Symptom Management among Patients with Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) experience high symptom burden, both physical and psychological, that is underrecognized and undertreated. The high symptom burden significantly impacts the quality of life for patients and their families. This review enumerates the various physical and psychological symptoms that patients with CKD often experience and guides in the management of these symptoms. This review follows the recommended international guidelines and has been tailored to suit the Indian context. Copyright:

INTRODUCTION

Patients with chronic kidney disease (CKD) experience high symptom burden, both physical and psychological, with low socioeconomic status negatively affecting the experience of symptoms.[1] Recent evidence suggests that symptom burden is not dependent on CKD stage, with patients in all stages experiencing symptoms that could potentially impact their quality of life (QoL).[2] CKD patients have a median of five to six symptoms.[3] Patients with end-stage kidney disease (ESKD) report a median number of 5.7–7.5 symptoms.[4] Those with Stage 5 CKD have physical and psychological symptom burdens similar or greater than that of advanced cancer patients.[5] Health-care providers frequently underrecognize and undertreat symptoms in CKD.[6] Assessment of symptom burden should be done at the first visit and at every follow-up visit for emergence of new symptoms and to assess the effectiveness of treatment.

Validated global symptom assessment tools are available and are appropriate for routine screening in renal programs, which will aid the identification of common and troublesome symptoms. Some of the commonly used validated tools include the Edmonton Symptom Assessment System (ESAS)-Revised: Renal,[78] Integrated Palliative Care Outcome Scale-Renal (IPOS-Renal),[910] and Dialysis Symptom Index.[6] The use of validated questionnaires will facilitate the assessment of symptoms in a systematic manner and should be incorporated into routine clinical practice to optimize symptom management.

SYMPTOM MANAGEMENT

Insomnia[11121314151617181920]

Sleep disorders are present from an early stage of CKD, affecting both duration and quality of sleep. Insomnia is among the top five troublesome symptoms reported in terms of intensity and severity. The prevalence ranges from 20% to 83% among CKD patients and 50%–75% among ESKD patients, with daytime sleepiness being the most troubling. Sleep disturbances decrease QoL, worsen health-related risks such as immune system impairment and cardiovascular disease, and increase mortality. It can also lead to impaired neurocognition with difficulties in attention and lowered work performance. The causes of insomnia in CKD are both physical and psychological, and the mode of treatment of insomnia is both pharmacological and nonpharmacological.

Nonpharmacological management

A systematic review in dialysis-dependent patients for insomnia identified four interventional modalities:

Cognitive behavioral therapy (CBT) (Level 2, Grade B): This includes sleep education, stimulus control, sleep restriction, relaxation training, and sleep hygiene. CBT for insomnia is carried out over 6–8-week sessions. Further studies are needed to assess the potential of other interventions

Acupressure (Level 2, Grade C)

Physical exercise: Aerobic and flexibility exercise (Level 2, Grade C)

Change of dialysis modality (Level 2, Grade C).

Pharmacological management (Level 2, Grade C)

Adequate management of concurrent symptoms such as pain, pruritus, depression, and obstructive sleep apnea

If symptoms of restless leg syndrome (RLS), neuropathic pain, or uremic pruritus (UP) are present along with insomnia, then low-dose gabapentin 50–300 mg at night can be prescribed

Doxepin 10 mg at night as second line to be used in presence of neuropathic pain or pruritus

Zopiclone 3.75–5 mg is third line

Melatonin 2–5 mg regulates and improves sleep–wake cycle in the short term but not at 1 year.

Anxiety and depression[2122232425262728]

Depression is common in adults with CKD, with a prevalence of depression being 3–4 times higher in patients with CKD and ESKD as compared to general population. The presence of depression is associated with adverse psychosocial and clinical outcomes and lower QoL. The mortality risk is 1.5 times higher in the presence of depressive symptoms, with increased emergency department visits, hospitalizations, prolonged stay in hospital, cardiovascular events, withdrawal from dialysis, and suicide. The etiology of depression in CKD/ESKD is multifactorial, both biological and behavioral. The recommended screening tools include a two-question approach modified from the Patient Health Questionnaire, Hospital Anxiety and Depression Scale, Patient Health Questionnaire-9, and General Anxiety Disorder-7.

Depression in patients with CKD is undertreated, with approximately only 35% of those with diagnosable depression receiving treatment. Although an improvement in depressive symptoms and psychosocial outcomes was observed when treated with a combination of antidepressants and psychotherapy, data regarding the benefits of pharmacotherapy are sparse and inconclusive.

Nonpharmacological management (not graded)

CBT, exercise therapy, and more frequent dialysis have been shown to be effective in improving depression in patients with CKD, however, the studies were of low quality and more research is required.

Pharmacological management

ESKD has no effect on the pharmacokinetics of selective serotonin reuptake inhibitors, and they are recommended as first-line treatment in all stages of CKD. Sertraline 50–200 mg/day, escitalopram 10–20 mg/day, or fluoxetine 20–60 mg/day is recommended (Level 2, Grade B)

For episodic anxiety, a short trial of benzodiazepines and beta-blockers may be tried (Level 2, Grade C)

Mirtazapine 15–45 mg/day in CKD 1–4. 50% dose reduction for patients in Stage 5 CKD (Level 2, Grade C)

Duloxetine 40–120 mg/day. Better avoided once estimated glomerular filtration rate (eGFR) <30 (Level 2, Grade C)

Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors are not recommended in CKD.

A recent Cochrane review highlighted the lack of evidence for efficacy of antidepressants in CKD and emphasized the need for further research.

Uremic pruritus[2930313233]

In advanced kidney failure, UP is a common and burdensome symptom, often affecting multiple health-related QoL outcomes such as sleep, general mood, and social function and independently affects mortality. It is experienced in up to 46% of hemodialysis (HD) patients. UP is described as a daily or near-daily occurrence of itch involving large surface areas and is not restricted by dermatomal pattern. The pathophysiology of UP is often multifactorial. Uremic neuropathy, substance P, inflammation from chronic systemic inflammation of skin or nerves, and an increase in activity of µ-opioid receptors, all contribute to the pathogenesis of UP. There is growing evidence in favor of nonhistamine pathways in the pathogenesis of UP, and only a small proportion of cases have histamine as an implicating factor.

Management of patients with UP should involve assessment for any contributing and reversible factors. An associated fungal infection, drug hypersensitivity, allergic or contact dermatitis should be addressed prior to treatment of UP.

Appropriate skincare: To maintain short, smooth fingernails; wear gloves at night and avoid scratching. Moisturizers (e.g., baths with lukewarm water and gentle moisturizing soaps with no fragrances or additives; moisturize with aqueous emollients within 2 min of bath; the use of nonperfume coconut oil, Aloe vera cream, Vaseline lotion, and Lacto Calamine lotion are useful emollients to be used for managing UP (Level 2, Grade A)

Topical application: Capsaicin 0.025% or 0.03% ointment; pramoxine 1%; menthol/camphor/phenol 0.3% each either separately or in combination with each other; g-linolenic acid cream 2.2% (Level 2, Grade B)

Phototherapy (UVB) (Level 2, Grade C): 400–4800J/m2 three times weekly for a 3-week trial; impractical in Indian setting in view of availability of centers offering the therapy and the cost involved (opinion statement)

Modification in dialysis (Level 2, Grade B): High-flux HD and hemodiafiltration over a period of 12 weeks have been significantly found to reduce symptoms of UP compared to conventional HD.

PHARMACOLOGICAL MANAGEMENT

Gabapentinoids (Level 1, Grade A): Gabapentin or pregabalin has a significant benefit in reducing symptoms of UP. However, long-term effects have not been studied. Recommended dose: Gabapentin 100 mg daily (2 h before sleep) or 300 mg post HD thrice weekly; pregabalin 50 mg thrice weekly or 75 mg twice weekly post HD. Common side effects: somnolence, dizziness, and nausea

Antihistamine and mast cell stabilizer (Level 2, Grade B): Hydroxyzine 25 mg once daily or montelukast 10 mg daily

TCA: Doxepin 10 mg at bedtime, upon consultant prescription in patients on regular follow-up

Others: κ-opioid receptor agonist nalfurafine (Level 1, Grade B – 5 mcg – currently not available in India) and thalidomide (100 mg daily).

Restless leg syndrome (RLS)[29303435]

The prevalence of RLS ranges from 6.6% to 80% among dialysis population. The definition of RLS was revised during the National Institutes of Health consensus conference (2002), Bethesda, USA, to include:

Urge to move the legs usually with unpleasant sensations in the legs; arms and other body parts are occasionally involved

Symptoms begin or worsen during periods of rest or inactivity

Symptoms partially or totally relieved by movement and as long as the activity continues

Symptoms are worse during the evening or night than during the day.

Abnormalities in the dopamine pathway of the central nervous system (subcortical area) have been implicated. Other contributing factors include iron deficiency, anemia, hyperparathyroidism, elevated serum calcium and phosphorus, inadequate dialysis, and poor sleep hygiene. RLS is associated with decreased QoL and increased cardiovascular morbidity and mortality.

Removal of stimulants such as alcohol, caffeine, nicotine; optimizing sleep hygiene; aerobic exercises; pneumatic compressions, and regular mental alerting activities such as solving puzzles and board games were found to be useful in reducing RLS. Other contributing and reversible factors such as concurrent use of dopaminergic antagonists, iron deficiency, anemia, hyperparathyroidism, and elevated serum phosphorus must be addressed and corrected.

Pharmacological management

Gabapentin (Level 1, Grade A): As the drug is excreted by the kidney (77%), dose must be reduced owing to its long half-life in CKD patients. It modulates various receptor sites and alters dopamine, serotonin, and norepinephrine release. Recommended dose: Gabapentin 100 mg daily (2 h before sleep) or 300 mg post HD thrice weekly

Synthetic dopamine agonist (Level 1, Grade B): Ropinirole; increased selectivity to D3 and D4 receptors. Advantages: short plasma half-life with primary liver metabolism. Recommended dose: To initiate with 0.25 mg, taken 1 h before bedtime with slow titrating to a maximum of 4 mg per day. Pramipexole: Only immediate-release tablet is approved for use in RLS. Recommended dose: To initiate with 0.25 mg, taken 1 h before bedtime with slow titrating to a maximum of 0.75 mg per day

Antioxidants Vitamin C and E (Level 2, Grade A): Found to be effective when compared to placebo with minimal side effects

Others: Levodopa (Improves symptoms but not routinely used owing to increased vomiting, agitation, headaches, dry mouth, and gastrointestinal symptoms), benzodiazepines (increased risk of frequent falls but considered for use in patients who cannot take oral drugs), and iron dextran (less likely to have added benefit beyond correction of iron deficiency and anemia).

Chronic pain[29303637383940]

Pain has been recognized as one of the most common symptoms, affecting up to one-third of CKD patients. Majority of them experience moderate-to-severe pain. Pain often is musculoskeletal in origin, and chronic pain in CKD is often a mix of nociceptive and neuropathic pain. Management should involve patient assessment including physical examination, medical history, and patient's primary diagnosis and determine the effects of the pain on the patient's psychologic status, social functioning, functional status, and QoL.

Determine pain intensity: Modified Edmonton Symptom Assessment Version 2 (m-ESAS v.2). Convenant Health, Alberta, Canada and IPOS-Renal (POS-renal) are screening tools to be used A separate visual pain scale to be used for follow-up assessments, among patients in whom chronic pain forms the predominant symptom

Identify chronicity and possible reversible causes for the pain: Patients on dialysis experience recurrent pain from arteriovenous fistula cannulation, leg cramps, steal syndrome, etc., Adequate and effective pain control during episodes of acute pain reduces the incidence of chronic pain. As pain becomes more chronic, the original triggers become less important and somatosensory/psychologic mechanisms assume relevance

Type of pain – nociceptive, neuropathic, or combined: Neuropathic pain has a poor response to nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids and often requires adjuvant drug (drug that has a primary indication other than pain). In contrast, nociceptive pain responds well to nonopioid and opioid analgesics, at least in the short term. Since chronic pain in CKD is often mixed, addressing the neuropathic component first with adjuvant therapy avoids inapt use of opioids

Plan treatment goals: The goal of therapy should be realistic and aim to reduce pain to a tolerable level (at least by 30% on the pain scale), thereby allowing for routine day-to-day work and improving QoL. Slow introduction with upward titration of analgesics, starting with nonopioids followed by weak-to-strong opioids as per the WHO analgesic ladder, should form the basis of treatment plan. Before starting opioids, one needs to assess the risk for substance abuse and strategy to reduce opioid dependence should be part of the treatment plan. There should be an ongoing assessment and titration of drug doses, and any side effects should be actively managed.

Aerobic exercise, acupressure, acupuncture, physiotherapy, and local heat application help a minority of patients and reduce the use of pharmacological agents in them. Cognitive-behavioral therapy, psychotherapy, and relaxation reduce drug dependency among patients with neuropathic pain.

Pharmacological management [Table 2]

Acetaminophen (Level 1, Grade A): Maximum of 3 g daily, preferably oral route. Mild anti-inflammatory agent, it is an analgesic of choice for mild-to-moderate pain

NSAIDs (Level 1, Grade B): Only for acute pain and short-term use. Avoid in patients with good residual kidney function/urine output. No change in dose for majority of NSAIDs even when used in patients on HD. Commonly used NSAIDs such as ibuprofen, indomethacin, naproxen, and rofecoxib should be accompanied by a short course of proton-pump inhibitors. Topical diclofenac (5% or 10%) gel for local musculoskeletal pain is preferred to reduce systemic NSAID exposure ex: For pain localized to a small joint.

Tramadol (Level 1, Grade B): Half-life is prolonged in patients with kidney failure. Recommended dose: eGFR 10–30 mls/min = 50–100 mg twice daily. For eGFR <10 mls/min (and on dialysis): 50 mg twice daily. To be administered post dialysis as the drug is dialyzable

Tapentadol: The drug is not recommended in CKD patients with eGFR <30 ml/min. Recommended dose: Start at 50 mg twice daily, principally as an extended-release form, and titrate further upward based on tolerance

Fentanyl (Level 2, Grade B): As transdermal patch (12 mcg/h to 100 mcg/h) or parental route (i. v. or i. m.; 50–100 mcg as an initial dose followed by 50 mcg of additional supplemental dose if required). Advised to start with the lowest dose and then titrate upward to avoid excessive sedation. To use in opioid-tolerant patients with persistent moderate-to-severe chronic pain requiring continuous or prolonged opioid administration

Buprenorphine (Level 2, Grade C): Transdermal 5 mcg/h/sublingual 0.2–0.4 mg two to three times a day; parental (i. v./i. m./s. c.) 0.3–0.6 mg per day. Advise patients to report for possible side effects such as constipation and urinary retention

Methadone (Level 2, Grade A): Methadone available in India is a mixture of R and S racemic forms. It is effective both in nociceptive and neuropathic pain. It is also efficient to treat central sensitization, reduce tolerance, and in opioid-induced hyperalgesia. Recommended dose: 2.5 mg tablet twice daily oral, to further titrate upward up to a maximum of 20 mg per day

Nalbuphine (not graded): Parenteral (s. c or i. v.) 10–30 mg per day. For acute pain.

Drugs currently not available or available only on special request in India: hydromorphone and oxycodone. Not recommended for patients with advanced kidney failure: codeine and morphine.

Gastrointestinal symptoms[2941]

Gastrointestinal symptoms are common, especially in advanced stage of CKD. If not yet initiated on HD (CKD ND), patient symptoms could be related to uremia and initiation of dialysis will improve most of the symptoms and helps in increasing the appetite. If already on dialysis, adequacy of the same should be looked at. Measures should be taken to correct factors contributing to inadequate dialysis and improve uremia. If still there is no improvement, then appropriate additional steps as described should be implemented.

NAUSEA AND VOMITING

The reported prevalence of nausea in advanced kidney failure is approximately 46%.[29] Nausea in patients could be multi-factorial. Reasons including uremia, drugs (e.g., opioids, antibiotics, and anticonvulsants), diabetic gastroparesis and/or uremic gastropathy further worsenthese symptoms. There could be delayed gastric emptying more so in diabetic CKD. A short course of proton-pump inhibitors should be used, if gastritis is contributory. Prokinetic agents such as metoclopramide (10 mg q 8th hourly) with 50% dose reduction for patients with eGFR <40 ml/min (extrapyramidal symptoms due to metoclopramide should be watched for) and itopride can be tried for gastroparesis with close monitoring for any side effects (Level 2, Grade C). Haloperidol (0.5–2 mg q 12 h) or levomepromazine (12.5–25 mg q 8 h) is commonly used for nausea and GI symptoms but requires dose reduction due to their propensity for cerebral sensitivity.

Xerostomia is commonly seen in advanced kidney failure, which could be due to uremia. Patients are often suggested to try lozenges such as xylitol, mints, and ice chips. No specific medication is approved.

Constipation

Dietary restriction and poor appetite in advanced kidney failure can be contributory. It could be quite severe in a few patients needing inhospital intervention. Drugs such as opioids, iron supplements, phosphate binders, when on can contribute or worsen constipation. Nonpharmacological strategies include consuming fiber (20–38 gm/day) and fluid intake within allowed dietary restriction and physical activity. Pharmacological recommendations include oral osmotic laxatives (lactulose 15–30 ml once daily), stimulant laxatives (bisacodyl 5–15 mg PO once daily), sodium picosulfate, and stool softeners. Psyllium fiber husk/roughage powder is not commonly recommended as often patients are on strict fluid restriction.

Dyspnea

Dyspnea is very common in CKD Stage 5. It is commonly due to volume overload (pulmonary edema), cardiovascular cause, or anemia. If it is volume related, a trial of loop diuretics at the higher end of recommended dosing, initiation and intensification of dialysis, slow continuous ultrafiltration will help in alleviating the symptoms. If any cardiac cause is identified and corrected, it will also relieve the symptoms. Anemia should be corrected promptly, with iron supplementation and erythropoietin. In end stages, general measures such as propped-up position, inhaled oxygen (if there is hypoxia), and medications to reduce anxiety can be tried. A small dose of opioids can be used for dyspnea end-of-life care. Short-acting benzodiazepines like lorazepam 0.5–1.0 mg oral or sublingual at 6–8-h interval can be tried. Especially at the end of life, midazolam at a dose of 1.25–2.5 mg (Level 2, Grade B) can be given subcutaneously with close monitoring. It could be very difficult for the patient and family to manage severe dyspnea at home and may need hospital admission for the same. Especially at the end of life, a combination of low-dose opioids and benzodiazepines either as intermittent doses or continuous infusions helps in great relief.

CONCLUSION

There is an increased prevalence of unpleasant physical and psychological symptoms in patients with CKD. These symptoms impact the QoL adversely. Routine assessment and management of these symptoms throughout the disease trajectory should be a priority. While managing symptoms, toxicity of medications which impair residual kidney function, delayed drug clearance, and the effect of dialysis on drug clearance should be considered. This paper addresses the commonly experienced symptoms in patients with CKD and its management [Appendix 1]. The general rule is to preserve cognitive, physical, and kidney function and address the symptom burden with awareness that management priorities may change with time. Clear communication and shared decision-making should guide choosing conservative kidney management, advance care planning, and psychosocial support along with dialysis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Table 1

The strength of recommendation is indicated as Level 1/Level 2/not graded, based on the quality of supporting evidence available (A, B, or C)

Grade	Strength of recommendation	Grade	Quality of evidence#
Level 1	Most patients should receive the recommended course of action	A	High
Level 2	Different choices for different patients based on the patient’s values and preferences	B	Moderate
Not graded*	Based on common use and individual experience or where adequate application of evidence is not possible	C	Low

*The ungraded statements are simple declarative statements based on experience of their use among clinicians and should not be interpreted as stronger recommendation than Level 1 or 2, #The general hierarchical pyramid for quality of evidence which includes meta-analysis, systemic/ Cochrane reviews, randomized control trials, cohort studies, and case series

Table 2

Drug recommendation for management of chronic pain

Type of pain*	Drug class recommendation (step ladder)	Alternate drugs with caution
Nociceptive pain	Step 1: Acetaminophen	NSAIDs: Caution in the elderly and patients with good residual kidney function
	Step 2: Tramadol; tramadol+acetaminophen
	Step 3: Methadone/fentanyl	Buprenorphine/nalbuphine
Neuropathic pain	Step 1: Start with adjuvant therapy	Duloxetine: Dose reduction with a maximum dose of 30 mg daily in patients with eGFR of>30 ml/min. In patients with eGFR<30 ml/min use with caution
	First line: Gabapentin (50-100 mg daily at night), Pregabalin (25-50 mg at night or 75 mg post HD)
	Second line: Tricyclic antidepressants, amitriptyline starting at 10-25 mg daily or doxepin starting at 10 mg at bedtime
	Step 2: For additional analgesia add a weak opioid or opioid-like analgesic to step 1; tramadol 25-50 mg
	Step 3: Add a strong opioid to step 1; transdermal fentanyl/methadone/nalbuphine

*For mixed type of pain: Address neuropathic pain with an adjuvant drug first with addition of opioids for additional pain relief. NSAIDs: Nonsteroidal anti-inflammatory drugs, HD: Hemodialysis, eGFR: Estimated glomerular filtration rate