Symptoms in the Month Before Death for Stage 5 Chronic Kidney Disease Patients Managed Without Dialysis

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1 342 Journal of Pain and Symptom Management Vol. 40 No. 3 September 2010 Original Article Symptoms in the Month Before Death for Stage 5 Chronic Kidney Disease Patients Managed Without Dialysis Fliss E. Murtagh, PhD, MRCGP, MSc, Julia Addington-Hall, BA, PhD, Polly Edmonds, FRCP, Paul Donohoe, FRCP, PhD, Irene Carey, MRCPI, MSc, Karen Jenkins, RN, PG Dip HE, and Irene J. Higginson, PhD, FFPHM Department of Palliative Care, Policy and Rehabilitation (F.E.M., I.J.H.), King s College London, London; School of Nursing and Midwifery (J.A.-H.), University of Southampton, Southampton; King s College Hospital NHS Foundation Trust (P.E., P.D.), London; Guy s and St. Thomas NHS Foundation Trust (I.C.), London; Department of Renal Medicine (K.J.), East Kent Hospitals NHS Trust, Kent and Canterbury Hospital, Canterbury, United Kingdom Abstract Context. There is little evidence on the symptoms experienced by those with advanced (Stage 5) chronic kidney disease (CKD), managed without dialysis, as they approach death. As palliative care extends to noncancer illnesses, understanding symptom prevalence and severity close to death will clarify which symptom interventions are most needed and which elements of (largely cancerdriven) models of palliative care best translate into end-of-life care for this population. Objectives. To determine symptom prevalence and severity in the last month of life for patients with Stage 5 CKD, managed without dialysis. Methods. Longitudinal symptom survey in three U.K. renal units, using the patient-completed Memorial Symptom Assessment Scale-Short Form (MSAS-SF). We calculated the prevalence of individual symptoms (with 95% confidence intervals [CI] to reflect sample size), plus MSAS-SF subscales, in the month before death. Comparison is made with previously published data on symptoms in the last month of life in advanced cancer, also measured using the MSAS-SF. Results. Seventy-four patients (mean age: 81 years; standard deviation [SD]: 6.8) were recruited (response rate: 73%); 49 (66%) died during follow-up (mean age: 81 years; SD: 5.7). Month before death symptom data were available for 43 (88%) of the 49 participants who died. Median time of data collection was 18 days from death (interquartile range: 12e26 days). More than half had lack of energy (86%; 95% CI: 73%e94%), itch (84%; 70%e93%), drowsiness (82%; 68%e91%), dyspnea (80%; 66%e90%), poor concentration (76%; 61%e87%), pain (73%; 59%e85%), poor appetite (71%; 57%e83%), swelling arms/legs (71%; 57%e83%), dry mouth This work was funded by Guy s and St. Thomas Charity and completed at King s College London. Address correspondence to: Fliss Murtagh, PhD, MRCGP, MSc, Department of Palliative Care and Policy, Ó 2010 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. Weston Education Centre, Cutcombe Road, London, SE5 9RJ, United Kingdom. fliss.murtagh@ kcl.ac.uk Accepted for publication: January 26, /$ - see front matter doi: /j.jpainsymman

2 Vol. 40 No. 3 September 2010 Symptoms in the Month Before Death in Stage 5 CKD 343 (69%; 55%e82%), constipation (65%; 50%e78%), and nausea (59%; 44%e73%). Levels of distress correspond to prevalence, with the exception of dyspnea, which was disproportionately more distressing. The median number of symptoms reported was 16.6 (range: 6e27), rising to 20.4 (range: 7e34) if additional renal symptoms were included. On average, psychological distress was moderate (mean MSAS-PSYCH: 1.55) but with wide variation (SD: 0.50; range: 0.17e2.40), suggesting diverse levels of individual distress. The prevalence of both physical and psychological symptoms and the number reported were higher than those in advanced cancer patients in the month before death. Conclusion. Stage 5 CKD patients have clinically important physical and psychological symptom burdens in the last month of life, similar or greater than those in advanced cancer patients. Symptoms must be addressed through routine symptom assessment, appropriate interventions, and with pertinent models of end-of-life care. J Pain Symptom Manage 2010;40:342e352. Ó 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Symptoms, prevalence study, end of life, noncancer palliative care, chronic kidney disease, end-stage kidney disease Introduction In developed countries, the prevalence of chronic kidney disease (CKD) is rising steadily, with a disproportionately greater increase among older people. The most advanced stage of CKDdStage 5, when renal replacement therapy is requireddis defined by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative as kidney failure with a glomerular filtration rate of less than 15 ml/minute/1.73 m 2. In the United Kingdom, 25% of all patients starting renal replacement therapy are now older than 75 years, compared with 18% in There is increasing recognition that dialysis may not always be the most appropriate choice, especially for older patients with high levels of comorbidity and poor functional status. 2e5 This has led to the development of conservative management pathways as an alternative to dialysis for (mainly older) patients with Stage 5 CKD. These conservative pathways do not include dialysis but, instead, focus on measures to slow deterioration of renal function, active management of symptoms and the complications of renal disease, and anticipation of decline through advance planning. 6e10 Despite the focus on symptom management within these conservative pathways, little is known of the epidemiology of symptoms in this population. A systematic review of symptoms in Stage 5 CKD identified considerable evidence on symptom prevalence in dialysis populations but no evidence in patients with conservatively managed CKD. 11 One prospective 12 and one retrospective 13 study have described the symptoms experienced by patients close to death, but only in those withdrawing from dialysis. Cohen et al. report that most deaths after dialysis withdrawal are perceived as good, although pain in the last 24 hours is not uncommon (47%) and can be severe (5%). 12 In contrast, Chater et al. reported that pain, agitation, and dyspnea occurred in more than 20% in the last 24 hours and found that palliative care interventions improved symptom management. 13 However, both studies related only to those who withdrew from dialysis; evidence has not yet been published on the symptoms in those managed without dialysis. This article, therefore, aims to describe the prevalence and severity of symptoms, and overall symptom burden, in the month before death in patients with Stage 5 CKD managed conservatively, without dialysis. Methods Context/Design These data are part of a wider longitudinal study that described symptoms over time and toward death in this group of patients. Here, we undertake a cross-sectional analysis of symptom data collected in the month before death.

3 344 Murtagh et al. Vol. 40 No. 3 September 2010 Symptoms at first assessment after recruitment into the study have been reported previously. 14 Study Participants Patients with Stage 5 CKD being managed conservatively (without dialysis) were recruited from three renal units in London and South East England, over an 18-month period from April 2005 to October Inclusion/Exclusion Criteria Known Stage 5 CKD patients, with a current estimated glomerular filtration rate (egfr) equal to or less than 15 ml/minute (as estimated by the Modification of Diet in Renal Disease (MDRD) formula 15 ), who had made a definite decision (supported by their renal team) for management without dialysis (referred to as conservative management ), were included. Patients were excluded if they lacked capacity to consent to research participation, as judged by clinician assessment. Data Collection After recruitment, symptom data were collected from each participant every 28 (7) days, by postal questionnaire, until death or study end. Symptom data were sought using the Memorial Symptom Assessment Scale- Short Form (MSAS-SF). 16 This is a patientcompleted symptom assessment instrument that asks about the presence of each of 28 physical symptoms during the past week and then asks the patient to rate the level of distress or bother each symptom caused, if present. It also asks about the presence and frequency of four additional psychological symptoms. The MSAS-SF has been validated in populations with advanced disease, including both cancer and noncancer conditions. 16,17 It also has been adapted for use in patients with CKD. 18 Four MSAS-SF summary scores have been validated: a 10-item Global Distress Index (MSAS- GDI) considered to measure overall symptom distress; a physical symptom subscale (MSAS- PHYS), based on 12 physical symptoms (lack of appetite, lack of energy, pain, feeling drowsy, constipation, dry mouth, nausea, vomiting, change in taste, weight loss, feeling bloated, and dizziness); a psychological symptom subscale (MSAS-PSYCH) derived from six psychological symptoms (two of which are in the main 28 symptomsddifficulty sleeping, and difficulty concentratingdand four of which are the additional psychological symptomsd worrying, feeling sad, feeling nervous, and feeling irritable); and a total score (TMSAS) of the mean distress level for all 32 symptoms. For this study, a further seven physical symptoms (muscle cramps, dry skin, muscle soreness, headaches, bone or joint pain, chest pain, and restless legs) were appended to the 32 symptoms included in the MSAS-SF, without altering the original format of the MSAS-SF. These additional symptoms are those identified as important in populations with Stage 5 CKD, 11 and are identical to those used in a specific adaptation of MSAS-SF for patients with advanced chronic renal disease (this adaptation is known as the Dialysis Symptom Index). 18 To maintain MSAS-SF validity and to facilitate comparisons with other palliative populations, these additional renal symptoms are reported separately. Data were classified as missing if the whole MSAS-SF was not completed within seven days of the expected time of data collection or if individual survey items were not completed. Research participants also reported whether they had any help in completing the questionnaire from informal or professional carers. Data on physical status also were collected using the Palliative Performance Scale version 2 (PPSv2). This is a version of the Karnofsky Performance Status (KPS) scale modified to relate to home and outpatient care rather than hospitalization. 19 Demographics Demographic and clinical data were collected, through record review, on age, sex, ethnicity (using UK Office for National Statistics categories), disease severity (as measured by egfr, using the MDRD formula 15 ), primary renal pathology (using UK Renal Registry categories 20 ), and comorbidity (using the comorbidity score developed by Davies et al. 21 ). This scores seven domains of active comorbid disease, which are: malignancy (active, noncutaneous); ischemic heart disease (as evidenced by previous myocardial infarction, angina pectoris, positive coronary angiography, or other diagnostic procedure); peripheral vascular disease (distal aortic, renovascular, lower limb, and cerebrovascular diseasedeither symptomatic or significant stenosis on imaging); left ventricular dysfunction (clinical evidence of pulmonary edema not attributable to errors in fluid

4 Vol. 40 No. 3 September 2010 Symptoms in the Month Before Death in Stage 5 CKD 345 balance and/or moderate to severe left ventricular dysfunction on echocardiogram); diabetes mellitus (Type I or II), systemic collagen vascular disease; or other significant pathology (which must be severe enough to impact on survival in the general population). This comorbidity score has been compared with the betterknown Charlson comorbidity score by van Manen et al.; they found that both indices explained about the same percentages of variance in health status (as measured by SF-36, symptom scores, and KPS). 22,23 Analysis Month before death is defined as 0e35 days before death, in keeping with the 28 (7)-day schedule for data collection. To allow the representativeness of the study sample to be assessed, demographic and clinical data are compared between the study sample and the population from which the sample was drawn (all patients with conservatively managed CKD Stage 5 at the study centers) and between those who died during the study follow-up and those who were still alive at study end. The Mann- Whitney U test was used to compare nonparametric continuous data, and Chi-squared test was used to compare categorical data. Symptom prevalence and severity is reported in simple proportions (numbers and percentages) for overall prevalence (with 95% confidence intervals calculated to provide the reader with an estimate of the precision of these prevalence data, given the relatively small sample size) and also according to the level of severity. Consent and Ethical Approval All patients included in this study signed informed consent, and the study received formal ethical approval from the King s Main National Health Service Research Ethics Committee (Central Office for Research Ethics Committees number ). Results Across the three renal units, 142 patients with CKD Stage 5 were conservatively managed. Twenty-three had insufficient capacity to participate, and 17 died or transferred out before recruitment, leaving 102 patients who were invited to participate. Of these, 74 were recruited (response rate: 73%). During the study, 49 participants (66%) died, whereas 25 (34%) remained alive at the end of the study. For these 49 participants, survival from study entry ranged from seven to 669 days. Table 1 presents the demographic and clinical data for the study population and compares those who died during the study with those still alive at the end of the study. The median PPS (collected at study entry) for those who died was 60% (interquartile range [IQR]: 50%e70%), whereas for those still alive at study end, it was 70% (IQR: 60%e70%) (Mann-Whitney U test Z ¼ 2.64, P ¼ 0.008). The prevalence and severity of symptoms in the last month of life for those who died are reported in Tables 2e4, with symptoms ordered according to overall prevalence (most prevalent placed first). Those MSAS-SF physical symptoms reported by more than 25% of patients are also illustrated graphically in Fig. 1. Figure 1 demonstrates that, in general, symptoms are reported as more severe (distressing or bothering the patient quite a lot or very much ) in a pattern that follows overall prevalence, with the exceptions of lack of energy and dyspnea, with proportionately higher levels of distress. MSAS-SF subscales and the total number of symptoms experienced are presented in Tables 5 and 6, respectively. Median score on the PPS at the time of data collection in the last month of life was 50% (IQR: 40%e50%); a score of 50% means requiring considerable assistance and frequent medical care, with ordinary social relationships likely to be significantly impaired. The median time from data collection to death was 18 days (IQR: 12e26 days). Missing data are described in full in Tables 2e4. Despite the population being relatively close to death, levels of missing data were lowdthe whole questionnaire was missing for six (12%) participants (in every instance, because the study participant was too ill to complete the symptom questionnaire), and single items were missing in a further two questionnaires. The research team strove to minimize missing data by providing initial and followthrough support with questionnaire completion, personalized monthly telephone follow-up, and detailed participant liaison on changes in place of care. Although MSAS-SF is a patient-completed instrument, participants could have help in questionnaire completion; of the 43 completed questionnaires, 21 (49%)

5 346 Murtagh et al. Vol. 40 No. 3 September 2010 Table 1 Demographic and Clinical Data of 1) All Participants, 2) Those Who Died, and 3) Those Still Alive at Study End (With Statistical Comparison of Those Who Died With Those Still Alive) 1) All Participants (n ¼ 74) 2) Those Who Died (n ¼ 49) 3) Those Still Alive (n ¼ 25) Statistics Comparing 2) and 3) Age in years, mean (SD) 80.7 (6.78) 80.9 (5.71) 80.3 (8.62) Mann-Whitney U test Z ¼ 0.69 P ¼ 0.49 Male, n (%) 38 (51.4) 24 (49.0) 14 (56.0) X 2 ¼ 0.33 P ¼ 0.57 Estimated glomerular filtration rate at study start Mean (SD) 11.5 (2.78) 11.0 (2.82) 12.6 (2.37) Mann-Whitney U test Z ¼ 2.39 P ¼ 0.02 Range 4.1e e e15.0 Ethnicity, n (%) X 2 ¼ 4.17 White 51 (68.9) 32 (65.3) 19 (76.0) P ¼ 0.24 Black 12 (16.2) 10 (20.4) 2 (8.0) South Asian 6 (8.1) 5 (10.2) 1 (4.0) Chinese 0 (0.0) 0 (0.0) 0 (0.0) Other 5 (6.8) 2 (4.1) 3 (12.0) Renal pathology, n (%) X 2 ¼ 5.05 Etiology uncertain 26 (35.1) 16 (32.7) 10 (40.0) P ¼ 0.65 Glomerulonephritis 4 (5.4) 2 (4.1) 2 (8.0) Pyelonephritis 1 (1.4) 1 (2.0) 0 (0.0) Diabetes mellitus 18 (24.3) 15 (30.6) 3 (12.0) Renal vascular disease 16 (21.6) 9 (18.4) 7 (28.0) Hypertension 2 (2.7) 1 (2.0) 1 (4.0) Polycystic kidneys 1 (1.4) 1 (2.0) 0 (0.0) Other 6 (8.1) 4 (8.2) 2 (8.0) Malignancy, n (%) 13 (17.6) 9 (18.4) 4 (16.0) X 2 ¼ 0.06 P ¼ 0.80 Ischemic heart disease, n (%) 24 (32.4) 17 (34.7) 7 (28.0) X 2 ¼ 0.34 P ¼ 0.56 Peripheral vascular disease, n (%) 7 (9.5) 3 (6.1) 4 (16.0) X 2 ¼ 1.89 P ¼ 0.17 Left ventricular dysfunction, n (%) 23 (31.1) 16 (32.7) 7 (28.0) X 2 ¼ 0.17 P ¼ 0.68 Diabetes mellitus, n (%) 25 (33.8) 18 (36.7) 7 (28.0) X 2 ¼ 0.57 P ¼ 0.45 Collagen vascular disease, n (%) 2 (2.7) 2 (4.1) 0 (0.0) X 2 ¼ 1.05 P ¼ 0.31 Other significant pathology, n (%) 22 (29.7) 16 (32.7) 6 (24.0) X 2 ¼ 0.59 P ¼ 0.44 Davis comorbidity score, n (%) X 2 ¼ 1.19 Grade 0 (score: 0) 14 (18.9) 10 (20.4) 4 (16.0) P ¼ 0.55 Grade 1 (score: 1e2) 44 (59.5) 27 (55.1) 17 (68.0) Grade 2 (score: $3) 16 (21.6) 12 (24.5) 4 (16.0) SD ¼ standard deviation. were completed without help; 19 (44%) with the help of a relative or friend; two (5%) were completed with help from a professional or researcher; and in one questionnaire, this information was missing. Discussion This study demonstrates that a range of symptoms was common among conservatively managed patients with Stage 5 CKD in the last month of life. These symptoms also cause high levels of distressdlack of energy, itch, drowsiness, dyspnea, poor concentration, and pain are reported as quite or very distressing for over two-fifths of these patients in the last month of life. Symptom distress and symptom prevalence correspond closely (Fig. 1), with the most prevalent symptoms also proving to be most distressing. Dyspnea or breathlessness is the exception to this and is disproportionately more distressing for patients. In addition, the total number of symptoms is high, with patients experiencing an average of 20 symptoms each.

6 Vol. 40 No. 3 September 2010 Symptoms in the Month Before Death in Stage 5 CKD 347 Table 2 Symptom Prevalence in the Last Month of Life for Participants Who Died (n ¼ 49)dPhysical Symptoms Sought Using the MSAS-SF Prevalence By Severity Overall Prevalence (All Levels of Severity) 95% Confidence Intervals for Overall Prevalence Not Present or Present but Causing No Distress A Little or Somewhat Quite a Lot or Very Missing Data Symptoms n (%) % n (%) n (%) n (%) n (%) Physical symptoms identified using MSAS-SF, in order of prevalence Lack of energy 42 (86) 73e94 1 (2) 8 (16) 34 (69) 6 (12) Itching 41 (84) 70e93 3 (6) 19 (39) 21 (43) 6 (12) Feeling drowsy 40 (82) 68e91 5 (10) 17 (35) 21 (43) 6 (12) Shortness of breath 39 (80) 66e90 5 (10) 12 (24) 26 (53) 6 (12) Difficulty concentrating 37 (76) 61e87 8 (16) 13 (27) 22 (45) 6 (12) Pain 36 (73) 59e85 7 (14) 16 (33) 20 (41) 6 (12) Lack of appetite 35 (71) 57e83 8 (16) 17 (35) 18 (37) 6 (12) Swelling of arms/legs 35 (71) 57e83 12 (24) 14 (29) 17 (35) 6 (12) Dry mouth 34 (69) 55e82 11 (22) 22 (45) 10 (20) 6 (12) Constipation 32 (65) 50e78 14 (29) 24 (49) 5 (10) 6 (12) Nausea 29 (59) 44e73 20 (41) 16 (33) 7 (14) 6 (12) Cough 23 (47) 33e62 22 (45) 17 (35) 4 (8) 6 (12) Difficulty sleeping 21 (43) 29e58 24 (49) 11 (22) 8 (16) 6 (12) Dizziness 20 (41) 27e56 25 (51) 15 (31) 3 (6) 6 (12) Changes in skin 19 (39) 25e54 25 (51) 13 (27) 5 (10) 6 (12) Vomiting 18 (37) 23e52 27 (55) 15 (31) 1 (2) 6 (12) Feeling bloated 17 (35) 22e50 30 (61) 7 (14) 6 (12) 6 (12) Numbness/tingling 14 (29) 17e43 30 (61) 11 (22) 2 (4) 6 (12) in hands/feet Changes in taste 13 (27) 15e41 30 (61) 8 (16) 5 (10) 6 (12) Problems with urination 12 (24) 13e39 32 (65) 6 (12) 5 (10) 6 (12) I don t look like myself 10 (20) 10e34 34 (69) 8 (16) 1 (2) 6 (12) Sweats 7 (14) 6e27 37 (76) 5 (10) 1 (2) 6 (12) Mouth sores 7 (14) 6e27 36 (73) 5 (10) 1 (2) 7 (14) Weight loss 5 (10) 3e22 40 (82) 2 (4) 1 (2) 6 (12) Diarrhea 4 (8) 2e20 39 (80) 3 (6) 1 (2) 6 (12) Difficulty swallowing 4 (8) 2e20 40 (82) 1 (2) 2 (4) 6 (12) Hair loss 1 (2) 0e11 42 (86) 1 (2) 0 (0) 6 (12) Problems with sexual interest 0 (0) 0e7 42 (86) 0 (0) 0 (0) 7 (14) This study has several strengths. First, the detailed clinical databases maintained in the renal units enabled comparison between the study population and the population from which the sample was drawn. This is a specific issue in end-of-life researchdthere is risk of selection bias when those patients most ill are least easily recruited. This was avoided in this Table 3 Symptom Prevalence in the Last Month of Life for Participants Who Died (n ¼ 49)dPsychological Symptoms Sought Using the MSAS-SF Prevalence by Severity Overall Prevalence (All Levels of Severity) 95% Confidence Intervals for Overall Prevalence Rarely or Occasionally Frequently or Almost Constantly Missing Data Symptom n (%) % n (%) n (%) n (%) Psychological symptoms Worrying 38 (78) 63e88 27 (55) 11 (22) 6 (12) Feeling sad 32 (65) 50e78 22 (45) 10 (20) 6 (12) Feeling nervous 27 (55) 40e69 24 (49) 3 (6) 6 (12) Feeling irritable 24 (49) 34e64 15 (31) 9 (18) 6 (12)

7 348 Murtagh et al. Vol. 40 No. 3 September 2010 Table 4 Symptoms in the Last Month of Life for Participants Who Died (n ¼ 49)dAdditional Renal Symptoms Appended to Those in the MSAS-SF Prevalence by Severity Overall Prevalence (All Levels of Severity) 95% Confidence Intervals Not Present or Present but Causing No Distress A Little or Somewhat Quite a Lot or Very Missing Data Symptom n (%) % n (%) n (%) n (%) n (%) Additional renal symptoms Restless legs 32 (65) 50e78 12 (24) 25 (51) 6 (12) 6 (12) Muscle cramps 30 (61) 46e75 13 (27) 22 (45) 8 (16) 6 (12) Bone/joint pain 28 (57) 42e71 16 (32) 15 (31) 12 (24) 6 (12) Dry skin 25 (51) 36e66 22 (45) 14 (29) 7 (14) 6 (12) Muscle soreness 24 (49) 34e64 21 (43) 16 (33) 6 (12) 6 (12) Chest pain 14 (28) 17e43 32 (65) 8 (16) 3 (6) 6 (12) Headaches 6 (12) 5e25 37 (76) 6 (12) 0 (0) 6 (12) study, with participants and nonparticipants being similar across demographic and clinical variables, especially regarding comorbidities, where those with higher burden of comorbidity might be expected to be less likely to participate. Ethnicity is the only variable to differ significantly between the two groups, but ethnic minority groups are over- rather than underrepresented in the study sample. Further comparison, between those who died and those still alive at study end, similarly demonstrates that these groups are comparable, with the exceptions of estimated GFR (unsurprisingly lower in the group that died) and 0% 20% 40% 60% 80% 100% Lack of energy Itch Drowsiness Dyspnea Poor concentration Pain Loss of appetite Swelling arms/legs Dry mouth Constipation Nausea Cough Poor sleep Dizziness Changes in skin Vomiting Feeling bloated Numbness hands/feet Change in taste Quite or very distressing A little or somewhat distressing None or no distress Missing Fig. 1. Symptoms in the last month of life for participants who dieddphysical symptoms from MSAS-SF with overall prevalence >25%, illustrated according to severity (n ¼ 49).

8 Vol. 40 No. 3 September 2010 Symptoms in the Month Before Death in Stage 5 CKD 349 Table 5 Total Number of Symptoms Experienced in the Last Month of Life for Participants Who Died (n ¼ 43) Mean (SD) Range Number of symptoms identified using MSAS-SF (maximum possible ¼ 32) Number of additional renal symptoms (maximum possible ¼ 7) Total number of symptoms identified using MSAS-SF and added renal symptoms (maximum possible ¼ 39) SD ¼ standard deviation (4.04) 6e (1.73) 0e (5.20) 7e34 performance scale (again poorer among those who died). Both these variables are known to be predictors of mortality in older patients with end-stage CKD 24,25 and in advanced cancer. 26 These comparisons largely support the representativeness of the sample, particularly as regards age, gender, primary renal pathology, and comorbidity. Second, selection bias is often compounded by high rates of attrition as death approaches, and participants become more ill and find it difficult to complete symptom questionnaires. In this study, detailed individual follow-up of each participant, with regular telephone contact and place-of-care tracking, minimized missing data. Data within a month before death were obtained for all but six (12%) of the 49 participants who died. It should be noted, however, that a high proportion (almost 50%) of the participants received help from a relative/friend or professional in completing their symptom questionnaire, a further potential source of bias discussed later. A third strength comes from the use of a generic instrument validated in both cancer and noncancer populations approaching the end of life 16,17,27 and which also has undergone some validation in renal patients. 18,28 This facilitates comparison of this study population with other populations studied using the same instrument (MSAS-SF). Weisbord et al., who evaluated symptoms in just 19 severely ill dialysis patients, 28 found similar symptoms to be most prevalent; he identified lack of energy and drowsiness as most common, with dry mouth, pain, itch, and dyspnea all among the eight most common symptoms, similar to the findings of this study. However, it is not clear that the symptoms identified by Weisbord et al. 28 reflect the last month of life, because survival data are not included. Hwang et al. studied 41 patients with advanced cancer in the last month of life, 29 although with younger participants than in this study (median age: 65 years; range: 28e89 years). They reported lower medians and ranges for all the MSAS- SF subscales, with a median GDI of 1.36 (IQR: 1.06e2.08) compared with 2.10 (1.72e 2.32) in this study, a median physical symptom subscale of 1.53 (1.00e1.93) compared with 1.73 (1.13e1.93), and a median psychological symptom subscale of 0.67 (0.00e1.38) compared with 1.57 (1.27e1.87). This suggests that conservatively managed renal patients in the last month of life have overall higher levels of symptoms, with greater overall distress and greater physical and psychological symptom burden, than advanced cancer patients in the last month of life. Detailed comparisons are limited by the small number of studies describing symptoms in the last month of life. This is true even for advanced cancer, which has been much more widely studied than noncancer conditions. A recent systematic review of symptom prevalence in cancer patients reports just six studies (a total of 2,219 patients) dealing with symptom prevalence in the last fortnight of life. 30 If findings from this systematic review are compared with this study, then lack of energy is equally common in both populations, but itch, drowsiness, and dyspnea are much more Table 6 MSAS-SF Subscales in the Last Month of Life for Participants Who Died (n ¼ 43) Mean (SD) Median Interquartile Range Range MSAS-GDI a (Global Distress Index) 1.97 (0.49) e e2.72 MSAS-PHYS a (physical symptom subscale) 1.57 (0.53) e e2.40 MSAS-PSYCH a (psychological symptom subscale) 1.55 (0.50) e e2.40 TMSAS a (average severity score for all symptoms) 1.29 (0.39) e e2.06 SD ¼ standard deviation. a All subscales give a score between 0 and 4, with 0 as no symptoms and 4 as the highest possible score.

9 350 Murtagh et al. Vol. 40 No. 3 September 2010 prevalent for conservatively managed renal patients than for advanced cancer patients in the last month of life. Pain and lack of appetite are common in both populations. More detail of the variations in prevalence of individual symptoms can be seen through comparison with individual studies. Morita et al. described symptoms in 200 patients with advanced cancer (with median survival of 24 days but notably younger than this renal populationdmean age: 65 years; standard deviation: 13). 31 They identified similar prevalence of constipation (71% vs. 65% in this study), edema (65% vs. 71%), and dry mouth (61% vs. 69%), but lack of appetite (94% vs. 71%) and nausea (48% vs. 59%) were more prevalent in cancer patients, and breathlessness (66% vs. 80%) was more prevalent in the renal patients. Conill et al. described symptoms in 176 advanced cancer patients assessed in the last days of life but again in a younger population than in this study (mean age: 67.7 years; range: 25e93 years). 32 They identified similar prevalence of lack of appetite (80% vs. 71%) constipation (55% vs. 65%), and dry mouth (70% vs. 69%), but difficulty sleeping (28% vs. 43%), pain (30% vs. 73%), nausea (13% vs. 59%) and breathlessness (47% vs. 80%) were all more prevalent in the renal patients in this study. In summary, global levels of symptom distress and both physical and psychological symptoms are, contrary to popular perception, higher in patients with advanced renal disease than patients with advanced cancer approaching the end of life. The patterns of individual symptoms are different, as might be expected. Itch, drowsiness, and dyspnea are more common in those with advanced renal disease at end of life, but pain, surprisingly, appears equally or even more commonly in the renal as in the cancer end-of-life population. Constipation, edema, and dry mouth are similarly common across both populations. This study did not seek the underlying causes of symptoms; hence, it does not elucidate the reasons for this high symptom burden or the different patterns of symptoms. Variations in individual symptom prevalence (with high levels of drowsiness, itch, and dyspnea) may, in part, be accounted for by uremia and complications of renal disease (such as fluid overload), although comorbidities, such as cardiac and respiratory disease, may play a part. It is unclear, however, whether the high overall symptom burden is because of the primary disease (clinical experience suggests that this is unlikely), because of the comorbid disease, or is reflective of limitations in the symptom management provided to patients with renal disease at the end of life, particularly as compared with the advanced cancer patients included in prevalence studies. It is also unclear how the older age of this renal study population influences observed patterns of symptom prevalence and severity; few studies have been carried out in older populations with advanced cancer, and hence detailed comparison and elucidation is not possible. One of the limitations of this study is the relatively small numbers studied. In general, the numbers managed conservatively (without dialysis) in each renal center are small, and it is, therefore, challenging to recruit a large sample without greater resources and more study sites. In addition, it is ethically challenging to include those unable to give consent, but excluding this group also reduces sample size; in this study, 23 potential participants lacked capacity for consent. This also introduces bias, because this group with impaired capacity may be more ill and have the greatest symptom burden; this bias, therefore, will likely cause symptom burden to be underestimated. Given the small sample in this study, 95% confidence intervals for the overall prevalence data are included, which allows the estimation of the extent to which our reported data approaches the likely true prevalence. The small numbers also limit the number of covariables that can be usefully explored; for this reason, we chose to use a Comorbidity Index, rather than individual comorbidities, as recommended by Van Manen et al. 23 Although the response rate that we achieved was moderate, it is comparable to that achieved in similar studies of patients approaching the last months or years of life. A further limitation is the use of proxy assistance for questionnaire completion. The influence of proxy assistance on patient-completed questionnaires is unknown, although there is extensive evidence on the relationship between independent patient and proxy responses. Kutner et al., in a study of 86 patient/family/professional triads, suggest that proxy response is a fair

10 Vol. 40 No. 3 September 2010 Symptoms in the Month Before Death in Stage 5 CKD 351 (though not ideal) substitute toward the end of life. 33 These are unique data; symptom prevalence and distress have not been reported previously in conservatively managed patients with Stage 5 CKD in the last month of life. A number of studies have explored symptoms in patients on dialysis, including symptoms after withdrawal from dialysis, 34,35 but none have yet focused on end-of-life symptoms in patients with conservatively managed Stage 5 CKD. In nephrology, the predominant focus has been on dialysis and interventions to minimize disease progression or manage complications. There has been debate in both nephrology and specialist palliative care circles about whether and how models of palliative care might extend from cancer to noncancer care. 36e38 This study has clarified that patients with conservatively managed Stage 5 CKD have considerable need for proactive assessment and management of symptoms at the end of life. The most prevalent symptoms are also those that are most distressing; hence, the more common symptoms need most attention to reduce distress, although particular attention should be paid to breathlessness, which is disproportionately distressing for patients. Clinical services need to ensure that regular symptom assessment is part of routine care for conservatively managed CKD patients. Regular symptom assessment, which is integral to specialist palliative care for advanced cancer patients, is one component of care needed by these patients but is not yet routine in nephrological care. Second, further research needs to be directed toward interventions to ameliorate the most common and distressing symptoms, particularly those that cannot be improved through active management to delay disease progression or manage complications. Lastly, as the numbers of Stage 5 CKD patients steadily increase and the conservative management pathway itself becomes more common, there is urgent need to develop and evaluate appropriate models of care for these patients and their families. Acknowledgments Thanks to the participants for their considerable commitment and willingness to help this research and to the funders, Guy s and St. Thomas Charity, without whose support this study could not have been undertaken. References 1. Ansell D, Feest T, Rao R, Williams A, Winearls C. UK Renal Registry Report Bristol, UK: UK Renal Registry, Smith C, Silva-Gane M, Chandna S, et al. Choosing not to dialyse: evaluation of planned non-dialytic management in a cohort of patients with end-stage renal failure. Nephron Clin Pract 2003;95(2):c40ec Burns A. Conservative management of endstage renal failure: masterly inactivity or benign neglect? Nephron Clin Pract 2003;95(2):c37ec Murtagh FE, Marsh JE, Donohoe P, et al. Dialysis or not? A comparative survival study of patients over 75 years with chronic kidney disease stage 5. Nephrol Dial Transplant 2007;22(7):1955e Munshi SK, Vijayakumar N, Taub NA, et al. Outcome of renal replacement therapy in the very elderly. Nephrol Dial Transplant 2001;16(1):128e Burgess E. Conservative treatment to slow deterioration of renal function: evidence-based recommendations. Kidney Int Suppl 1999;70:S17eS Murtagh FE, Murphy E, Shepherd KA, et al. End-of-life care in end-stage renal disease: renal and palliative care. Br J Nurs 2006;15(1):8e Chan CH, Noble H, Lo SH, et al. Palliative care for patients with end-stage renal disease: experiences from Hong Kong. Int J Palliat Nurs 2007; 13(7):310e Noble H, Rees K. Caring for people who are dying on renal wards: a retrospective study. EDTNA ERCA J 2006;32(2):89e Noble H, Chesser A, Kelly D. The cessation of dialysis in patients with end-stage renal disease: developing an appropriate evidence base for practice. EDTNA ERCA J 2005;31(4):208e Murtagh F, Addington-Hall J, Higginson IJ. The prevalence of symptoms in end-stage renal disease: a systematic review. Adv Chronic Kidney Dis 2007; 14(1):82e Cohen LM, Germain MJ, Poppel DM, et al. Dying well after discontinuing the life-support treatment of dialysis. Arch Intern Med 2000;160(16): 2513e Chater S, Davison SN, Germain MJ, Cohen LM. Withdrawal from dialysis: a palliative care perspective. Clin Nephrol 2006;66(5):364e Murtagh F, Addington-Hall J, Edmonds P, et al. Symptoms in advanced renal diseaseda crosssectional survey of symptom prevalence in stage 5

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