Patients with CKD often experience a wide variety of symptoms as disease progresses. These same patients may have symptoms related to the effects of aging, the various comorbidities common to this population, or one or more of the medications prescribed for them (1,2). A challenge for the nephrologist is to consider if initiating dialysis will alleviate these symptoms. This becomes particularly important as patients approach ESRD, because the clinician must help decide with the patient and his/her family if and how the patient will benefit from starting dialysis. This review will focus on the timing of dialysis initiation and the effect of dialysis on health–related quality of life (HRQOL) and uremic symptoms.
Initiation of Dialysis
What is the best advice to provide to patients concerning the optimal time to initiate dialysis? Life ceases when the GFR reaches zero unless RRT is started. Patients will likely develop life-threatening complications of uremia, such as pericarditis, pulmonary edema, neurologic problems, and/or metabolic abnormalities (such as severe hyperkalemia), as kidney function becomes marginal. Common practice has been to initiate dialysis at some point after stage 5 CKD develops but before renal function ceases to avoid these complications. In addition to life-threatening complications of ESRD, patients often report various clinical symptoms as GFR declines. Dialysis is sometimes initiated relatively early in stage 5 CKD after initial symptoms appear or in an effort to avoid these symptoms completely. Early start of dialysis was defined in the Initiating Dialysis Early and Late (IDEAL) Trial as starting dialysis with an eGFR of ≥10 ml/min per 1.73 m2 (3). In the United States, these early-start dialyses have become very common. Over 40% of patients who start dialysis do so when the eGFR is >10 ml/min per 1.73 m2, although there seems to be a slight decrease in this percentage from 2010 to 2013 (4).
Do patients benefit from the early initiation of dialysis? Does early-start dialysis improve survival, reduce the likelihood of uremic complications, or reduce the frequency and/or intensity of uremic symptoms?
Recent studies of early dialysis initiation do not show improved outcomes. The IDEAL Trial randomized patients to an early (eGFR of 10.0–14.0 ml/min per 1.73 m2 estimated by the Cockcroft–Gault equation) versus late initiation of dialysis (eGFR of 5.0–7.0 ml/min per 1.73 m2) (3). The actual mean eGFR at initiation of dialysis was 12.0 ml/min per 1.73 m2 in the early-start group compared with 9.8 ml/min per 1.73 m2 in the late-start group. In this trial, the early initiation of dialysis did not result in significant improvements in mortality rates, cardiovascular or infectious events, or quality of life measures. However, interpretation of this study is complicated by the fact that 76% of the patients in the late-start group started dialysis when the eGFR was above the target of 7.0 ml/min per 1.73 m2 due to development of symptoms attributed by clinicians to renal failure.
Similar findings were observed in two other data registries: the US Renal Data System and the Canadian Registry (5,6). Scialla et al. (5) reported outcomes in 89,547 United States patients starting dialysis in 2008 with eGFR between 5 and 20 ml/min per 1.73 m2. They found no associated harm or benefit with early dialysis initiation. However, Clark et al. (6) examined the Canadian Registry and noted that early initiation of dialysis (mean±SD eGFR of 15.5±7.7 ml/min per 1.73 m2) compared with late initiation (mean±SD eGFR of 7.1±2 ml/min per 1.73 m2) was actually associated with a higher mortality rate, which was not fully explained by differences in baseline patient characteristics. Notably, this study based renal function on an eGFR; a lower creatinine in malnourished patients could lead to a falsely high eGFR, which can confound the data on mortality rates.
It is important to keep in mind that dialysis initiation at any level of GFR can be associated with an increase in cardiovascular events; a recent review of data from over 300 dialysis centers found increased cardiovascular events after hemodialysis (HD) initiation from the first week to the fifth month (7). The immediate period after dialysis initiation was noted to be associated with a particularly high risk of cardiovascular events (7).
Given the evidence that dialysis initiation may at times be associated with adverse outcomes or increased mortality, it is important to examine carefully the evidence that does exist suggesting that dialysis reduces or avoids the symptoms associated with advancing kidney failure. We might hypothesize that early-start dialysis prevents or delays the development, frequency, or intensity of uremic symptoms. However, the hypothesis that dialysis reduces uremic symptoms has not been tested rigorously and in fact, is not well supported by the literature. The interpretation of the literature is challenging, because the symptoms associated with uremia are often vague, difficult to quantify objectively, and difficult to distinguish from symptoms that can be attributed to conditions coexisting with advanced CKD or side effects of medications used to manage these conditions. Patients with stage 4 or 5 CKD are prescribed a mean of eight different medications (8,9). Many patients without comorbidities remain surprisingly asymptomatic until eGFRs are well below 10 ml/min per 1.73 m2. Some patients may have symptoms but adapt to and downplay these symptoms, reporting an acceptable sense of wellbeing, although family members may have noticed a change in level of functioning. Importantly, health care providers are often not aware of patients’ symptom burden, thus complicating their advice about when to start dialysis (10). This can make the decision to initiate dialysis for symptom relief challenging and difficult to clearly articulate in a formal guideline. In fact, in a questionnaire distributed to Canadian nephrologists, only 3% indicated that their institution had a formal policy for the initiation of dialysis (11).
Traditionally, the indications for initiating dialysis have been divided into two broad categories: absolute and relative indications (1,2). The 2015 Kidney Dialysis Outcome Quality Improvement (KDOQI) guidelines (“KDOQI clinical practice guideline for hemodialysis adequacy: 2015 Update”) recommend initiation of dialysis “based upon an assessment of signs and/or symptoms associated with uremia, evidence of protein-energy wasting, ability to safely manage metabolic abnormalities and/or volume overload rather than based on a specific level of kidney function if these symptoms or signs are absent” (2). Absolute indications that are generally agreed on include the presence of uremic pericarditis, uremic encephalopathy, intractable fluid overload, and/or electrolyte abnormalities that cannot be managed without dialysis. Relative indications include the presence of a constellation of symptoms that are attributable to advanced renal failure. These signs and symptoms were noted in the updated KDOQI 2015 guidelines and are adapted in Table 1 (2). What makes the interpretation of these symptoms so challenging is that their etiology is often multifactorial and can be related, at least in part, to various comorbidities, medications, or other complications of renal failure, such as anemia, volume overload, hyperparathyroidism, cardiovascular disease, hypertension, psychosocial stressors, etc.
Table 1. -
Signs and symptoms of patients with CKD attributable to advanced renal failure
|Symptoms of neuropathy
Modified from Kidney Dialysis Outcome Quality Improvement clinical practice guidelines (2
Effect of Dialysis Initiation on HRQOL
Assessments of HRQOL for patients with CKD not on dialysis using standardized instruments have generally shown lower scores (indicating worse patient perception of their quality of life) compared with the general population, particularly for the physical compared with the mental domain (12,13). HRQOL scores for patients with CKD not on dialysis are generally higher than scores reported for patients on dialysis (12,13). These scores decline progressively with decreasing renal function (12). Many variables correlate with the HRQOL scores, including age, sex, presence of diabetes, cardiovascular comorbidities, and stage of CKD (12).
Several tools to assess symptoms of patients on dialysis have been validated, including the Dialysis Symptom Index, the Choice Health Experience Questionnaire (CHEQ), and the Kidney Disease Quality of Life instrument (14–16). The initiation of dialysis has been reported to have a variable effect on these HRQOL measures. This was carefully studied in a national prospective cohort of patients initiating dialysis—the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) Study. This study looked at the quality of life at the time of dialysis initiation and 1 year later using the CHEQ (15). This questionnaire includes the 36–Item Short–Form Health Survey (SF-36) as well as questions examining 14 dialysis-specific domains. Changes in the SF-36 domains were examined over time and categorized as worsened, no change, or improved; 20%–31% of patients had worsening, 42%–60% had no change, and 19%–28% had improvement in the eight domains of this instrument. In the dialysis-specific domains, 19%–30% had worsening, 50%–65% had no change, and 16%–24% had improvement after 1 year of dialysis therapy. It, therefore, seemed that dialysis treatment showed no consistent relationship to quality of life measures or dialysis-specific symptoms. There were no statistically significant differences between HD and peritoneal dialysis (PD) on the effect of therapy on any of the SF-36 or dialysis-specific domains. The CHOICE Study has some important limitations. There was no control group (that is, patients with advanced CKD not starting dialysis); 928 patients completed a baseline CHEQ, but only 525 completed the questionnaire 1 year later. In total, 101 of the initial 928 patients died, which highlights the high mortality in the ESRD population and could have contributed to an underestimation of the negative effect of dialysis initiation on quality of life. In addition, it should be noted that the initial CHEQs were completed shortly after the initiation of dialysis (not before the start), thus perhaps missing an improvement in HRQOL during that initial period of RRT.
Similarly, in the IDEAL Trial (3), which looked at the timing of dialysis initiation and survival, HRQOL was also examined using two measures: the SF-36 and the Assessment of Quality of Life. The Assessment of Quality of Life is a generic instrument that measures quality of life for health interventions across five dimensions (illness, independent living, social relationships, physical senses, and psychologic wellbeing). Importantly, there were no differences with either instrument comparing early- with late-start patients on dialysis during the period of the study (17).
Effect of Dialysis on Uremic Symptoms
Looking at the effect of dialysis on various symptoms associated with advanced renal failure, much attention has been focused on worsening nutritional status and the development of cachexia that occurs as renal failure progresses (18). By the time that dialysis is started, patients can be significantly malnourished. It has been recommended that dialysis be initiated to prevent a worsening of the malnutrition that occurs with advancing CKD (19). In an international survey on initiation of dialysis, 72% of respondents selected malnourishment as a reason to start dialysis early (20).
Nutritional parameters clearly improve in the first 12 months after the initiation of dialysis, with the most striking improvements occurring in younger patients and those with the lowest serum albumin levels (21,22). However, it is important to note that malnutrition is highly prevalent in the dialysis population, is associated with poor outcomes, increases with dialysis vintage, and does not improve with increasing dose of dialysis. In the analysis of the nutritional status of the first 1000 patients randomized in the Hemodialysis Study, the majority had protein and energy intakes below the 2002 National Kidney Foundation–KDOQI guidelines at the time of enrollment (23). Only those patients who had been on dialysis for at least 3 months were included, and those with serum albumin levels <2.6 g/dl were excluded. In a 3-year follow-up period, nutrition parameters, such as serum albumin levels and postdialysis weights, were not affected by intensity of dialysis therapy (24). In a cohort study of 3009 patients, dialysis vintage had a significant inverse relationship with albumin, prealbumin, and cholesterol (25). This data suggest that initiating dialysis in patients with CKD may not affect nutritional status. However, other factors, such as dietary restrictions, inflammation from systemic illness, comorbidities, and the catabolic effect of dialysis, may complicate analysis as confounding variables.
Fatigue is a common symptom of patients with CKD and has been reported to be present in up to 89% of patients with advanced renal failure (26). It is multifactorial in etiology with CKD associations, including anemia, depression, low albumin levels, sleep disturbances, and restless legs syndrome (RLS) (27). In the CHOICE Study, patients with CKD reported vitality scores (a measure of fatigue) on the SF-36 of about 40 compared with 100 in the general population (15). One year after dialysis initiation, only 24% of patients reported improvement, and 27% reported worsened vitality (15). Other possible measures related to fatigue on SF-36, such as the domains of physical function and physical role, showed similar results (15). The HD procedure itself may cause patients to feel tired or washed out. Moreover, a mean of 4 hours of recovery time after each HD session to resume normal activities may contribute to the perception of fatigue (28).
Patients with progressive CKD develop cognitive impairment related to a variety of factors, including cerebrovascular disease, systemic inflammation, comorbidities, and exposure to uremic toxins (29–32). In a cross-sectional study that evaluated cognitive function with multiple standardized tests among patients with stages 3–5 CKD on HD, a graded decline in function with progression of CKD was noted (33). Similarly, in a cohort of 119 patients with stages 3–5 CKD (mean eGFR of 35±16 ml/min per 1.73 m2), there were significant cognitive deficits when memory, information processing speed, and executive function were compared with control patients (30). Cognitive impairment in patients on dialysis is also well documented (31,32).
There is no good evidence to support the idea that early initiation of dialysis will alter the severity of cognitive difficulties. In fact, in the CHOICE Study, only 17% of patients had an improvement in self-reported symptoms of cognitive functioning 1 year after dialysis initiation, whereas 26% had a worsening; cognitive performance function tests were not performed in this study (15). Interestingly, a recent study of 28 patients with ESRD showed improvements in various cognitive function tests (including measuring memory, attention, and executive functions) several hours later after a single HD session (32). This could suggest a reversible component to the impaired cognitive performance in this population. However, increasing the dose of dialysis does not improve cognitive function; in the Frequent Hemodialysis Network Trial, more frequent HD was not associated with any improvement in the primary cognitive outcome (34).
Neuropathy, which frequently develops in advanced stages of CKD, is characterized by a slowly progressive distal symmetrical polyneuropathy. Its clinical features include paresthesias, weakness, muscle wasting, and decreased deep tendon reflexes and vibration sensation (35). In a cross-sectional study of 100 adult patients with CKD and mean eGFR of 19.3±8.1 ml/min per 1.73 m2 who were evaluated with motor nerve conduction studies, 70% had evidence of polyneuropathy, which was asymptomatic in 6%, symptomatic and nondisabling in 51%, and disabling in 13% (36). The mean conduction nerve velocities decreased with increases in serum creatinine levels (36). The effect of dialysis on preventing further deterioration on uremic neuropathy was reported as early as 1967, when dialysis provided for >1 year resulted in a significant increase in mean motor nerve conduction velocities (37). Subsequent studies have shown that uremic neuropathy remains unchanged during up to 5 years of HD treatment (38).
Pruritus can be a distressing symptom that affects patients with CKD. A recent study showed that the prevalence of pruritus was 19% in patients with CKD, independent of the stage of CKD (39). However, in patients maintained on chronic HD, up to 84% of the patients reported pruritus occurring almost daily, and 42% reported that the pruritus was moderate to extreme (40,41). Pruritus was associated with poor sleep quality, reduced physical and mental composite scores on the SF-36, and depression (41).
Sleep disturbances are commonly reported by patients with CKD and often unrecognized by renal providers. These are well documented by polysomnography and associated with lower cognitive function scores, poorer patient–reported quality of life, and depressive symptoms (10,42,43). Interestingly, these sleep disturbances are independent of GFR but associated with age, sex, comorbidities, and medications (12,44). Sleep disturbances are more common and of greater severity in patients on HD compared with patients with CKD not on dialysis (44). Formal sleep testing shows that patients on HD have more sleep problems than patients with CKD not on dialysis, with less total sleep time and rapid eye movement sleep and higher brief arousal index, respiratory disturbance index, and numbers of sleep apneas (43,44). After the initiation of dialysis in the CHOICE Study, only 19% reported an improvement in sleep symptoms, and 24% reported a worsening of symptoms (15).
Sleep in CKD can also be affected by other factors, such as RLS, which has a prevalence of up to 25% in patients on dialysis (45,46). RLS has also been associated with higher cardiovascular mortality, decreased quality of life, and increased morbidity in these patients (46). The prevalence of RLS in patients with CKD not on dialysis is variable, with some authors reporting a prevalence similar to that in the general population, whereas others report a prevalence up to 26% (47–49). In a study of 110 patients with stages 2–4 CKD, 21 patients were classified as having probable RLS with self-administered questionnaires, but only in five patients was the diagnosis confirmed after careful questioning by a trained investigator. This suggests that self-administered questionnaires can overestimate the frequency of RLS and that the leg discomfort could be secondary to other disorders mimicking RLS (49).
Clinical depression diagnosed with a structured interview as well as depressive symptoms are commonly noted in both patients with CKD and patients with ESRD. Patients on dialysis, however, consistently have higher depression scores than patients with CKD not on dialysis. Clinical depression diagnosed by a structured interview affects about 20%–25% of patients with CKD and 25%–30% of patients on maintenance dialysis (50). Depressive symptoms are associated with an increased risk of death and a lower quality of life in both patients with CKD and patients with ESRD (51). The initiation of dialysis is associated with an increased incidence of depressive symptoms, with 44% of patients who recently initiated dialysis having Beck Depression Inventory scores above the validated cutoff value for clinical depression in patients with ESRD (52).
Challenge for the Nephrologist
Thus, the symptom burden and high level of disability in patients with advanced CKD are not necessarily improved by dialysis. Patients need to be informed that dialysis may or may not result in an improvement in their quality of life and functional status (53). It is difficult to accurately identify those individuals who are unlikely to benefit from dialysis. However, it is important to keep in mind that the dialysis procedure itself, both PD and HD, can have an effect on patients’ HRQOL. This relates to the burden and frequency of the procedure itself as well as the complications of treatment. Some of these concerns are outlined in Table 2. When health care providers discuss RRT with patients and their families, the potential benefits are usually emphasized, and the negative aspects of treatment are often not discussed or minimized.
Table 2. -
Selected dialysis-related issues that affect health-related quality of life
of patients on dialysis
|Weight gain (60)
||Myocardial stunning (61)
|Glucose control (62)
||Postdialysis recovery time (28)
|Peritoneal access issues (63)
||Vascular access issues (64)
|Daily dialysis routine (67)
||Three or more times per week treatment (67)
|Visits to dialysis facility (67)
||Transportation to hemodialysis unit (67)
|Exit site infections (65)
|Ultrafiltration problems (69)
||Cerebral ischemia (70)
|Encapsulating peritoneal sclerosis (71)
||Recurrent hypotension (72)
One of the challenges for nephrologists after symptom screening information has been obtained is what health care providers should do to address these symptoms. This requires a discussion among the clinician, the patient, and the patient’s family to set up realistic expectations by trying to sort out the effect of the symptoms on the patient’s quality of life and the risks and benefits of potential treatments. The executive summary of the Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference on Supportive Care in CKD (53) emphasized the difficulties in the development of treatment strategies given the significant variation in level of evidence for symptom management and the complexity of patients with CKD. Patients with CKD have a variety of symptoms that affect their perception of their quality of life, work, and social life. These symptoms can significantly add constraints to patients’ lives, particularly when combined with complex treatment regimens, medications and their side effects, and dietary restrictions (54). The multiplicity of symptoms that patients with CKD experience and the complexity of the patients can make the development of treatment strategies challenging and difficult. Nonpharmacologic and pharmacologic interventions can be potentially effective for managing these symptoms. The executive summary of the KDIGO Controversies Conference on Supportive Care in CKD (53) provides a list of symptoms experienced by patients with CKD and a high-level synthesis of the literature summarizing treatment strategies.
A time-limited trial of dialysis is a reasonable option when a patient has an uncertain prognosis, it is not clear if the individual will benefit from dialysis, or there is a lack of consensus from the patient/family about proceeding with RRT. This trial allows the patient and the family to evaluate the effect of dialysis and permits the clinician to evaluate the clinical response of symptoms to the treatment. In such circumstances, it is important to establish clear parameters delineating the decision to continue with dialysis (55). The duration of such a trial needs to be assessed on an ongoing basis taking into account the patient’s response to treatment. According to the clinical practice guidelines on shared decision making from the Renal Physicians Association and the American Society of Nephrology, it is appropriate to discontinue dialysis in the following situations: those patients who request to discontinue dialysis, those without capacity who previously indicated refusal of dialysis in oral or written advanced directive, and those without capacity whose appointed legal agents request for it to be discontinued (56).
Another approach to consider is an incremental approach to dialysis initiation defined as a gradual increase in the dialysis prescription over time for those patients with residual renal function. It has been proposed that this approach could potentially offer several benefits, including lessening the effect of the dialysis treatment itself, preservation of residual renal function, access preservation for those on HD and preservation of the peritoneal membrane for those on PD, reduced costs, and the potential for symptom relief with decreased treatment burden. Although there are no randomized, controlled trials comparing incremental with conventional dialysis, in a recent analysis of a cohort of patients on incident HD (57), there was no difference in overall mortality for the incremental HD group (twice weekly HD or less) compared with the conventional HD group (thrice weekly). However, those on incremental HD with a higher comorbidity burden had an associated higher mortality, suggesting that the approach of incremental HD would be most viable in those with fewer comorbidities. Similarly, this incremental approach has also been explored in patients on PD, as illustrated in a small report of patients on PD on an initial regimen of two icodextrin exchanges per day in an off-label use (58). This approach requires close monitoring, because adjustments are required to maintain adequacy as residual renal function declines with time.
Conclusion and Future Directions
In summary, the role of dialysis in managing the symptom burden of patients with advanced CKD is unclear. A variety of symptoms often develops as CKD progresses. Sorting out the relative contribution of the uremic environment from aging, the effect of various comorbidities, and the effect of myriad medications is challenging. HRQOL assessments suggest that, although some symptoms improve with the start of dialysis, others will not improve. Furthermore, the early initiation of dialysis does not improve patient outcomes or quality of life compared with late initiation.
The decision to initiate dialysis and the timing of that decision may or may not have an effect on the symptoms and quality of life of patients with advanced CKD. In this complex environment, dialysis initiation should be a shared decision–making process among the CKD/dialysis team, the patient, and the family. The information that is provided to patients and their families should include the benefits and harms of the various treatment options specific to that individual and the possible positive and negative effects on patient symptoms and quality of life. It is important that patients and families have realistic expectations of potential treatment options. Helping patients and families to be part of a problem-solving approach to individualized management will maximize treatment benefits.
Future research is needed to develop a better understanding of the effect of advanced CKD on patients’ symptoms and their perception of their quality of life. In addition, attention needs to be focused on better appreciating the effect of dialysis itself (and the different dialysis regimens) on patients’ quality of life. This can help guide the decision of when to initiate dialysis and the role of nondialytic supportive care in individual patient management.
Lastly, the routine incorporation of assessments of patient symptoms and the severity of these symptoms into routine care of the patient with CKD is critically important (59). Regulatory agencies have focused on the measurement of more easily quantifiable laboratory examinations rather than the more subjective assessments of patient perceptions of their symptoms and quality of life. This is perhaps beginning to change now, because some patient symptoms, such as depressive symptoms, are being incorporated into standardized patient care. However, assessing the entire constellation of uremic symptoms on an ongoing basis will indeed be challenging.
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