psychiatric problems affecting candidacy are identified, the consultant may be called upon to help the candidate stabilize sufficiently to become eligible.

Capacity may be affected by misunderstanding of the procedure and its prob-

able results. Unrealistic expectations of return to a predisease state of health

should be uncovered in the course of assessment, as should significant gaps in

the patient’s understanding of the posttransplant burden of care and the risks

of noncompliance. Cognitive impairment from delirium or uremic dementia

should be detected and its effect on the patient’s decision-making capacity deter-

mined. In this respect, a pretransplant capacity evaluation should include a

structured cognitive assessment tool, with or without formal neuropsychologi- cal testing. As an example, the Structured Interview for Renal Transplantation (SIRT) has been developed by Mori and colleagues (2000) as a comprehensive tool and clinical guideline for the pretransplant assessment of the renal patient.

It collects information relevant to the transplant team’s assessment and deci- sion, including data on the patient’s understanding of the illness, coping style, mental health history, and cognition (Mori et al., 2000).

It should be recognized that the presence of a psychiatric history itself does not preclude a patient from giving valid, informed consent to renal transplan- tation, particularly if the psychiatric illness has been responsive to treatment (Cohen et al., 2006). Even patients with prohibitive burdens of psychopathology, including psychosis and suicidality, can be treated and reevaluated for capacity when in remission.

The capacity of candidate donors is subject to its own set of potential failings.

Given that the procedure offers under the best of circumstances no benefit to the health of the donor, a high standard of capacity should be required in terms of retaining and understanding risks and potential consequences. Leo and col- leagues (2003) identify chronic psychosis, severe mood disorders, suicidality, mental retardation, active substance abuse, and severe personality disorder as conditions likely to preclude well-informed decisions about renal donation.

The consultant also needs to assess the individual donor’s motivation.

Inappropriate familial pressure or unfair external emotional leverage on a can- didate donor may preclude exercise of a valid choice. Guilt, fear of retaliation, and expectations of reciprocal emotional commitment are additional examples of inappropriate donor motivations. Unexplored ambivalence may ultimately sabotage donor compliance with preoperative protocol (Leo et al., 2003), and Levy (1994) feels that “the potential donor with an ambivalent relationship with the recipient should not be encouraged to donate.” Financial enticements of donors are both unethical and illegal. Leo and associates (2003) offer a useful guideline for the structured interview of prospective kidney donors.

Available data show renal transplant candidates to be less candid than the general population about past psychiatric treatment history (Mori et al., 2000;

Rundell and Hall, 1997). This is problematic, since survival of transplanted organ

recipients is dependent on strict treatment compliance, which can be undercut

by psychiatric disorders, including anxiety disorders, depression, and substance

abuse (DiMartini et al., 2005). In one longitudinal study, depression and age

were the two most important predictors of survival in renal candidates (Levenson

and Olbrisch, 1993; Mori et al., 2000). Levy (1994) identifies as higher risk those

patients who have become psychiatrically symptomatic in the context of ESRD

and dialysis. He also points to a family history of psychiatric illness as a signifi-

cant factor, and stresses the necessity of pretransplant education about the possi-

ble complications of immunosuppressant therapies as a buffer against unpleasant

surprises. Active substance abuse contraindicates transplantation, though patients

with at least 6 months’ abstinence can be reconsidered (Cohen et al., 2006), par-

ticularly if active in treatment. Personality disorders are likely to pose a challenge

to the patient’s ability to work with the treatment team and to the team’s ability to

metabolize the patient’s behavior. Personality-disordered patients are, when trans-

planted, likely to require a specialized behavioral treatment plan with close coor-

dination among psychiatric and nonpsychiatric team members. The consultant’s

pretransplant role with these patients includes helping the team to realistically

gauge whether its program will be able to effectively contain the patient. As always, a past history of treatment compliance is the most direct predictor of a candidate’s future behavior. A pattern of missed dialysis sessions, dietary indis- cretions, and medication noncompliance contraindicates renal transplantation (Cohen et al., 2006).

Postoperative psychiatric issues are not uncommon among renal transplant patients. Data from Fukunishi and colleagues (2001) show a peak prevalence of psychiatric disorders among adult living-related renal transplant recipients of 28%, occurring 3 months after surgery and subsequently declining at 1 and 3 years.

Delirium is the most common disorder during the early postoperative period, closely followed by major depression, dysthymic disorder, and adjustment disor- ders. Brief psychotic disorder, somatization disorder, substance-related disorders, and posttraumatic stress disorder (PTSD) are also represented. Depression is the most common longer term psychiatric problem among recipients. A paradoxical psychiatric syndrome precipitated by guilt regarding the donor’s sacrifice is identified by Fukunishi and colleagues in 5% of kidney recipients.

Other authors have noted that postoperative delirium in renal transplant patients can be precipitated by diverse factors, including narcotics, immunosup- pressant and glucocorticoid-induced neurotoxicity, infection, and residual uremia (Cohen et al., 2006). Demented patients are at increased risk for delirium. As in all delirium management, identification and correction of precipitants is the pri- mary approach, with adjunctive use of medications for symptomatic management of agitation, disorganization, disinhibited behavior, hallucinosis, and delusions.

Haloperidol, oral or parenteral, remains the first-line medication for agitated delirium (Cohen et al., 2006). Droperidol and atypical antipsychotics such as risperidone can be tried, although hypotension and reflex tachycardia are of con- cern. It should be noted that all antipsychotics commonly used in delirium carry the risk of QT interval prolongation with attendant arrhythmias.

Posttransplantation depression can be precipitated by immunosuppressant medications, including steroids (Levy, 1994), by graft rejection (Iwashige et al., 1990), and by psychodynamic factors (Fukunishi et al., 2001). Transplanted patients are also vulnerable to anxiety caused by medications as well as by the chronic threat of rejection and organ failure. Psychological comfort with the donated kidney can be an ongoing issue for the patient, with “internalization”

of the foreign organ occurring only incrementally (Levy, 1994; Muslin, 1971).

The psychiatric consultant should also be aware that tacrolimus can precipi- tate anxiety and akathisia—with clinical incidence related to plasma level (DiMartini et al., 1996). Antidepressant management and anxiolysis in ESRD are discussed elsewhere in this chapter, with similar concerns for the trans- plant patient in the transitional postoperative period. Mania, including that produced by glucocorticoids, can be treated with mood stabilizers, with the considerations attendant to renal management as noted elsewhere in this chap- ter. Steroid-induced psychosis should prompt treatment with antipsychotic medications.

It should be noted that altered pharmacokinetics in the setting of resolving

renal failure continues to affect the selection and dosing of psychotropic med-

ications in the posttransplant period. The consultant should also be aware that

most maintenance psychotropic medications are held on the day of surgery. Since

most of these medications are not dependent on renal metabolism, they should

generally be restarted postoperatively. Medication withdrawal is of particular

concern in patients maintained on benzodiazepines, and perioperative institution of an equipotent dosage of parenteral lorazepam should be considered.

Pharmacotherapy after renal transplantation is further complicated by the presence of immunosuppressants in the patient’s regimen. The psychiatric con- sultant should be aware of the psychiatric effects of immunosuppressants com- monly used in renal transplantation. As detailed by DiMartini and colleagues (2005), each immunosuppressant agent is associated with common, annoying side effects and with less common but more worrisome neurotoxic symptoms.

Cyclosporine commonly causes headache, restlessness, and tremor; a minority of patients can suffer delirium, psychotic states, cortical blindness, seizures, loss of speech, and coma. Cyclosporine neurotoxicity can precipitate demyelination, may be likelier with higher doses and IV administration, and is potentiated by hypocholesterolemia, hypertension, and hypomagnesemia (DiMartini et al., 2005). Tacrolimus commonly causes tremor, restlessness, and headache. It can also commonly cause sleep disruption, anxiety, and akathisia. Neurotoxic states can manifest in agitation, dysarthria, delirium, cognitive deficits, seizures, hemi- plegia, cortical blindness, and coma. Tacrolimus neurotoxicity can be mediated by demyelination, and is associated with higher plasma levels and with pathology that disrupts the blood–brain barrier (DiMartini et al., 2005). Demyelinating syndromes require imaging, ideally magnetic resonance imaging (MRI), for diagnosis. Azathioprine may precipitate depression (DiMartini et al., 2005).

Mycophenolate mofetil in combination with other immunosuppressants may also be associated with neuropsychiatric toxicities, including anxiety, agitation, psychosis, delirium, somnolence, and seizures (DiMartini et al., 2005). The panoply of steroid-induced neuropsychiatric syndromes will be familiar to the practicing consultation psychiatrist.

Agents such as tacrolimus and cyclosporine require therapeutic blood levels to prevent rejection and are more prone to cause neurotoxicity when supratherapeu- tic (DiMartini et al., 2005). For this reason, particular attention needs to be paid to pharmacokinetic interactions of immunosuppressants with cytochrome P-450 (CYP450)-inhibiting psychotropics, particularly those blocking or inducing the IIIA4 subsystem. As an example, carbamazepine can induce hepatic metabolism and precipitate a decrease in cyclosporine levels, resulting in organ rejection. In this respect, valproate may be a less problematic choice. CYPIIIA4 inhibitors such as nefazodone and fluvoxamine can elevate cyclosporine and tacrolimus levels.

Use of the common herbal psychotropic St. John’s wort can also induce CYP450 IIIA4 and decrease both cyclosporine and tacrolimus levels (Cohen et al., 2006).

In turn, immunosuppressant medications may affect psychotropic blood levels; an example of this would be the tendency of cyclosporine to raise levels of quetiap- ine. Pharmacodynamic interactions of psychotropics with immunosuppressants may also occur. An example of this would be serotonin syndrome precipitated by synergism between cyclosporine and sertraline (Wong et al., 2002).

Finally, the consultant should be aware that there have been cases of inten- tional overdose of immunosuppressants by suicidal patients, along with cases of unintentional toxic ingestion. Acute overdoses of tacrolimus have been remark- ably well tolerated (Curran et al., 1996; Mrvos et al., 1997; Sein et al., 2005).

Cyclosporine overdoses have been more injurious, with neurotoxicity the most salient acute effect (Nghiem, 2002; Sketris et al., 1993; Zylber-Katz et al., 1994).

In acute toxicity, CYP450 IIIA4-inducers like phenytoin have been used to bring

down levels of these medications more quickly.

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