Symptom Management in Advanced Chronic Kidney Disease

Lien Centre for Palliative Care
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Symptom Management in Advanced Chronic Kidney Disease

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Statement of Intent

The content of this guideline is to guide symptom management in patients with advanced chronic kidney disease on supportive care. The guideline is developed based on current clinical evidence, available guidelines, current local clinical practice and the drug formulary of Singapore General Hospital (SGH).

This guideline is not intended to serve as the standard of medical care and should not be construed to include all proper methods of care.

The use of this guideline in clinical practice is still dependent on the clinical judgment of a qualified healthcare practitioner.

Symptom Management in advanced Chronic Kidney Disease on Supportive Care

Pain

Definition: unpleasant sensory or emotional experience associated with actual or potential tissue damage

General characteristics:

Somatic pain: aching, throbbing, sharp
Visceral pain: aching, dull, vague
Neuropathic pain: burning, tingling, shooting, pins and needles, electric currents

Causes:

Kidney-specific pain (e.g. polycystic kidneys, calciphylaxis)
Musculoskeletal pain (e.g. hyperparathyroidism, osteomyelitis, restless legs syndrome, muscle cramps)
Neuropathic pain (e.g. diabetic neuropathy)
Ischaemic pain (e.g. peripheral vascular disease, vasculitis)
Metabolic abnormalities (e.g. hypomagnesaemia, hyponatraemia, hyperkalaemia)
Medications that may cause muscle cramps (e.g. nifedipine, statins, β-blockers, benzodiazepines)

Non-pharmacological management:

RICE (rest, ice, compress, elevate), massage and stretch cramped muscle, apply heat pads
Prevent cramps by limiting caffeine and alcohol, wearing comfortable shoes, doing light exercises
Physical and occupational therapy
Psychotherapy
Acupuncture

Pharmacological Management:

Treat underlying cause if appropriate or possible

Avoid:

Opioids such as morphine (high doses), pethidine, codeine, IM/IV tramadol due to risk of accumulation
Non-steroidal anti-inflammatory drugs (NSAIDs) due to risk of acute kidney injury and potential to worsen kidney function

Available Drugs	Indication / Special Mention	Dosing Regimen	Monitoring Parameters / Side Effects
Paracetamol 500mg tablet		500mg-1g TDS-QDS PRN Max: 4g/day	Generally well tolerated
Paracetamol 450mg, Orphenadrine 35mg tablet		2 tab TDS PRN Max: 6 tab/day	Drowsiness, dry mouth
Tramadol 50mg tablet		25-50mg TDS-QDS PRN Max: 200mg/day	Respiratory rate, side effects of opioids (nausea, vomiting, constipation, sedation, dry mouth, hallucinations)
Morphine 2mg/ml, 1mg/ml syrup		1-2mg TDS-QDS PRN, guided by symptoms Consider switching to fentanyl patch at morphine equivalent dose >15mg/day (15mg of morphine/day ≈ 6mcg/h fentanyl patch)
Fentanyl injection (100mcg/2ml, 500mcg/10ml), patch (12mcg/hr, 25mcg/hr 50mcg/hr)		IV/SC 5-10mcg Q1H PRN IV/SC 5-10mcg/hr continuous infusion may be started for patients with constant/ baseline pain (opioid naïve) as required and tolerated Convert to fentanyl patch when stable on IV/SC regimen; Stop IV/SC fentanyl infusion 10 hours after patch is applied. Continue with IV/SC fentanyl Q1H PRN for breakthrough pain
Gabapentin 100mg, 300mg capsule	Indication: neuropathic pain Other indications: restless legs syndrome, pruritus	100mg ON and titrate slowly against symptoms Max: dose up to 300mg/day may be attempted	Drowsiness, dizziness
Pregabalin 25mg, 75mg capsule		25mg ON and titrate slowly against symptoms Max: 75mg/day	Drowsiness, dizziness
Venlafaxine XR 75mg tablet	Indication: neuropathic pain	75mg ON Max: 75mg/day (theoretical max of 112.5mg but unable to halve tablet)	Headache, nausea, insomnia, drowsiness, hypertension
Clonazepam 0.5mg tablet	Indication: Cramps	PO 0.25-1mg ON Max: 1mg ON
Baclofen 10mg tablet	Indication: Cramps	PO 2.5mg BD PRN Max: 5mg/day	Drowsiness, nausea, constipation
Lignocaine 5% patch		1 patch per day (leave on for only 12H, then off for 12H) Max number of patches/day: brand specific	Local irritation
Ketoprofen 30mg patch, 2.5% gel		Patch: 1 patch BD Gel: BD-QDS	Local irritation, increased risk of sunburn

Treatment Algorithm

References:

Douglas, C. (2014) Palliative care for patients with advanced chronic kidney disease. The Journal of the Royal College of Physicians of Edinburgh, 44(3), 224-231. Doi:10.4997/jrcpe.2014.309
Symptom Assessment and Management. (2017, August). Retrieved February 01, 2018, from http://www.bcrenalagency.ca/health-professionals/clinical-resources/symptom-assessment-and-management
Supportive Care Guidelines for Patients with End Stage Renal Disease. (2017, June). Retrieved February 01, 2018, from https://www.thinkkidneys.nhs.uk/
End of Life Care in Advanced Kidney Disease. (2017, October). Retrieved February 01, 2018, from http://www.gloshospitals.nhs.uk/SharePoint75/Palliative%20Care%20Web%20Documents/SUPPORTIVE%20CARE%20FOR%20RENAL%20PATIENTS%20V5%20Oct%2017.pdf
Pham, P. C., Khaing, K., Sievers, T. M., Pham, P.M., Miller,J. M., Pham, S. V., Pham, P. T. (2017). 2017 update on pain management in patients with chronic kidney disease. Clinical Kidney Journal, 10(5), 688-697. doi:10.1093/ckj/sfx080
Lexicomp. (2018). Lexi-CLINICAL SUITE [Online database]. Retrieved from http://online.lexi.com/lco/action/home/switch?siteid=129

Shortness of Breath

Definition: Difficult, laboured or uncomfortable breathing as experienced by the patient

Common Causes (not exhaustive):

Anaemia
Fluid overload (fluid / dietary indiscretions, heart failure, worsening kidney function)
Acidosis
Respiratory conditions (e.g. asthma, chronic obstructive pulmonary disease [COPD], pneumonia)
Pleural effusion
Pulmonary embolus

Non-pharmacological management:

Treat underlying cause if appropriate or possible
Limit fluid and salt intake (if able to) and manage dry mouth (see specific section for details)
- Monitor weight and lower limb swelling at home. If patient and/or caregivers are confident and competent, they can be educated to adjust furosemide at home if weight gained >2kg with increased lower limb swelling and dyspnoea
Sit in upright position
Relaxation techniques
Place fan near face
Emotional support and calm environment
Breathing technique such as “pursed lip breathing”
Energy conservation techniques such as pacing during activities, shower using a stool (seated)
Home modifications e.g. grab bars, use of commode
Manage/ avoid constipation (reduce straining) – regular laxatives
Manage dry mouth

Available Drugs	Indication / Special Mention	Dosing Regimen	Monitoring Parameters / Side Effects
Morphine 2mg/ml, 1mg/ml syrup		PO 1-2mg TDS-QDS PRN May be given 30min before activity as needed Max: 10mg/day	Respiratory rate, drowsiness
Fentanyl injection (100mcg/2ml, 500mcg/10ml) or patch (12mcg/hr, 25mcg/hr 50mcg/hr)		IV/ SC 10mcg Q1H PRN May be given just before activity as needed IV/SC 5-10mcg/hr continuous infusion may be started for patients with constant/ baseline dyspnoea (opioid naïve) Fentanyl patch indicated for chronic dyspnoea. Stop IV/SC fentanyl infusion 10 hours after patch is applied. Continue with IV/SC fentanyl Q1H PRN for breakthrough dyspnoea. No maximum dose	Respiratory rate, drowsiness
SL lorazepam 1mg tablet (only if SOB exacerbated by anxiety, adjunct to opioids)	Only if SOB exacerbated by anxiety, adjunct to opioids	SL 0.5mg Q4H PRN Usual max: 5mg/day; up to 10mg/day (anxiety)	Respiratory rate, drowsiness
SC midazolam 5mg/5ml injection (only if SOB exacerbated by anxiety)	Only if SOB exacerbated by anxiety	SC 1-2.5mg Q2-4H PRN (if swallowing is a problem) Use with caution	Respiratory rate, drowsiness

Treatment Algorithm

References

Del Fabro E, Dalal S, Bruera E. (2006). Symptom control in palliative care. Part III: dyspnea and delirium. J Palliat Med 9:422-36.
End of Life Care in Advanced Kidney Disease. (2017, October). Retrieved February 01, 2018, from http://www.gloshospitals.nhs.uk/SharePoint75/Palliative%20Care%20Web%20Documents/SUPPORTIVE%20CARE%20FOR%20RENAL%20PATIENTS%20V5%20Oct%2017.pdf
Chambers, E. J., Germain, M. J., & Brown, E. A. (2010). Supportive care for the renal patient. doi:10.1093/acprof:oso/9780199560035.001.0001\
Supportive Care Guidelines for Patients with End Stage Renal Disease. (2017, June). Retrieved February 01, 2018, from https://www.thinkkidneys.nhs.uk/
Lexicomp. (2018). Lexi-CLINICAL SUITE [Online database]. Retrieved from http://online.lexi.com/lco/action/home/switch?siteid=129

Weakness or Lack of Energy / Fatigue

Causes:

Anaemia
Uraemia
Metabolic abnormalities (e.g. hyponatraemia, hyperkalaemia)
Poor nutrition
Hypotension
Insomnia
Depression
Physical inactivity/ deconditioning
Medications (e.g. antihypertensives, diuretics, opioids, steroids, medications that may cause sedation)
Chronic illness (e.g. hypothyroidism, heart failure, chronic obstructive pulmonary disease)

Non-pharmacological management:

Improve nutritional status/intake where possible/ appropriate
Energy conservation techniques
Appropriate regular exercise as tolerated

Pharmacological Management:

Treat underlying cause if possible

References:

Supportive Care Guidelines for Patients with End Stage Renal Disease. (2017, June). Retrieved February 01, 2018, from https://www.thinkkidneys.nhs.uk/
End of Life Care in Advanced Kidney Disease. (2017, October). Retrieved February 01, 2018, from http://www.gloshospitals.nhs.uk/SharePoint75/Palliative%20Care%20Web%20Documents/SUPPORTIVE%20CARE%20FOR%20RENAL%20PATIENTS%20V5%20Oct%2017.pdf

Nausea / Vomiting

Definitions:
Nausea: unpleasant sensory and emotional experience; ‘sick’ feeling with or without a sense of impending vomiting or retching
Vomiting: rapid, forceful evacuation of gastric contents from the stomach up to and out of the mouth

Causes

Uraemia
Gastrointestinal causes (e.g. gastric stasis, severe constipation, bowel obstruction, gastro-oesophageal reflux, ascites)
Metabolic abnormalities (e.g. hypercalcaemia, hyponatraemia, hyperglycaemia)
Vestibular dysfunction
Medications (e.g. iron supplements, phosphate binders, opioids, anticholinergics, antibiotics, selective serotonin reuptake inhibitors [SSRIs] etc)
Oral candidiasis
Anxiety

Non-pharmacological management:

Reduce or avoid foods that cause nausea (e.g. spicy, oily, high-fat or strong-smelling foods)
Avoid environmental stimuli (sights, smells, sounds) that cause nausea
Eat frequent, small, high calorie meals
Consider consuming ginger products or lime/lemon/peppermint sweets
Maintain good oral hygiene to reduce unpleasant mouth taste. Consider rinsing mouth before meals
Wear loose clothing
Avoid lying down immediately after meals

Pharmacological Management:

Treat underlying cause if possible

Avoid:

Prokinetics such as metoclopramide if patient has complete intestinal obstruction, gastrointestinal perforation
Combinations of drugs with conflicting mechanisms of action (e.g. prokinetic and anticholinergic)

Antiemetics	Indication / Special Mention	Dosing Regiment	Potential Side Effects
Metoclopramide 10mg tablet, 5mg/ml injection		IM/IV/PO 10mg TDS PRN	Extrapyramidal reactions
Domperidone 10mg tablet		PO 10mg TDS PRN	QTc prolongation
Ondansetron 8mg tablet, 2mg/ml injection		IM/IV/PO 4-8mg TDS PRN	QTc prolongation, constipation
Haloperidol 0.5mg tablet, 1.5mg tablet, 5mg tablet, 5mg/ml injection		IV/SC/PO 0.25-2mg TDS PRN or SC continuous infusion. Max: 10mg/day	Sedation, anticholinergic activity, extrapyramidal reactions, QTc prolongation
Lorazepam 1mg tablet	Usually for anticipatory nausea	PO/Sublingual 0.5-1mg ON-TDS PRN Max: 10mg/day	Sedation, dizziness, irritability, weakness
Cinnarizine 25mg tablet	Indication: For vestibular causes only	PO 25mg Q8-6H PRN	Sedation
Betahistine mesilate (Merislon) 6mg tablet	Indication: For vestibular causes only	PO 8-12mg TDS PRN Max: 36mg	Generally well-tolerated
Betahistine HCl 24mg		PO 24mg BD Max: 48mg	Generally well-tolerated
Prochlorperazine 5mg tablet, 12.5mg/ml injection		PO 5-10mg TDS-QDS PRN IM 5-10mg BD-TDS PRN Max: 40mg/day (Use is contraindicated in Canadian labelling)	Extrapyramidal reactions, dry mouth, hypotension
Olanzapine 10mg tablet		PO 2.5mg-10mg OD-Q4H PRN Max: 10mg/day	Orthostatic hypotension, drowsiness, extrapyramidal reactions

Treatment Algorithm

References

Smith H.S. (2005). A receptor-based paradigm of nausea and vomiting. Journal of Cancer Pain and Symptom Palliation, 1, 11-23
Supportive Care Guidelines for Patients with End Stage Renal Disease. (2017, June). Retrieved February 01, 2018, from https://www.thinkkidneys.nhs.uk/
Symptom Assessment and Management. (2017, August). Retrieved February 01, 2018, from http://www.bcrenalagency.ca/health-professionals/clinical-resources/symptom-assessment-and-management
Glare, P., Miller, J., N., & T. (2011). Treating nausea and vomiting in palliative care: a review. Clinical Interventions in Aging, 6, 243-259. doi:10.2147/cia.s13109
Nausea and vomiting in palliative care. (2014). The Pharmaceutical Journal. doi:10.1211/pj.2014.11135047
Chambers, E. J., Germain, M. J., & Brown, E. A. (2010). Supportive care for the renal patient. doi:10.1093/acprof:oso/9780199560035.001.0001
Davison, S. N., Levin, A., Moss, A. H., Jha, V., Brown, E. A., Brennan, F et al. (2015). Executive summary of the KDIGO Controversies Conference on Supportive Care in Chronic Kidney Disease: developing a roadmap to improving quality care. Kidney International, 88(3), 447-459. doi:10.1038/ki.2015.110
Lexicomp. (2018). Lexi-CLINICAL SUITE [Online database]. Retrieved from http://online.lexi.com/lco/action/home/switch?siteid=129
AA Pharma Inc. (2012). Prochlorperazine: Prescribing Information. Vaughan, Ontario. Author.

Poor Appetite / Anorexia

Causes:

Uraemia
Fluid and dietary restrictions
Poorly controlled symptoms (e.g. pain, nausea/vomiting, dyspnoea, fatigue)
Gastrointestinal causes (e.g. constipation, dyspepsia, oesophagitis, reflux)
Oral condition (e.g. oral thrush, dry mouth, taste changes)
Metabolic abnormalities (e.g. hypercalcemia)
Anaemia
Depression/ anxiety

Non-pharmacological management:

Educate patient and caregivers to manage expectations
Eat frequent, high calorie foods in small portions. Consider nutritional supplements if tolerated.
Loosen dietary restrictions (depends on clinical condition)
Eat with family and/or friends
Drink liquids between meals instead of with meals to avoid early satiety
Encourage physical activity as tolerated
Engage the help of others to prepare meals
Avoid foods that patients are averse to
Consider use of spices in seasoning
Attractive plating of food
Consider referral to dietician if appropriate

Pharmacological Management

Treat underlying cause if appropriate.
No medications specifically proven for its use in the chronic kidney disease population.

References

Symptom Assessment and Management. (2017, August). Retrieved February 01, 2018, from http://www.bcrenalagency.ca/health-professionals/clinical-resources/symptom-assessment-and-management
Supportive Care Guidelines for Patients with End Stage Renal Disease. (2017, June). Retrieved February 01, 2018, from https://www.thinkkidneys.nhs.uk/
Lexicomp. (2018). Lexi-CLINICAL SUITE [Online database]. Retrieved from http://online.lexi.com/lco/action/home/switch?siteid=129

Constipation

Definition: Passage of hard faeces infrequently and with difficulty

Causes:

Inadequate fluid and fibre intake (due to restrictions)
Physical inactivity
Medications (e.g. iron supplements, calcium-based phosphate binders, opioids etc)
Metabolic abnormalities (e.g. hypercalcaemia, hypothyroidism)
Depression

Non-pharmacological management:

Increase fluid and fibre intake (within the restrictions and where possible/ appropriate)
Increase physical activity where possible

Before initiating laxatives:
Exclude intestinal obstruction

Pharmacological Management:

Treat underlying cause if possible/ appropriate

Avoid:

Oral sodium phosphate (Fleet®), Sodium picosulfate (Picoprep®) (can cause fluid and electrolyte disturbances)
Ispaghula husk (Fybogel®) (must be taken with >250ml of water, not ideal for patients on fluid restriction and may exacerbate constipation if fluid intake is insufficient)
Mineral oil (impair absorption of fat-soluble vitamins and may cause aspiration pneumonia)
Sodium phosphate (Fleet®) enema and oral sodium phosphate (fleet®) in patient known to have high serum phosphate levels

Available Drugs	Dosing Regiment	Monitoring Parameters
Lactulose	5-10ml BD-TDS PRN Max: 60ml daily (in 2 to 3 divided doses)	Bowel output (BO) frequency
Senna 7.5mg tablet	1-2 tab ON-BD Max: 4 tabs BD
Bisacodyl 5mg tablet	5-10mg ON PRN Max: 15mg daily (3 x 5mg tab)
Bisacodyl 10mg suppository	10mg (1 supp) OD PRN
Glycerin 2g suppository	2g (1 supp) OD PRN
Olive oil enema (to soften impacted hard stools)	1 enema PRN
Macrogol 10g powder (polyethylene glycol [PEG])	Short term use for resistant constipation due to need for ~250ml water with each dose	BO frequency Fluid status
Colonic lavage mixture (PEG)	Use judiciously in small volume (250ml)	BO frequency Fluid status
Sodium chloride (Centa®) Enema	1 tube OD PRN	BO frequency

Treatment Algorithm

Reference

Symptom Assessment and Management. (2017, August). Retrieved February 01, 2018, from http://www.bcrenalagency.ca/health-professionals/clinical-resources/symptom-assessment-and-management
Chambers, E. J., Germain, M. J., & Brown, E. A. (2010). Supportive care for the renal patient. doi:10.1093/acprof:oso/9780199560035.001.0001
Lexicomp. (2018). Lexi-CLINICAL SUITE [Online database]. Retrieved from http://online.lexi.com/lco/action/home/switch?siteid=129

Sore or Dry Mouth

Causes:

Inadequate fluid intake (due to fluid restrictions)
Uraemia
Oral candidiasis
Medications (e.g. antihistamines, anticholinergics)

Non-pharmacological management:

Increase fluid intake (within the restrictions)
Suck on ice chips or sugar-free candies
Maintain good oral hygiene

Pharmacological Management:

Remove offending drug if appropriate.
Avoid alcohol-based mouth washes as they may cause further drying.

Available Drugs	Indication / Special Mention	Dosing Regiment
Oral 7® moisturizing gel		1-2cm of gel ON-TDS
Oral 7® moisturizing mouth wash		Gargle 10-15ml BD- TDS
Sodium bicarbonate mouth wash		5g of powder in 250ml water. Use as a gargle TDS-QDS PRN
Viscous lignocaine 2% solution	Indication: Mucositis Use with caution in patients with dysphagia as may worsen dysphagia	15ml Q3H PRN; may be swallowed Max dose is brand specific
Triamcinolone 0.1% oral paste	Indication: Mouth ulcer	1 application BD-QDS ≥30min before food or drink
Nystatin 100,000units/ml suspension	Indication: Thrush	5ml QDS, swish and maintain in mouth as long as possible before swallowing

References

End of Life Care in Advanced Kidney Disease. (2017, October). Retrieved February 01, 2018, from http://www.gloshospitals.nhs.uk/SharePoint75/Palliative%20Care%20Web%20Documents/SUPPORTIVE%20CARE%20FOR%20RENAL%20PATIENTS%20V5%20Oct%2017.pdf
Lexicomp. (2018). Lexi-CLINICAL SUITE [Online database]. Retrieved from http://online.lexi.com/lco/action/home/switch?siteid=129

Drowsiness / Somnolence

Definition: Inability to stay awake or alert throughout the course of the day, resulting in sleepiness or inadvertent dozing during daily activity.

Causes:

Uraemia
Medications (e.g. opioids, antihistamines, dopaminergic agents, gabapentin, pregabalin, selective serotonin reuptake inhibitors, tricyclic antidepressants)
Sleep disturbances from underlying conditions (e.g. sleep apnoea, restless legs syndrome, uncontrolled pain/ breathlessness) or poor sleep hygiene
Depression

Non-pharmacological management:

Practise sleep hygiene e.g. no caffeine after 12pm, regular sleep schedule and routine, peaceful sleep environment

Pharmacological Management:

Treat underlying cause if possible/ appropriate.

References

Maung, Stephanie C, et al. “Sleep and Neurologic Disorders in Chronic Kidney Disease.” World Journal of Nephrology, vol. 5, no. 3, 6 May 2016, pp. 224–232., doi:10.5527/wjn.v5.i3.224.
Symptom Assessment and Management. (2017, August). Retrieved February 01, 2018, from http://www.bcrenalagency.ca/health-professionals/clinical-resources/symptom-assessment-and-management
Lexicomp. (2018). Lexi-CLINICAL SUITE [Online database]. Retrieved from http://online.lexi.com/lco/action/home/switch?siteid=129

Itch / Generalised Pruritus

Causes:

Uraemia
Metabolic abnormalities (e.g. hypercalcaemia, hyperphosphatemia)
Medical conditions (e.g. cholestatic pruritus)
Haematological disorders (e.g. iron deficiency anaemia, polycythemia vera)
Skin conditions (e.g. eczema, psoriasis, scabies, contact dermatitis)
Allergic reaction (e.g. to drug)

Non-pharmacological management:

Keep fingernails short and clean. Avoid scratching
Avoid hot showers
Use fragrance-free soap for sensitive skin
Apply moisturiser immediately after shower & regularly every day
Apply cold compresses to itchy areas
Avoid wearing rough clothing/materials that irritate the skin
Use mild detergent for clothes and sheets
Ultraviolet B light therapy

Points to note:
1. Consider referral to dermatologist for diagnosis and management if there are skin lesions or changes to suggest underlying dermatological conditions
2. Rule out allergic reaction

Pharmacological Management:

Treat underlying cause

Avoid

Lotions (lower concentration of lipids than creams or ointments)
Excessive, prolonged use of topical steroids (thinning of skin can aggravate pruritus)

Suggested Topicals and Drugs	Indication/ Special Mention	Dosing Regimen^	Side Effects
Emulsifying ointment	Advise patients to apply liberally on body and limbs TDS and after bath, rubbing in the cream from proximal to distal direction	OD-BD for bath
Cetaphil® cleanser		OD-BD for bath
Aqueous cream		TDS PRN
QV® cream		BD-TDS
Suubalm® cream		BD-TDS	May have unpleasant burning sensation for people who cannot tolerate menthol
Hydrocortisone 1% cream	Minimise duration. Limit use to only localised pruritus in inflammatory skin conditions	TDS-QDS PRN
Betamethasone valerate 0.025%, 0.05%, 0.1% cream/ointment		BD PRN	Prolonged use of high potency can lead to skin atrophy, telangiectasia, striae, acne, HPA suppression
Loratadine 10mg tablet	Higher frequency of OD used in practice generally well-tolerated	10mg EOD	Watch for headache, but generally well-tolerated
Fexofenadine 180mg tablet	Higher frequency of BD used in practice generally well-tolerated	180mg OD	Watch for headache, but generally well-tolerated
Chlorpheniramine 4mg tablet	Indication: allergies, skin conditions For itch due to other causes, consider use at night to reduce scratching	4mg ON-TDS PRN Max: 24mg/day (3-6 divided doses)	Somnolence, dry mouth
Hydroxyzine 10mg, 25mg tab		10mg ON-QDS PRN or 25mg ON-TDS PRN Max: 100mg/day (3 to 4 divided doses, may consider maximum of 50mg/day)	Somnolence, dry mouth
Gabapentin 100mg capsule	Indication: Uraemic itch 1st line if patient has concomitant neuropathic pain, restless legs syndrome	100mg ON Max: dose up to 300mg/day may be attempted	Drowsiness, dizziness
Pregabalin 25mg, 75mg		25-75mg ON Max: 75mg/day (as a single or 2 divided doses)	Drowsiness, dizziness
Doxepin 10mg, 25mg	Indication: Uraemic itch 1st line if patient has concomitant depression	10mg TDS or 10-30mg ON	Antihistaminergic side effects, fatigue, extrapyramidal reaction
Sertraline 25mg tablet		25mg-50mg ON (higher doses needed for concomitant depression)	Insomnia or drowsiness, serotonin syndrome
Mirtazapine	Indication: Uraemic itch 1st line if patient has concomitant depression Useful for patients with poor appetite or insomnia	15mg ON	Drowsiness, dry mouth
Montelukast 10mg tablet	Indication: Uraemic itch (last line)	10mg OM	Generally well-tolerated
Tacrolimus 0.03% ointment	Effective on facial areas e.g. perioral and periorbital	Apply thin layer BD	May have burning sensation, erythema, rash

Treatment Algorithm

References

Scherer, J. S., Combs, S. A., & Brennan, F. (2017). Sleep Disorders, Restless Legs Syndrome, and Uremic Pruritus: Diagnosis and Treatment of Common Symptoms in Dialysis Patients. American Journal of Kidney Diseases, 69(1), 117-128. doi:10.1053/j.ajkd.2016.07.031
Combs, S. A., Teixeira, J. P., & Germain, M. J. (2015). Pruritus in Kidney Disease. Seminars in Nephrology, 35(4), 383-391. doi:10.1016/j.semnephrol.2015.06.009
Chambers, E. J., Germain, M. J., & Brown, E. A. (2010). Supportive care for the renal patient. doi:10.1093/acprof:oso/9780199560035.001.0001
Symptom Assessment and Management. (2017, August). Retrieved February 01, 2018, from http://www.bcrenalagency.ca/health-professionals/clinical-resources/symptom-assessment-and-management
Supportive Care Guidelines for Patients with End Stage Renal Disease. (2017, June). Retrieved February 01, 2018, from https://www.thinkkidneys.nhs.uk/
Davison, S. N., Levin, A., Moss, A. H., Jha, V., Brown, E. A., Brennan, F et al. (2015). Executive summary of the KDIGO Controversies Conference on Supportive Care in Chronic Kidney Disease: developing a roadmap to improving quality care. Kidney International, 88(3), 447-459. doi:10.1038/ki.2015.110
Siemens,W., Xander, C., Meerpohl,J. J., Buroh, S., Antes, G., Schwarzer, G. , & Becker, G. (2016). Pharmacological interventions for pruritus in adult palliative care patients. Cochrane Database of Systematic Reviews. doi:10.1002/14651858.cd008320.pub3
Lexicomp (2018). Lexi-CLINICAL SUITE [Online database]. Retrieved from http://online.lexi.com/lco/action/home/switch?siteid=129
Gholyaf,M., Sheih, V., Yasrebifar,F. et al. (2020). Effect of mirtazapine on puritus in patients on haemodialysis a cross-over pilot study. Int Urol Nephrol, 52, 1155-1165. doi: 10.1007/s11255-020-02473-3
Mohammadi, Y., Gholyaf,M., Sheikh, V. et al. (2020). Evaluation of Efficacy of Mirtazapine on Pruritus and Serum Histamine and Serotonin Levels in Patients Undergoing Haemodialysis: A Before-After Pilot Clinical Trial. Int J Nephrol Renovasc Dis, 13, 129-138. doi: 10.2147/IJNRD.S246393

Poor Sleep / Difficulty Sleeping

Includes: Insomnia, poor quality sleep

Causes:

Poor sleep hygiene
Poorly controlled symptoms (e.g. pain, pruritus, dyspnoea, nocturia)
Restless Legs Syndrome
Obstructive sleep apnoea
Medications (e.g. steroids, antidepressants, pseudoephedrine)
Depression/ anxiety

Non-pharmacological management:

Avoid caffeine after lunch
Avoid alcohol and smoking, especially in the evening
Avoid eating a large meal close to bedtime
Practise sleep hygiene
Promote physical activity
Consider relaxation techniques (e.g. breathing exercises)

Pharmacological Management:

Treat underlying cause

Available Drugs	Dosing Regiment	Comments
Zopiclone 7.5mg tablet	Max: 3.75mg ON	Look out for excessive sedation
Zolpidem CR 6.25mg, 12.5mg tablet	6.25mg-12.5mg ON PRN Max: 12.5mg ON
Melatonin 2mg tablet	2mg (1-2hr before bedtime)
Short-acting benzodiazepine (e.g. lorazepam 1mg tablet)	PO 0.5mg-1mg ON PRN. Max doses as below: <65 years old: 2mg ON ≥65 years old: 1mg ON

Treatment Algorithm

References

Symptom Assessment and Management. (2017, August). Retrieved February 01, 2018, from http://www.bcrenalagency.ca/health-professionals/clinical-resources/symptom-assessment-and-management
Supportive Care Guidelines for Patients with End Stage Renal Disease. (2017, June). Retrieved February 01, 2018, from https://www.thinkkidneys.nhs.uk/
Davison, S. N., Levin, A., Moss, A. H., Jha, V., Brown, E. A., Brennan, F et al. (2015). Executive summary of the KDIGO Controversies Conference on Supportive Care in Chronic Kidney Disease: developing a roadmap to improving quality care. Kidney International, 88(3), 447-459. doi:10.1038/ki.2015.110
Lexicomp. (2018). Lexi-CLINICAL SUITE [Online database]. Retrieved from http://online.lexi.com/lco/action/home/switch?siteid=129

Restless Leg Syndrome (RLS)

Clinical features:

Characterized by urge to move legs that may be accompanied by uncomfortable or unpleasant sensations in the legs
Worsens during period of rest or inactivity
Partially or totally relieved with movements
Worse in the evening or night

It is a diagnosis of exclusion after excluding other medical or behavioral condition (e.g. myalgia, venous stasis, leg oedema, leg cramp, positional discomfort, habitual foot tapping).

Definitions:
Intermittent: bothersome symptoms that require treatment, on average occur less than twice per week
Chronic persistent: frequent and bothersome symptoms that require daily treatment, on average occur at least twice per week
Augmentation: drug-induced worsening of RLS (earlier onset, spread of symptoms to the arms, worsening of symptoms with dose increase, shorter effect of medication)
Refractory: Unresponsive to monotherapy of first-line agents due to adverse effects, augmentation or efficacy reduction

Causes:

Iron deficiency
Uraemia
Hypoparathyroidism, hyperphosphataemia
Sleep deprivation
Medications
- antipsychotics (e.g. quetiapine)
- antidepressants (selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants [TCAs], mirtazapine)
- carbamazepine
- lithium
- beta blockers
- first-generation antihistamines
- dopamine-receptor antagonists (e.g. metoclopramide)
- calcium channel blockers

Non-pharmacological management:

Take warm or cool showers. Apply warm towel/ heating pad or cold compresses.
Stretch and/or massage legs. May consider pneumatic compressions
RLS during the day: listen to quiet, calming music or do activities that help relax or take mind away from the feelings of restlessness (e.g. doing puzzles)
RLS at night: practice sleep hygiene
Avoid or limit intake of caffeine, alcohol and nicotine
Engage in physical activities during the day to help with sleep at night
Engage in mental activities such as video games and crossword puzzles
Practice good sleep hygiene

Pharmacological Management:

Treat underlying cause if possible/ appropriate

Available Drugs	Dosing Regiment	Side Effects
Credanil 125mg (levodopa 100mg/carbidopa 25mg) Sinemet CR 250mg (levodopa 200mg/carbidopa 50mg) tablet	Levodopa 100mg-200mg/day (increased risk of augmentation at ≥200mg/day)	Orthostatic hypotension (increased risk of falls), dizziness, weakness, insomnia, peripheral edema, cardiac arrhythmia, psychosis, augmentation
Codeine 30mg tablet	30-90mg before bed	Constipation, nausea
Tramadol 50mg tablet	50-100mg before bed	Constipation, nausea, occasionally associated with augmentation
Zopiclone 7.5mg tablet	Max: 3.75mg ON	Look out for excessive sedation
Zolpidem CR 6.25mg, 12.5mg tablet	6.25mg-12.5mg ON PRN Max: 12.5mg ON
Benzodiazepine (e.g. lorazepam 1mg tablet)	PO 0.5mg-1mg ON PRN. Max doses as below: <65 years old: 2mg ON ≥65 years old: 1mg ON
Gabapentin 100mg, 300mg capsule	100mg ON (up to 300mg/day)	Drowsiness, dizziness
Pregabalin 25mg, 75mg capsule	25-75mg ON Max dose: 75mg/day (as a single or 2 divided doses)	Drowsiness, dizziness
Ropinirole 0.25mg, 1mg, 2mg tablet	Start at 0.25mg ON (1-3hr before bedtime), may be increased after 2 days to 0.5mg daily, and after 7 days to 1 mg daily. Dose may be further titrated upward in 0.5 mg increments every week until a daily dose of 3mg during week 6 as tolerated and needed. Max dose: 3mg/day Taper dose if withdrawing treatment	Nausea, fatigue, giddiness More likely to have orthostatic hypotension but less risk for augmentation compared to levodopa Sleep attacks may be a class effect especially at higher doses; driving not recommended. Reduce dose immediately if sleep attacks occur. Risk for impulse control disorder (average onset: 9 months) For patients who require twice daily regimen (e.g. in mild augmentation), first dose may be taken in the late afternoon or early evening. Do not discontinue abruptly.
Pramipexole 0.125mg tablet	0.125mg 2-3hours before bedtime. Double dose every 14 days up to 0.5mg. Attempt up to 0.75mg cautiously as population of CrCl<20 was not studied. Dose earlier, divide into multiple evening doses or increase dose if augmentation occurs. (Gradual reduction every 4-7 days on discontinuation) *risk of possible accumulation

Treatment Algorithm

References

Silber, M. H., Buchfuhrer, M. J., Earley,C. J., Koo, B. B., Manconi, M., Winkelman, J. W., & Scientific and Medical Advisory Board of the Restless Legs Syndrome Foundation. (2021). The Management of Restless Legs Syndrome: An Updated Algorithm. Mayo Clinic proceedings, 96(7), 1921-1937. doi: 10.1016/j.mayocp.2020.12.026
Giannaki, C. D., Hadjigeorgiou, G. M., Karatzaferi, C., Pantzaris, M. C., Stefanidis, I., & Sakkas, G. K. (2014). Epidemiology, impact, and treatment options of restless legs syndrome in end-stage renal disease patients: an evidence-based review. Kidney International, 85(6), 1275-1282. doi:10.1038/ki.2013.394
Sahli, Z. T., Jo, J., Mousa, S. A., & Tarazi, F. I. (2017). Clinical management of restless legs syndrome in end-stage renal disease patients. CNS Spectrums, 22(01), 14-21. doi:10.1017/s109285291600064x
Novak, M., Winkelman, J. W., & Unruh, M. (2015). Restless Legs Syndrome in Patients With Chronic Kidney Disease. Seminars in Nephrology, 35(4), 347-358. doi:10.1016/j.semnephrol.2015.06.006
Scherer, J. S., Combs, S. A., & Brennan, F. (2017). Sleep Disorders, Restless Legs Syndrome, and Uremic Pruritus: Diagnosis and Treatment of Common Symptoms in Dialysis Patients. American Journal of Kidney Diseases, 69(1), 117-128. doi:10.1053/j.ajkd.2016.07.031
Chambers, E. J., Germain, M. J., & Brown, E. A. (2010). Supportive care for the renal patient. doi:10.1093/acprof:oso/9780199560035.001.0001
Symptom Assessment and Management. (2017, August). Retrieved February 01, 2018, from http://www.bcrenalagency.ca/health-professionals/clinical-resources/symptom-assessment-and-management
Davison, S. N., Levin, A., Moss, A. H., Jha, V., Brown, E. A., Brennan, F et al. (2015). Executive summary of the KDIGO Controversies Conference on Supportive Care in Chronic Kidney Disease: developing a roadmap to improving quality care. Kidney International, 88(3), 447-459. doi:10.1038/ki.2015.110
Lexicomp. (2018). Lexi-CLINICAL SUITE [Online database]. Retrieved from http://online.lexi.com/lco/action/home/switch?siteid=129

Skin changes specific to advanced Chronic Kidney Disease (CKD)

Type of Skin Changes	Description	Pathogenesis	Management
Acquired perforating dermatosis	• Moderate-severe pruritus • Pruritic, firm, dome-shaped papules or nodules with central keratotic plug on extensor surfaces of extremities and trunk	Unknown	Topical • Clobetasol propionate 0.025% cream and/or keratolytic (salicylic acid, urea) • Betamethhasone 0.1% ointment • Tretinoid cream Oral • Antihistamines • Allopurinol • Doxycycline • Acitretin
Porphyria cutanea tarda	Vesicular/ bullous eruptions on skin and/or mucous membranes	Accumulation of photosensitive molecules in the skin that lead to skin fragility and vesiculation on ultraviolet light exposure	• Avoiding triggers (alcohol, hepatotoxic medications, sun exposure) • Use sunscreen • Decreasing iron overload
Metastatic calcification	Calcinosis Cutis (CC): firm white papules/ plaques and nodules in periarticular areas and fingertips Calcific uremic arteriolopathy (CUA), also known as calciphylaxis: thrombosis of calcified small and medium sized arteries and arterioles, fibrosis commonly affecting the dermis and subcutaneous fats. Distributed bilaterally, symmetrically and commonly in lower extremities, abdomen, buttocks	Deposition of calcium salts into the cutaneous and/or subcutaneous tissues as a result of elevated levels of calcium and phosphate CUA: Unknown but multifactorial.	CC: correct serum phosphate levels. Local excision or laser for smaller lesions. CUA: correct serum calcium, phosphate, iPTH levels. Pain management. Consider IV or intralesional sodium thiosulphate (refer to respective section in this guideline for details) Consider a dermatologist consult if needed.
Nephrogenic systemic fibrosis	• Scleroderma-like disorder • Initially, severely painful, symmetrical erythema and oedema • Lesions (sclerodermatous and erythematous skin induration with firm papules/ plaques and nodules) with symmetrical distribution on lower extremities, less on arms and trunk • Can have hyper- or hypopigmentation of skin, skin thickening and swelling, especially of hands • Progression of skin fibrosis can lead to flexion contractures	Related to gadolinium-based contrast agents exposure and presence of concomitant triggering event (vascular injury, infection, high-dose erythropoietin therapy)	Long term avoidance of gadolinium-based contrast agents. Limited benefit: oral corticosteroids, sirolimus, methotrexate, pentoxifylline, high-dose intravenous immunoglobulin, plasmapheresis, ultraviolet A phototherapy Consider a

Reference:

Galperin, T. A., Cronin, A. J., & Leslie, K. S. (2014). Cutaneous Manifestations of ESRD. Clinical Journal of the American Society of Nephrology, 9(1), 201-218. doi:10.2215/cjn.05900513

Diarrhoea

Definition: Passage of >3 unformed stools in a day

Causes

Spurious/ overflow diarrhoea secondary to constipation or intestinal obstruction
Medications (e.g. antibiotics, laxatives)
Infection (e.g. clostridium difficile infection, gastroenteritis)
Uraemia
Drugs (e.g. resonium)
Irritable bowel syndrome
Malabsorption

Non-pharmacological management:

Stop existing laxatives (if any) except if its spurious diarrhoea from constipation
Adequate rehydration
Replacement of electrolytes
Avoid spicy and fatty food, milk and lactose-containing products
Consume simple carbohydrates such as crackers

1. Work up for underlying infectious causes if:
i. Patient is febrile
ii. Presence of bloody stools
iii. Persistent diarrhoea for ≥2 days
2. Avoid anti-diarrhoeals if cause is constipation, intestinal obstruction, or infectious diarrhoea

Pharmacological Management:

Treat underlying cause if possible/ appropriate

Available Drugs	Dosing Regiment	Side Effects
Oral rehydration salts (ORS)	1 sachet in 250ml water BD-TDS	Fluid overload, electrolyte abnormalities
Charcoal 250mg tablet	2 tab TDS-QDS PRN	Constipation
Kaolin mixture	15ml 4-8x/day (generally given as 10ml TDS)
Smecta powder 3g	3g TDS (max 18g/day in the acute initial phase)
Lacteol Forte capsules or sachets	2 cap BD, 4 cap may be given for 1st dose 1 sachet BD, 2 sachets may be given for 1st dose
Loperamide 2mg tablet	16mg/day (max dose) (In acute diarrhoea: 4mg then 2mg after each episode In chronic diarrhea: 2-3 divided doses)
Lomotil (diphenoxylate 2.5mg, atropine 0.025mg) tablet	2 tab QDS	Constipation, urinary retention, sedation, hallucinations, confusion

References

Alderman, J. (2005). Diarrhea in Palliative Care. Journal of Palliative Medicine, 8(2), 449-450. doi:10.1089/jpm.2005.8.449
Diarrhoea. (n.d.). Retrieved February 04, 2018, from http://www.palliativecareguidelines.scot.nhs.uk/guidelines/symptom-control/Diarrhoea.aspx
Lexicomp. (2018). Lexi-CLINICAL SUITE [Online database]. Retrieved from http://online.lexi.com/lco/action/home/switch?siteid=129

Workgroup

Dr Sim Mui Hian
Principal Clinical Pharmacist, Department of Pharmacy
Singapore General Hospital

A/Prof Jason Choo Chon Jun
Senior Consultant, Department of Renal Medicine
Singapore General Hospital

Dr Kwek Jia Liang
Consultant, Department of Renal Medicine
Singapore General Hospital

Dr Alethea Yee
Senior Consultant, Division of Supportive and Palliative Care
National Cancer Centre Singapore

Dr Peh Tan Ying
Senior Consultant, Division of Supportive and Palliative Care
National Cancer Centre Singapore

Dr Lee Guozhang
Consultant, Department of Internal Medicine
Singapore General Hospital

Dr Lee Puay Hoon
Senior Principal Clinical Pharmacist, Department of Pharmacy
Singapore General Hospital

The workgroup would like to thank Dr Oh Choon Chiat (Consultant, Department of Dermatology, Singapore General Hospital) for his input on the section on Itch and Skin Changes secondary to advanced CKD.