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

Open AccessPublished:June 28, 2010DOI:https://doi.org/10.1016/j.jpainsymman.2010.01.021

      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 cancer-driven) 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: 12–26 days). More than half had lack of energy (86%; 95% CI: 73%–94%), itch (84%; 70%–93%), drowsiness (82%; 68%–91%), dyspnea (80%; 66%–90%), poor concentration (76%; 61%–87%), pain (73%; 59%–85%), poor appetite (71%; 57%–83%), swelling arms/legs (71%; 57%–83%), dry mouth (69%; 55%–82%), constipation (65%; 50%–78%), and nausea (59%; 44%–73%). 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: 6–27), rising to 20.4 (range: 7–34) 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: 0.17–2.40), 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.

      Key Words

      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 CKD—Stage 5, when renal replacement therapy is required—is 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 m2. In the United Kingdom, 25% of all patients starting renal replacement therapy are now older than 75 years, compared with 18% in 1998.
      • Ansell D.
      • Feest T.
      • Rao R.
      • Williams A.
      • Winearls C.
      UK Renal Registry Report 2005.
      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.
      • 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.
      • Burns A.
      Conservative management of end-stage renal failure: masterly inactivity or benign neglect?.
      • Murtagh F.E.
      • Marsh J.E.
      • Donohoe P.
      • et al.
      Dialysis or not? A comparative survival study of patients over 75 years with chronic kidney disease stage 5.
      • Munshi S.K.
      • Vijayakumar N.
      • Taub N.A.
      • et al.
      Outcome of renal replacement therapy in the very elderly.
      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.
      • Burgess E.
      Conservative treatment to slow deterioration of renal function: evidence-based recommendations.
      • Murtagh F.E.
      • Murphy E.
      • Shepherd K.A.
      • et al.
      End-of-life care in end-stage renal disease: renal and palliative care.
      • Chan C.H.
      • Noble H.
      • Lo S.H.
      • et al.
      Palliative care for patients with end-stage renal disease: experiences from Hong Kong.
      • Noble H.
      • Rees K.
      Caring for people who are dying on renal wards: a retrospective study.
      • Noble H.
      • Chesser A.
      • Kelly D.
      The cessation of dialysis in patients with end-stage renal disease: developing an appropriate evidence base for practice.
      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.
      • Murtagh F.
      • Addington-Hall J.
      • Higginson I.J.
      The prevalence of symptoms in end-stage renal disease: a systematic review.
      One prospective
      • Cohen L.M.
      • Germain M.J.
      • Poppel D.M.
      • et al.
      Dying well after discontinuing the life-support treatment of dialysis.
      and one retrospective
      • Chater S.
      • Davison S.N.
      • Germain M.J.
      • Cohen L.M.
      Withdrawal from dialysis: a palliative care perspective.
      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%).
      • Cohen L.M.
      • Germain M.J.
      • Poppel D.M.
      • et al.
      Dying well after discontinuing the life-support treatment of dialysis.
      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.
      • Chater S.
      • Davison S.N.
      • Germain M.J.
      • Cohen L.M.
      Withdrawal from dialysis: a palliative care perspective.
      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. Symptoms at first assessment after recruitment into the study have been reported previously.
      • Murtagh F.
      • Addington-Hall J.
      • Edmonds P.
      • et al.
      Symptoms in advanced renal disease—a cross-sectional survey of symptom prevalence in stage 5 chronic kidney disease managed without dialysis.

      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 2006.

      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
      • Levey A.S.
      • Bosch J.P.
      • Lewis J.B.
      • et al.
      A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group.
      ), 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).
      • Chang V.T.
      • Hwang S.S.
      • Feuerman M.
      • Kasimis B.S.
      • Thaler H.T.
      The Memorial Symptom Assessment Scale Short Form (MSAS-SF).
      This is a patient-completed 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.
      • Chang V.T.
      • Hwang S.S.
      • Feuerman M.
      • Kasimis B.S.
      • Thaler H.T.
      The Memorial Symptom Assessment Scale Short Form (MSAS-SF).
      • Tranmer J.E.
      • Heyland D.
      • Dudgeon D.
      • et al.
      Measuring the symptom experience of seriously ill cancer and non cancer hospitalized patients near the end of life with the Memorial Symptom Assessment Scale.
      It also has been adapted for use in patients with CKD.
      • Weisbord S.D.
      • Fried L.F.
      • Arnold R.M.
      • et al.
      Development of a symptom assessment instrument for chronic hemodialysis patients: The Dialysis Symptom Index.
      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 symptoms—difficulty sleeping, and difficulty concentrating—and four of which are the additional psychological symptoms—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,
      • Murtagh F.
      • Addington-Hall J.
      • Higginson I.J.
      The prevalence of symptoms in end-stage renal disease: a systematic review.
      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).
      • Weisbord S.D.
      • Fried L.F.
      • Arnold R.M.
      • et al.
      Development of a symptom assessment instrument for chronic hemodialysis patients: The Dialysis Symptom Index.
      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.
      • Anderson F.
      • Downing G.M.
      • Hill J.
      • Casorso L.
      • Lerch N.
      Palliative performance scale (PPS): a new tool.

      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
      • Levey A.S.
      • Bosch J.P.
      • Lewis J.B.
      • et al.
      A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group.
      ), primary renal pathology (using UK Renal Registry categories
      • Ansell D.
      • Feest T.
      • Ahmad A.
      • Rao R.
      UK Renal Registry Report 2004.
      ), and comorbidity (using the comorbidity score developed by Davies et al.
      • Davies S.J.
      • Phillips L.
      • Naish P.F.
      • Russell G.I.
      Quantifying comorbidity in peritoneal dialysis patients and its relationship to other predictors of survival.
      ). 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 disease—either symptomatic or significant stenosis on imaging); left ventricular dysfunction (clinical evidence of pulmonary edema not attributable to errors in fluid 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 better-known 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).
      • Van Manen J.G.
      • Korevaar J.C.
      • Dekker F.W.
      • et al.
      How to adjust for comorbidity in survival studies in ESRD patients: a comparison of different indices.
      • Van Manen J.G.
      • Korevaar J.C.
      • Dekker F.W.
      • et al.
      Adjustment for comorbidity in studies on health status in ESRD patients: which comorbidity index to use?.

      Analysis

      “Month before death” is defined as 0–35 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 04-03-092).

      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.
      Table 1Demographic 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=74)2) Those Who Died (n=49)3) Those Still Alive (n=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=0.69
      • P=0.49
      Male, n (%)38 (51.4)24 (49.0)14 (56.0)
      • X2=0.33
      • P=0.57
      Estimated glomerular filtration rate at study start
      • Mann-Whitney U test
      • Z=2.39
      • P=0.02
       Mean (SD)11.5 (2.78)11.0 (2.82)12.6 (2.37)
       Range4.1–15.04.1–15.06.5–15.0
      Ethnicity, n (%)
      • X2=4.17
      • P=0.24
       White51 (68.9)32 (65.3)19 (76.0)
       Black12 (16.2)10 (20.4)2 (8.0)
       South Asian6 (8.1)5 (10.2)1 (4.0)
       Chinese0 (0.0)0 (0.0)0 (0.0)
       Other5 (6.8)2 (4.1)3 (12.0)
      Renal pathology, n (%)
      • X2=5.05
      • P=0.65
       Etiology uncertain26 (35.1)16 (32.7)10 (40.0)
       Glomerulonephritis4 (5.4)2 (4.1)2 (8.0)
       Pyelonephritis1 (1.4)1 (2.0)0 (0.0)
       Diabetes mellitus18 (24.3)15 (30.6)3 (12.0)
       Renal vascular disease16 (21.6)9 (18.4)7 (28.0)
       Hypertension2 (2.7)1 (2.0)1 (4.0)
       Polycystic kidneys1 (1.4)1 (2.0)0 (0.0)
       Other6 (8.1)4 (8.2)2 (8.0)
      Malignancy, n (%)13 (17.6)9 (18.4)4 (16.0)
      • X2=0.06
      • P=0.80
      Ischemic heart disease, n (%)24 (32.4)17 (34.7)7 (28.0)
      • X2=0.34
      • P=0.56
      Peripheral vascular disease, n (%)7 (9.5)3 (6.1)4 (16.0)X2=1.89

      P=0.17
      Left ventricular dysfunction, n (%)23 (31.1)16 (32.7)7 (28.0)X2=0.17

      P=0.68
      Diabetes mellitus, n (%)25 (33.8)18 (36.7)7 (28.0)
      • X2=0.57
      • P=0.45
      Collagen vascular disease, n (%)2 (2.7)2 (4.1)0 (0.0)
      • X2=1.05
      • P=0.31
      Other significant pathology, n (%)22 (29.7)16 (32.7)6 (24.0)
      • X2=0.59
      • P=0.44
      Davis comorbidity score, n (%)
      • X2=1.19
      • P=0.55
       Grade 0 (score: 0)14 (18.9)10 (20.4)4 (16.0)
       Grade 1 (score: 1–2)44 (59.5)27 (55.1)17 (68.0)
       Grade 2 (score: ≥3)16 (21.6)12 (24.5)4 (16.0)
      SD=standard deviation.
      The median PPS (collected at study entry) for those who died was 60% (interquartile range [IQR]: 50%–70%), whereas for those still alive at study end, it was 70% (IQR: 60%–70%) (Mann-Whitney U test Z=2.64, P=0.008).
      The prevalence and severity of symptoms in the last month of life for those who died are reported in Table 2, Table 3, Table 4, 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 Table 5, Table 6, respectively.
      Table 2Symptom Prevalence in the Last Month of Life for Participants Who Died (n=49)—Physical Symptoms Sought Using the MSAS-SF
      Prevalence By Severity
      Overall Prevalence (All Levels of Severity)95% Confidence Intervals for Overall PrevalenceNot Present or Present but Causing No Distress“A Little” or “Somewhat” Distressing“Quite a Lot” or “Very” DistressingMissing Data
      Symptomsn (%)%n (%)n (%)n (%)n (%)
      Physical symptoms identified using MSAS-SF, in order of prevalence
       Lack of energy42 (86)73–941 (2)8 (16)34 (69)6 (12)
       Itching41 (84)70–933 (6)19 (39)21 (43)6 (12)
       Feeling drowsy40 (82)68–915 (10)17 (35)21 (43)6 (12)
       Shortness of breath39 (80)66–905 (10)12 (24)26 (53)6 (12)
       Difficulty concentrating37 (76)61–878 (16)13 (27)22 (45)6 (12)
       Pain36 (73)59–857 (14)16 (33)20 (41)6 (12)
       Lack of appetite35 (71)57–838 (16)17 (35)18 (37)6 (12)
       Swelling of arms/legs35 (71)57–8312 (24)14 (29)17 (35)6 (12)
       Dry mouth34 (69)55–8211 (22)22 (45)10 (20)6 (12)
       Constipation32 (65)50–7814 (29)24 (49)5 (10)6 (12)
       Nausea29 (59)44–7320 (41)16 (33)7 (14)6 (12)
       Cough23 (47)33–6222 (45)17 (35)4 (8)6 (12)
       Difficulty sleeping21 (43)29–5824 (49)11 (22)8 (16)6 (12)
       Dizziness20 (41)27–5625 (51)15 (31)3 (6)6 (12)
       Changes in skin19 (39)25–5425 (51)13 (27)5 (10)6 (12)
       Vomiting18 (37)23–5227 (55)15 (31)1 (2)6 (12)
       Feeling bloated17 (35)22–5030 (61)7 (14)6 (12)6 (12)
       Numbness/tingling in hands/feet14 (29)17–4330 (61)11 (22)2 (4)6 (12)
       Changes in taste13 (27)15–4130 (61)8 (16)5 (10)6 (12)
       Problems with urination12 (24)13–3932 (65)6 (12)5 (10)6 (12)
       “I don't look like myself”10 (20)10–3434 (69)8 (16)1 (2)6 (12)
       Sweats7 (14)6–2737 (76)5 (10)1 (2)6 (12)
       Mouth sores7 (14)6–2736 (73)5 (10)1 (2)7 (14)
       Weight loss5 (10)3–2240 (82)2 (4)1 (2)6 (12)
       Diarrhea4 (8)2–2039 (80)3 (6)1 (2)6 (12)
       Difficulty swallowing4 (8)2–2040 (82)1 (2)2 (4)6 (12)
       Hair loss1 (2)0–1142 (86)1 (2)0 (0)6 (12)
       Problems with sexual interest0 (0)0–742 (86)0 (0)0 (0)7 (14)
      Table 3Symptom Prevalence in the Last Month of Life for Participants Who Died (n=49)—Psychological Symptoms Sought Using the MSAS-SF
      Prevalence by Severity
      Overall Prevalence (All Levels of Severity)95% Confidence Intervals for Overall Prevalence“Rarely” or “Occasionally” Distressing“Frequently” or “Almost Constantly” DistressingMissing Data
      Symptomn (%)%n (%)n (%)n (%)
      Psychological symptoms
       Worrying38 (78)63–8827 (55)11 (22)6 (12)
       Feeling sad32 (65)50–7822 (45)10 (20)6 (12)
       Feeling nervous27 (55)40–6924 (49)3 (6)6 (12)
       Feeling irritable24 (49)34–6415 (31)9 (18)6 (12)
      Table 4Symptoms in the Last Month of Life for Participants Who Died (n=49)—Additional Renal Symptoms Appended to Those in the MSAS-SF
      Prevalence by Severity
      Overall Prevalence (All Levels of Severity)95% Confidence IntervalsNot Present or Present but Causing No Distress“A Little” or “Somewhat” Distressing“Quite a Lot” or “Very” DistressingMissing Data
      Symptomn (%)%n (%)n (%)n (%)n (%)
      Additional renal symptoms
       Restless legs32 (65)50–7812 (24)25 (51)6 (12)6 (12)
       Muscle cramps30 (61)46–7513 (27)22 (45)8 (16)6 (12)
       Bone/joint pain28 (57)42–7116 (32)15 (31)12 (24)6 (12)
       Dry skin25 (51)36–6622 (45)14 (29)7 (14)6 (12)
       Muscle soreness24 (49)34–6421 (43)16 (33)6 (12)6 (12)
       Chest pain14 (28)17–4332 (65)8 (16)3 (6)6 (12)
       Headaches6 (12)5–2537 (76)6 (12)0 (0)6 (12)
      Figure thumbnail gr1
      Fig. 1Symptoms in the last month of life for participants who died—physical symptoms from MSAS-SF with overall prevalence >25%, illustrated according to severity (n=49).
      Table 5Total Number of Symptoms Experienced in the Last Month of Life for Participants Who Died (n=43)
      Mean (SD)Range
      Number of symptoms identified using MSAS-SF (maximum possible=32)16.65 (4.04)6–27
      Number of additional renal symptoms (maximum possible=7)3.70 (1.73)0–7
      Total number of symptoms identified using MSAS-SF and added renal symptoms (maximum possible=39)20.35 (5.20)7–34
      SD=standard deviation.
      Table 6MSAS-SF Subscales in the Last Month of Life for Participants Who Died (n=43)
      Mean (SD)MedianInterquartile RangeRange
      MSAS-GDI
      All subscales give a score between 0 and 4, with 0 as no symptoms and 4 as the highest possible score.
      (Global Distress Index)
      1.97 (0.49)2.101.72–2.320.26–2.72
      MSAS-PHYS
      All subscales give a score between 0 and 4, with 0 as no symptoms and 4 as the highest possible score.
      (physical symptom subscale)
      1.57 (0.53)1.731.13–1.930.13–2.40
      MSAS-PSYCH
      All subscales give a score between 0 and 4, with 0 as no symptoms and 4 as the highest possible score.
      (psychological symptom subscale)
      1.55 (0.50)1.571.27–1.870.17–2.40
      TMSAS
      All subscales give a score between 0 and 4, with 0 as no symptoms and 4 as the highest possible score.
      (average severity score for all symptoms)
      1.29 (0.39)1.350.99–1.520.38–2.06
      SD=standard deviation.
      a All subscales give a score between 0 and 4, with 0 as no symptoms and 4 as the highest possible score.
      Median score on the PPS at the time of data collection in the last month of life was 50% (IQR: 40%–50%); 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: 12–26 days).
      Missing data are described in full in Table 2, Table 3, Table 4. Despite the population being relatively close to death, levels of missing data were low—the 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 follow-through 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%) 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 distress—lack 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.
      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 research—there is risk of selection bias when those patients most ill are least easily recruited. This was avoided in this 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 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
      • Chandna S.M.
      • Schulz J.
      • Lawrence C.
      • Greenwood R.N.
      • Farrington K.
      Is there a rationale for rationing chronic dialysis? A hospital based cohort study of factors affecting survival and morbidity.
      • Merkus M.P.
      • Jager K.J.
      • Dekker F.W.
      • et al.
      Predictors of poor outcome in chronic dialysis patients: The Netherlands Cooperative Study on the Adequacy of Dialysis. The NECOSAD Study Group.
      and in advanced cancer.
      • Maltoni M.
      • Caraceni A.
      • Brunelli C.
      • et al.
      Prognostic factors in advanced cancer patients: evidence-based clinical recommendations—a study by the Steering Committee of the European Association for Palliative Care.
      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
      • Chang V.T.
      • Hwang S.S.
      • Feuerman M.
      • Kasimis B.S.
      • Thaler H.T.
      The Memorial Symptom Assessment Scale Short Form (MSAS-SF).
      • Tranmer J.E.
      • Heyland D.
      • Dudgeon D.
      • et al.
      Measuring the symptom experience of seriously ill cancer and non cancer hospitalized patients near the end of life with the Memorial Symptom Assessment Scale.
      • Portenoy R.K.
      • Thaler H.T.
      • Kornblith A.B.
      • et al.
      The Memorial Symptom Assessment Scale: an instrument for the evaluation of symptom prevalence, characteristics and distress.
      and which also has undergone some validation in renal patients.
      • Weisbord S.D.
      • Fried L.F.
      • Arnold R.M.
      • et al.
      Development of a symptom assessment instrument for chronic hemodialysis patients: The Dialysis Symptom Index.
      • Weisbord S.D.
      • Carmody S.S.
      • Bruns F.J.
      • et al.
      Symptom burden, quality of life, advance care planning and the potential value of palliative care in severely ill haemodialysis patients.
      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,
      • Weisbord S.D.
      • Carmody S.S.
      • Bruns F.J.
      • et al.
      Symptom burden, quality of life, advance care planning and the potential value of palliative care in severely ill haemodialysis patients.
      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.
      • Weisbord S.D.
      • Carmody S.S.
      • Bruns F.J.
      • et al.
      Symptom burden, quality of life, advance care planning and the potential value of palliative care in severely ill haemodialysis patients.
      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,
      • Hwang S.S.
      • Chang V.T.
      • Fairclough D.L.
      • Cogswell J.
      • Kasimis B.
      Longitudinal quality of life in advanced cancer patients: pilot study results from a VA medical cancer center.
      although with younger participants than in this study (median age: 65 years; range: 28–89 years). They reported lower medians and ranges for all the MSAS-SF subscales, with a median GDI of 1.36 (IQR: 1.06–2.08) compared with 2.10 (1.72–2.32) in this study, a median physical symptom subscale of 1.53 (1.00–1.93) compared with 1.73 (1.13–1.93), and a median psychological symptom subscale of 0.67 (0.00–1.38) compared with 1.57 (1.27–1.87). 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.
      • Teunissen S.C.C.M.
      • Wesker W.
      • Kruitwagen C.
      • et al.
      Symptom prevalence in patients with incurable cancer: a systematic review.
      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 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 population—mean age: 65 years; standard deviation: 13).
      • Morita T.
      • Tsunoda J.
      • Inoue S.
      • Chihara S.
      Contributing factors to physical symptoms in terminally-ill cancer patients.
      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: 25–93 years).
      • Conill C.
      • Verger E.
      • Henriquez I.
      • et al.
      Symptom prevalence in the last week of life.
      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.
      • Van Manen J.G.
      • Korevaar J.C.
      • Dekker F.W.
      • et al.
      Adjustment for comorbidity in studies on health status in ESRD patients: which comorbidity index to use?.
      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 (though not ideal) substitute toward the end of life.
      • Kutner J.S.
      • Bryant L.L.
      • Beaty B.L.
      • Fairclough D.L.
      Symptom distress and quality-of-life assessment at the end of life: the role of proxy response.
      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,
      • Cohen L.M.
      • McCue J.D.
      • Germain M.
      • Kjellstrand C.M.
      Dialysis discontinuation. A “good” death?.
      • Cohen L.M.
      • Germain M.
      • Poppel D.M.
      • Woods A.
      • Kjellstrand C.M.
      Dialysis discontinuation and palliative care.
      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.
      • Field D.
      • Addington-Hall J.
      Extending specialist palliative care to all?.
      • Addington-Hall J.
      • Fakhoury W.
      • McCarthy M.
      Specialist palliative care in nonmalignant disease.
      • Levy J.B.
      • Chambers E.J.
      • Brown E.A.
      Supportive care for the renal patient.
      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.

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