อ.เอกลักษณ์ Symptom burden in HD patient pdf

Symptoms Burden in Dialysis Patients: Tip of the Iceberg Eakalak Lukkanalikitkul M.D. Nephrology department, Srinagarind hospital, Khon Kean University

Scope • Prevalence of symptoms in dialysis patients • Symptom assessment in kidney disease patients • Clinical impact from symptom burden • Symptom management • Restless legs syndrome • Muscle cramp • Dialysis headache • Uremic pruritis • Sleep disorder • Depression • Pain

Weakness Fatigue Nausea and Pruritis Vomiting Cramps Anorexia Insomnia

Burden of symptoms across progressive of CKD Nature Reviews Nephrology volume 18 | March 2022

Symptoms of advanced kidney disease Organ system Symptoms Constitutional Neurological Fatigue or generalized weakness Gastrointestinal Decreased memory and concentration Musculoskeletal Myotonic jerks or seizures Dermatological Altered smell and taste Sexual Peripheral neuropathy Sleep disturbances and restless leg syndrome Psychological Anorexia Nausea and Vomiting Bone pain and arthropathy Muscle cramps Pruritus Amenorrhea, Sexual dysfunction Infertility Depression and anxiety Sara Davison and David Hui. Kidney Palliative Care. Oxford American Handbook of Hospice and Palliative Medicine and Supportive Care, 2016

Prevalence of symptoms in advanced CKD patients Prevalence of symptoms in ESRD • Patients with advanced kidney disease experience a high frequency of physical and psychological symptoms, comparable to patients with cancer. • Patients under report symptoms unless asked explicitly about them, that impact on patient’s burden, physical function, and QoL. • There is evidence that nephrologists underrecognize and undertreat these symptoms. EDTNA|ERCA JOURNAL 2006 XXXII 2

Prevalence of symptoms of CKD in Srinagarind Hospital อาการไมส่ ุขสบายของผูป้ ่ วย Palliative care 60 50 40 คล่นื ไสอ้ าเจียน 30 ทอ้ งผกู 20 นอนไมห่ ลบั 10 RLS คนั 0 โครงการพฒั นางาน: การพฒั นาระบบการดแู ลผปู้ ่ วยไตวายระยะสดุ ทา้ ยที่รกั ษาแบบ Conservative treatment โรงพยาบาลศรีนครินทร์

Barriers to Symptom Management HCPs are unaware of symptoms HCP (N=34) Caregiver (N=20) • Patient resignation leads to underreporting • Dialysis environment is not conducive to privacy 14 (41%) 8 (40%) • Inadequate time for patient to report 6 (17%) 4 (20%) • Variable symptomatology based on timing in relation to dialysis 7 (21%) 1 (5%) • Patients do not know who to report symptoms to 5 (15%) 4 (12%) - HCPs do not feel symptom management is their role - • Better adherence to current hemodialysis prescription would ameliorate 15 (44%) 2 (10%) symptoms 12 (35%) • Only symptoms related to dialysis should be treated by renal team 5 (15%) - • Reluctance to dispense narcotics and psychiatric medications - 16 (47%) Symptom management is difficult in the HD population 14 (34%) 6 (30%) • Symptoms are an unavoidable outcome of dialysis 13 (38%) 4 (20%) • Patients are resistant to longer treatments necessary to palliate symptoms 7 (21%) 7 (35%) • Time constraints/inadequate staffing 4 (12%) 1 (5%) • Financial considerations 1 (5%) • Scarce outpatient palliative care services JOURNAL OF PALLIATIVE MEDICINE Volume 16, Number 12, 2013

IdAeddastitfloe rteIxmt provement HCP Caregiver (N=34) (N=20) Dedicated programs for patient education 15 (44%) 4 (20%) Improved systems for communication with other disciplines 10 (29%) 1 (5%) Promote life outside dialysis 6 (18%) 6 (30%) Make dialysis time more productive 5 (15%) 3 (15%) Time with care providers away from the chairside 3 (9%) 1 (5%) JOURNAL OF PALLIATIVE MEDICINE Volume 16, Number 12, 2013

Symptom assessment • Regular symptom assessment using validated tools helps redirect treatment toward a patient-centered care model and provides the opportunity for discussions about appropriate supportive care options that should be incorporated into routine clinical practice. • Validated global symptom assessment tools for CKD patients including • Edmonton Symptom Assessment System-revised: Renal (ESAS-r: Renal) • Integrated Palliative Care Outcome Scale–Renal (IPOS-Renal) • Dialysis Symptom Index (DSI) Kidney International (2015) 88, 447–459

Tools for symptom appraisal in CKD Nature Reviews Nephrology volume 18 | March 2022



• The burden of symptoms at baseline was high prevalence ranged from 15-66%. • The most common symptoms • Lack of energy (66%) • Poor mobility (58%) • Trouble sleeping (53%) • Pain (47.5%) • The median number of symptoms experienced was 7/17 (IQR: 4-10). • 49% of patients experiencing at least 1 symptom they classified as severe or overwhelming. • Observational study of 160 prevalent dialysis patients. • Palliative care Outcome Scale symptom (POS-renal) at baseline and follow-up (median 3 months) Journal of Palliative Care 2020, Vol. 35(1) 59-65

Symptom prevalence at baseline and F/U • Individual symptoms newly occurred in 8-20% of patients, with 77% experiencing at least 1 new symptom. • Patients rating at least 1 symptom as severe or overwhelming was reduced from 49% → 39% (P = 0.040). Journal of Palliative Care 2020, Vol. 35(1) 59-65

Patient-reported outcomes in Dialysis patients Symptom Prevalence Clinical impact Fatigue 60-97% Depression • Reduced sleep quality Anxiety 22.8% (Interview) • Poor QOL 39.3% (Self-report scales) • Increased CVD, hospitalization and all-cause mortality Cramps 42% Pain • Non-adherence to dialysis 24-86% • Lower HR-QOL 60.5% (Chronic pain) • Increased mortality and hospitalizations • Increased risk of functional symptoms such as depression; • Affects mineral bone metabolism (decreased PTH) • Decreased perceived QOL and vitality levels • Increased length of hospitalization • Reduced quality of dialysis (reduced time or interruptions) • Reduced QOL • Reduced QOL • Insomnia and depression Nature Reviews Nephrology 18, 378–395 (2022)

Patient-reported outcomes in Dialysis patients Symptom Prevalence Clinical impact Pruritus 42% (moderate-extreme) • Poor sleep Restless legs 12-62% • Depression syndrome • Reduced QOL 75% (male) • Increased mortality Sexual dysfunction 29.7% (female) Sleep quality 49% • Sleep disturbances • Premature withdrawal from dialysis • Decreased QOL • Increased CVD morbidity and mortality • Decreased QOL • Increased CVD morbidity and mortality. • Decreased QOL • Increased CVD and mortality Nature Reviews Nephrology 18, 378–395 (2022)

PLOS Medicine April 6, 2022

PLOS Medicine April 6, 2022

Dialysis-related issues that affect health-related QOL Peritoneal Dialysis Hemodialysis • Peritoneal access issues • Daily dialysis routine • Vascular access issues • ≥ 3times per week treatment • Glucose control • Transportation to hemodialysis unit • Weight gain • Ultrafiltration problems • Post-dialysis recovery time • Recurrent hypotension • Exit site infections • Myocardial stunning • Peritonitis • Cerebral ischemia • Encapsulating peritoneal • Sepsis sclerosis • Endotoxemia JOURNAL OF PALLIATIVE MEDICINE Volume 16, Number 12, 2013

Symptom Management • In general, the approach to symptom management should involve: • Evaluation for cause and reversible factors • Level of distress or dysfunction caused by symptoms • Non-pharmacologic and pharmacologic intervention options • Expectation management • Acknowledgement of limitations of therapy • First-line treatment includes nonpharmacological interventions and then advancing to more complex therapies. • Second-line treatment is pharmacologic therapy. Consideration should be given to low-dose pharmacological therapy that may have efficacy across several symptoms. Am J Kidney Dis. 2020, 75(5):793-806

Symptom clusters defined as ≥ 2 related concurrent symptoms Journal of Nephrology (2022) 35:1427–1436

Restless Legs Syndrome • Restless Legs Syndrome (RLS) is a neurologic sensorimotor disorder • Common in 3 groups 1. Hereditary (40% AD), 2. 3rd trimester pregnancy, 3. ESKD • The diagnostic criteria for RLS, as determined by the International RLS Study Group (IRLSSG) 1. An irresistible impulse to move one’s legs, often accompanied by unpleasant sensations in lower limbs 2. Such urges or sensations start or are made worse by periods of inactivity 3. Such urges or sensations are partly or completely relieved with movement 4. Such urges or sensations are more severe in the evening or at night than during daytime 5. The clinical criteria are not caused by any other medical or behavioral condition that can possibly mimic restless legs syndrome (myalgia, venous stasis, leg cramps) Am J Kidney Dis. 2017 Jan;69(1):117-128.

Restless Legs Syndrome Dopaminergic cell group A-11 Tyrosine hydroxylase (with Fe+) In RLS loss of A-11 dopaminergic inhibition results in • increased sensory input to cortex (uncomfortable sensations or urge to move) • increased sensory activation of the spinal cord reflex arc • increased sympathetic activity

Restless Legs Syndrome Iron deficiency and RLS

Restless Legs Syndrome Management strategies Non-Pharmacologic Treatment • Intradialytic pedaling or exercise, leg massage Pharmacologic Treatment • Gabapentinoids: Inhibition of glutamate release • Gabapentin 100 mg o hs EOD titrate to 300 mg/day • Pregabalin 25 mg o hs EOD titrate to 50 mg/day • Dopaminergic drug: levodopa, non-ergot dopamine receptor agonists • Ropinirole 0.5 mg o hs OD titrate to 2 mg/day • Adverse effects: nausea, light headedness, and fatigue (reversible) • Long-term use carries risk for augmentation of symptoms. • Opioids: treat refractory idiopathic RLS • Iron supplementation: IV dextran improved RLS symptom Am J Kidney Dis. 2017 Jan;69(1):117-128.

Muscle cramps • Pathogenesis is unknown • Four most important predisposing factors (→ vasoconstriction) • Hypotension ● Hypovolemia (patient below dry weight) • High ultrafiltration rate ● Use of low-sodium dialysis solution vasoconstriction → Muscle hypoperfusion → Impairment of muscle relaxation • Muscle cramps most commonly occur in association with hypotension. Cramping increases logarithmically with weight loss weight losses of 2% → Cramping frequencies 2% 4% → 26% 6% → 49%

Muscle cramps • Hypomagnesemia, Hypocalcemia and Hypokalemia may precipitate cramping or may cause treatment-resistant muscle cramping • Prevention • Raising dialysate sodium levels and avoid low predialysis levels of magnesium, calcium, and potassium • Stretching exercises (first-line treatment) • Sequential compression devices • Medication: Quinine, Biotin , Carnitine, Oxazepam, Vitamin E, Gabapentin. • Quinine • Decreases excitability of motor end plate → reduces muscle contractility • 325 mg at nights or 2 hours before HD for 10 days (FDA not approved) • Adverse events: cardiac arrhythmias, severe allergic reactions, TTP-HUS. • Carnitine • Carnitine removed by dialysis → deficiency associate with muscle cramps • 20 mg/kg IV after HD or 330 mg oral two to three times per day Eur J Gen Med 2015;12(3):277-281

Dialysis headache (DH) Symptoms characteristics - Bifrontal discomfort (throbbing) - Nausea with or without vomiting - Aggravated by supine position - No accompanying visual disturbances The following International Headache Society (IHS) diagnostic criteria are proposed: • A. At least three attacks of acute headache fulfilling criteria C and D • B. Patient is on hemodialysis • C. Evidence of causation demonstrated by at least two of the following: • 1. Each headache developing during a hemodialysis session • 2. At least one of the following: • a) Each headache worsening during the dialysis session • b) Each headache resolving within 72 hours after the end of the dialysis session • 3. Headache episodes cease altogether after successful KT and termination of hemodialysis • D. Not better accounted by another diagnosis according to the International Classification of Headache Disorders, 3rd edition. Headache 2017 Jan;57(1):161-164.

Dialysis headache (DH) • The pathophysiology of DH has not yet been fully elucidated that might associated with - Caffeine withdrawal (removed during dialysis) - Acetate dialysate - Intradialytic hypo/hypertension - Hard water syndrome - Contaminated dialysate (Fluoride, Chloramine) - Dialyzer reaction - Hypomagnesemia -> ↓ brain mitochondria ATP -> release nociceptive transmission Management • Acute treatment: Oral analgesics (acetaminophen), avoid Ergot alkaloids → AVF dysfunction • Prevention • Bicarbonate dialysate • Slow dialysis with reduced blood flow rates • Sodium profile and or Ultrafiltration profile • Coffee ingestion during dialysis • Medication: chlorpromazine, ACEI, nortriptyline and magnesium oxide. Headache 2017 Jan;57(1):161-164.

Uremic Pruritus • Uremic Pruritis (UP) is common in kidney disease patients that influence mood, sleep quality, overall HR-QOL and mortality rate (increase 17% in HD patients). • Pathogenesis: uremic alterations in the immunochemical milieu in skin → sensation of itch is transmitted by unmyelinated C-fibers which a minority (10%) are histaminergic, and a majority (90%) are histamine-independent. Am J Kidney Dis. 2020, 75(5):793-806

Uremic Pruritis • Patient characteristics and dialysis parameters which may associated with Uremic pruritis - Older age - Male sex - Current or recent smoking - Underlying depression. - Hepatitis C virus positivity - Higher serum CRP levels - Higher serum Ca and/or PO4 levels - Low serum albumin levels - Elevated ferritin levels - Lower dialysis adequacy • The distribution of UP is almost always in large discontinuous bilateral skin areas involving the arms, legs, face and torso. • The most common skin finding is normal epidermis, with possible dryness or superficial excoriations. Presence of a rash suggests a primary dermatologic condition and warrants referral to dermatology Am J Kidney Dis. 2017 Jan;69(1):117-128.

Uremic Pruritus Management strategies: • Assess for modifiable contributing factors: anemia, hypercalcemia, hyperphosphatemia, xerosis, allergies, contact dermatitis. • Promote good skin care: • Avoid soap, but if used, use gentle soap; keep skin cool by wearing light and cool cloths • Avoid excessive bathing or bathing in hot water. • Avoid scratching – keep fingernails short and encourage massage rather than scratching • Topical agent • Tropical moisturizers are first-line treatment, if dry skin persists, substitute for oil- based moisturizer or Baby oil. • For localized itch, Capsaicin 0.025% combine with Menthol 3% 2-4 times daily (can cause burning) or Gamma-linolenic acid 2.2% apply bid. ANZSN Renal Supportive Care Guidelines 2013 Clin J Am Soc Nephrol 11: 1882–1891, 2016

Uremic Pruritus Management strategies: • Oral agents • Gabapentinoids (first line) • Gabapentin 100 mg o hs EOD up-titration to 100 mg o bid (200 mg/day) • Pregabalin 25 mg o hs EOD up-titration to 25 mg o bid (50 mg/day) • Evening Primrose Oil 1-2 capsules o bid. • Sertraline (second line) 50 mg o daily • Doxepin (second line) 10mg o hs up-titration to 10 mg o bid • Ultra-Violet B therapy: For refractory patients which requires a referral to Dermatologist ANZSN Renal Supportive Care Guidelines 2013 Clin J Am Soc Nephrol 11: 1882–1891, 2016

Itch intensity WI-NRS Outcomes Itch-Related QoL Outcomes Study Design: In KALM-1 and KALM-2, multicenter 1:1 RCT IV difelikefalin or placebo 3 times/wk for 12 weeks, followed by 52-week open-label extension. Intervention: IV difelikefalin at 0.5 mcg/kg (selective κ-opioid receptor agonist) or placebo. Outcomes: Itch intensity (WI-NRS) and itch related QoL (Skindex-10 and 5-D Itch questionnaires). Kidney Med. 2022; 4(8):100512

Sleep disorders • The International Classification of Sleep Disorders 3rd Edition (ICSD-3) defines insomnia as: • Difficulty initiating sleep, maintaining sleep, or waking up too early • Presence of these symptoms despite adequate opportunity for sleep • Day-time deficits. • Chronic insomnia occurs for 3 months with symptoms at least 3 times per week. • Acute insomnia lasts less than 3 months and typically is linked to a life event or stressor • The pathophysiology of insomnia remains elusive → imbalance of processes that either promote or inhibit sleep or wakefulness. • A small study showed that elevated phosphorus and serum urea nitrogen concentrations before dialysis were associated with a subjective decrease in sleep efficiency Am J Kidney Dis. 2017 Jan;69(1):117-128.

Sleep disorders Management strategies: • Assess for modifiable contributing factors: RLS, pruritus, pain, dyspnea, mood disorders and OSA. • Nonpharmacologic therapy (first management): • Exercise or having some physical activity during the day • Promote good sleep hygiene: • Avoid napping during the day • Avoid stimulants such as caffeine, alcohol and nicotine in the evening • Avoid TV and electronic devices in the evening • Avoid excessive fluid intake in the evening to minimize nocturia • Pharmacologic therapy: • Low dose gabapentin starting at 50–100 mg PO hs EOD titrate to effect • Benzodiazepines: lorazepam 0.5-1 mg, diazepam 2-5 mg, midazolam 7.5-15 mg PO hs • Antidepressants: amitriptyline, nortriptyline 10-25 mg PO hs • Melatonin 2 mg PO hs (limited data on long term efficacy) Clin J Am Soc Nephrol 11: 1882–1891, 2016

Depression • Mental illness, including depression, is common among patients with kidney disease and associated with increased mortality, higher hospitalization rates, longer lengths of stay, and higher rates of suicide. • Renal Disease (ESRD) Quality Improvement Program (QIP) mandated reporting of annual depression screening and follow-up plans in all patients receiving dialysis. • Many self-reporting tools, such as the Patient Health Questionnaire (PHQ-2 and PHQ-9) and the Beck Depression Inventory, have been validated in patients with CKD, including those with kidney failure. Am J Kidney Dis. 2020, 75(5):793-806

แบบประเมนิ ซมึ เศรา้ และฆา่ ตวั ตาย กรมสขุ ภาพจิต

Depression Management strategies: • Manage associated reversible symptoms: pain, sleep disorder, pruritus, RLS. • Assess and optimize social supports. • Nonpharmacologic therapy: • Exercise programs • Cognitive Behavioral therapy (CBT) or supportive psychotherapy • Pharmacologic therapy: • SSRI: Sertraline 10-25 mg daily (first line), Citalopram, Fluoxetine Side effect: nausea, anorexia, diarrhea, insomnia • TCA: Amitriptyline 10-25 mg daily Clin J Am Soc Nephrol 11: 1882–1891, 2016

Pain • Pain is a common symptom in patients with ESKD, and impacts significantly on quality of life, function, psychosocial distress, sleep disorders and depression. • Pathogenesis can be • Pain related to underlying kidney disease such as polycystic kidney disease, renal bone disease, amyloid deposition (carpal tunnel syndrome), and calciphylaxis. • Pain related to RRT, such as steal syndrome, intradialytic cramps, intradialytic headaches, abdominal pain with peritoneal dialysis. • Pain related to co-morbidities such as musculoskeletal disease, peripheral neuropathy, peripheral vascular disease, ischemic heart disease, gouty arthropathy. • Adopt a step-wise approach to analgesics such as that outlined in the World Health Organization Analgesic Ladder. Clin J Am Soc Nephrol 11: 1882–1891, 2016

Pain Management in ESKD WHO Ladder ANZSN Renal Supportive Care Guidelines 2013 EDTNA|ERCA JOURNAL 2006 XXXII 2

Summary of pharmacologic and nonpharmacologic approaches for common symptoms Kidney International Reports (2021) 6, 894–904

Summary of pharmacologic and nonpharmacologic approaches for common symptoms Kidney International Reports (2021) 6, 894–904

Take Home Message • Advanced CKD and ESKD associated with high symptom burden associated with poor quality of life and high mortality. • Symptom management is mandatory treatment in comprehensive kidney care. • Regular symptom assessment help to early recognized patient’s burden and active symptom management to improve patient’s outcomes and QOL • Symptom management approach: • Evaluated treatable or modifiable caused and factors • Favor non-pharmacologic >> pharmacologic treatment • Pharmacology treatment: Used medication that effective across several symptoms (e.g. gabapentin) → Start with low dose and slow titration up to efficacy and side effect.