Introduction
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
| Fatigue |
| Lethargy |
| Cognitive dysfunction |
| Symptoms of neuropathy |
| Uremic pruritus |
| Sleep disturbances |
| Anorexia, nausea |
| Restless legs |
| Depressive symptoms |
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
| Peritoneal Dialysis |
Hemodialysis |
| Weight gain (60) |
Myocardial stunning (61) |
| Glucose control (62) |
Postdialysis recovery time (28) |
| Peritoneal access issues (63) |
Vascular access issues (64) |
| Peritonitis (65) |
Sepsis (66) |
| 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) |
Endotoxemia (68) |
| 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.
Disclosures
None.
References
1. Hakim RM, Lazarus JM:
Initiation of dialysis. J Am Soc Nephrol 6: 1319–1328, 1995
2. National Kidney Foundation: KDOQI clinical practice guideline for hemodialysis adequacy: 2015 Update. Am J Kidney Dis 66: 884–930, 2015
3. Cooper BA, Branley P, Bulfone L, Collins JF, Craig JC, Fraenkel MB, Harris A, Johnson DW, Kesselhut J, Li JJ, Luxton G, Pilmore A, Tiller DJ, Harris DC, Pollock CA, Study I; IDEAL Study: A randomized, controlled trial of early versus late
initiation of dialysis. N Engl J Med 363: 609–619, 2010
4. Collins AJ, Foley RN, Chavers B, Gilbertson D, Herzog C, Ishani A, Johansen K, Kasiske BL, Kutner N, Liu J, St Peter W, Guo H, Hu Y, Kats A, Li S, Li S, Maloney J, Roberts T, Skeans M, Snyder J, Solid C, Thompson B, Weinhandl E, Xiong H, Yusuf A, Zaun D, Arko C, Chen SC, Daniels F, Ebben J, Frazier E, Johnson R, Sheets D, Wang X, Forrest B, Berrini D, Constantini E, Everson S, Eggers P, Agodoa L: US Renal Data System 2013 annual data report. Am J Kidney Dis 63[Suppl]: A7, 2014
5. Scialla JJ, Liu J, Crews DC, Guo H, Bandeen-Roche K, Ephraim PL, Tangri N, Sozio SM, Shafi T, Miskulin DC, Michels WM, Jaar BG, Wu AW, Powe NR, Boulware LE; DEcIDE Network Patient Outcomes in End Stage Renal Disease Study Investigators: An instrumental variable approach finds no associated harm or benefit with early dialysis initiation in the United States. Kidney Int 86: 798–809, 2014
6. Clark WF, Na Y, Rosansky SJ, Sontrop JM, Macnab JJ, Glassock RJ, Eggers PW, Jackson K, Moist L: Association between estimated glomerular filtration rate at
initiation of dialysis and mortality. CMAJ 183: 47–53, 2011
7. Eckardt KU, Gillespie IA, Kronenberg F, Richards S, Stenvinkel P, Anker SD, Wheeler DC, de Francisco AL, Marcelli D, Froissart M, Floege J; ARO Steering Committee: High cardiovascular event rates occur within the first weeks of starting hemodialysis. Kidney Int 88: 1117–1125, 2015
8. Manley HJ, Garvin CG, Drayer DK, Reid GM, Bender WL, Neufeld TK, Hebbar S, Muther RS: Medication prescribing patterns in ambulatory haemodialysis patients: Comparisons of USRDS to a large not-for-profit dialysis provider. Nephrol Dial Transplant 19: 1842–1848, 2004
9. Bailie GR, Eisele G, Liu L, Roys E, Kiser M, Finkelstein F, Wolfe R, Port F, Burrows-Hudson S, Saran R: Patterns of medication use in the RRI-CKD study: Focus on medications with cardiovascular effects. Nephrol Dial Transplant 20: 1110–1115, 2005
10. Weisbord SD, Fried LF, Mor MK, Resnick AL, Unruh ML, Palevsky PM, Levenson DJ, Cooksey SH, Fine MJ, Kimmel PL, Arnold RM: Renal provider recognition of symptoms in patients on maintenance hemodialysis. Clin J Am Soc Nephrol 2: 960–967, 2007
11. Mann BS, Manns BJ, Dart A, Kappel J, Molzahn A, Naimark D, Nessim SJ, Soroka S, Zappitelli M, Sood MM; Canadian Kidney Knowledge Translation and Generation Network (CANN-NET): An assessment of dialysis provider’s attitudes towards timing of dialysis initiation in Canada. Can J Kidney Health Dis 1: 3, 2014
12. Mujais SK, Story K, Brouillette J, Takano T, Soroka S, Franek C, Mendelssohn D, Finkelstein FO: Health-related
quality of life in CKD patients: Correlates and evolution over time. Clin J Am Soc Nephrol 4: 1293–1301, 2009
13. Perlman RL, Finkelstein FO, Liu L, Roys E, Kiser M, Eisele G, Burrows-Hudson S, Messana JM, Levin N, Rajagopalan S, Port FK, Wolfe RA, Saran R:
Quality of life in
chronic kidney disease (CKD): A cross-sectional analysis in the Renal Research Institute-CKD study. Am J Kidney Dis 45: 658–666, 2005
14. Weisbord SD, Fried LF, Arnold RM, Rotondi AJ, Fine MJ, Levenson DJ, Switzer GE: Development of a symptom assessment instrument for
chronic hemodialysis patients: The dialysis symptom index. J Pain Symptom Manage 27: 226–240, 2004
15. Wu AW, Fink NE, Marsh-Manzi JV, Meyer KB, Finkelstein FO, Chapman MM, Powe NR: Changes in
quality of life during hemodialysis and peritoneal dialysis treatment: Generic and disease specific measures. J Am Soc Nephrol 15: 743–753, 2004
16. Hays RD, Kallich JD, Mapes DL, Coons SJ, Carter WB: Development of the kidney disease
quality of life (KDQOL) instrument. Qual Life Res 3: 329–338, 1994
17. Harris A, Cooper BA, Li JJ, Bulfone L, Branley P, Collins JF, Craig JC, Fraenkel MB, Johnson DW, Kesselhut J, Luxton G, Pilmore A, Rosevear M, Tiller DJ, Pollock CA, Harris DC: Cost-effectiveness of initiating dialysis early: A randomized controlled trial. Am J Kidney Dis 57: 707–715, 2011
18. Kopple JD, Greene T, Chumlea WC, Hollinger D, Maroni BJ, Merrill D, Scherch LK, Schulman G, Wang SR, Zimmer GS: Relationship between nutritional status and the glomerular filtration rate: Results from the MDRD study. Kidney Int 57: 1688–1703, 2000
19. Lindsay R: The nutritional status of
chronic renal failure patients following the initiation of hemodialysis treatment. Am J Kidney Dis 40: 205–207, 2002
20. Ledebo I, Kessler M, van Biesen W, Wanner C, Wiecek A, Prichard S, Argilés A, Ritz E:
Initiation of dialysis-opinions from an international survey: Report on the dialysis opinion symposium at the ERA-EDTA Congress, 18 September 2000, nice. Nephrol Dial Transplant 16: 1132–1138, 2001
21. Pupim LB, Kent P, Caglar K, Shyr Y, Hakim RM, Ikizler TA: Improvement in nutritional parameters after initiation of
chronic hemodialysis. Am J Kidney Dis 40: 143–151, 2002
22. Mehrotra R, Berman N, Alistwani A, Kopple JD: Improvement of nutritional status after initiation of maintenance hemodialysis. Am J Kidney Dis 40: 133–142, 2002
23. Rocco MV, Paranandi L, Burrowes JD, Cockram DB, Dwyer JT, Kusek JW, Leung J, Makoff R, Maroni B, Poole D: Nutritional status in the HEMO study cohort at baseline. hemodialysis. Am J Kidney Dis 39: 245–256, 2002
24. Rocco MV, Dwyer JT, Larive B, Greene T, Cockram DB, Chumlea WC, Kusek JW, Leung J, Burrowes JD, McLeroy SL, Poole D, Uhlin L, Group HS; HEMO Study Group: The effect of dialysis dose and membrane flux on nutritional parameters in hemodialysis patients: Results of the HEMO study. Kidney Int 65: 2321–2334, 2004
25. Chertow GM, Johansen KL, Lew N, Lazarus JM, Lowrie EG: Vintage, nutritional status, and survival in hemodialysis patients. Kidney Int 57: 1176–1181, 2000
26. Artom M, Moss-Morris R, Caskey F, Chilcot J:
Fatigue in advanced kidney disease. Kidney Int 86: 497–505, 2014
27. Jhamb M, Liang K, Yabes J, Steel JL, Dew MA, Shah N, Unruh M: Prevalence and correlates of
fatigue in
chronic kidney disease and end-stage renal disease: Are sleep disorders a key to understanding
fatigue? Am J Nephrol 38: 489–495, 2013
28. Awuah KT, Afolalu BA, Hussein UT, Raducu RR, Bekui AM, Finkelstein FO: Time to recovery after a hemodialysis session: Impact of selected variables. Clin Kidney J 6: 595–598, 2013
29. Khatri M, Wright CB, Nickolas TL, Yoshita M, Paik MC, Kranwinkel G, Sacco RL, DeCarli C:
Chronic kidney disease is associated with white matter hyperintensity volume: The Northern Manhattan Study (NOMAS). Stroke 38: 3121–3126, 2007
30. Seidel UK, Gronewold J, Volsek M, Todica O, Kribben A, Bruck H, Hermann DM: The prevalence, severity, and association with HbA1c and fibrinogen of cognitive impairment in
chronic kidney disease. Kidney Int 85: 693–702, 2014
31. Drew DA, Bhadelia R, Tighiouart H, Novak V, Scott TM, Lou KV, Shaffi K, Weiner DE, Sarnak MJ: Anatomic brain disease in hemodialysis patients: A cross-sectional study. Am J Kidney Dis 61: 271–278, 2013
32. Schneider SM, Malecki AK, Müller K, Schönfeld R, Girndt M, Mohr P, Hiss M, Kielstein H, Jäger K, Kielstein JT: Effect of a single dialysis session on cognitive function in CKD5D patients: A prospective clinical study. Nephrol Dial Transplant 30: 1551–1559, 2015
33. Kurella M, Chertow GM, Luan J, Yaffe K: Cognitive impairment in
chronic kidney disease. J Am Geriatr Soc 52: 1863–1869, 2004
34. Kurella Tamura M, Unruh ML, Nissenson AR, Larive B, Eggers PW, Gassman J, Mehta RL, Kliger AS, Stokes JB; Frequent Hemodialysis Network (FHN) Trial Group: Effect of more frequent hemodialysis on cognitive function in the frequent hemodialysis network trials. Am J Kidney Dis 61: 228–237, 2013
35. Krishnan AV, Kiernan MC: Uremic neuropathy: Clinical features and new pathophysiological insights. Muscle Nerve 35: 273–290, 2007
36. Aggarwal HK, Sood S, Jain D, Kaverappa V, Yadav S: Evaluation of spectrum of peripheral neuropathy in predialysis patients with
chronic kidney disease. Ren Fail 35: 1323–1329, 2013
37. Jebsen RH, Tenckhoff H, Honet JC: Natural history of uremic polyneuropathy and effects of dialysis. N Engl J Med 277: 327–333, 1967
38. Ogura T, Makinodan A, Kubo T, Hayashida T, Hirasawa Y: Electrophysiological course of uraemic neuropathy in haemodialysis patients. Postgrad Med J 77: 451–454, 2001
39. Solak B, Acikgoz SB, Sipahi S, Erdem T: Epidemiology and determinants of
pruritus in pre-dialysis
chronic kidney disease patients. Int Urol Nephrol 48: 585–591, 2016
40. Mathur VS, Lindberg J, Germain M, Block G, Tumlin J, Smith M, Grewal M, McGuire D; ITCH National Registry Investigators: A longitudinal study of uremic
pruritus in hemodialysis patients. Clin J Am Soc Nephrol 5: 1410–1419, 2010
41. Pisoni RL, Wikström B, Elder SJ, Akizawa T, Asano Y, Keen ML, Saran R, Mendelssohn DC, Young EW, Port FK:
Pruritus in haemodialysis patients: International results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 21: 3495–3505, 2006
42. Kutner NG, Zhang R, Huang Y, Bliwise DL: Association of sleep difficulty with Kidney Disease
Quality of Life cognitive function score reported by patients who recently started dialysis. Clin J Am Soc Nephrol 2: 284–289, 2007
43. Parker KP, Bliwise DL, Bailey JL, Rye DB: Polysomnographic measures of nocturnal sleep in patients on
chronic, intermittent daytime haemodialysis vs those with
chronic kidney disease. Nephrol Dial Transplant 20: 1422–1428, 2005
44. Agarwal R, Light RP: Sleep and activity in
chronic kidney disease: A longitudinal study. Clin J Am Soc Nephrol 6: 1258–1265, 2011
45. Mucsi I, Molnar MZ, Ambrus C, Szeifert L, Kovacs AZ, Zoller R, BarĂłtfi S, Remport A, Novak M: Restless legs syndrome, insomnia and
quality of life in patients on maintenance dialysis. Nephrol Dial Transplant 20: 571–577, 2005
46. Novak M, Winkelman JW, Unruh M: Restless legs syndrome in patients with
chronic kidney disease. Semin Nephrol 35: 347–358, 2015
47. Lee J, Nicholl DD, Ahmed SB, Loewen AH, Hemmelgarn BR, Beecroft JM, Turin TC, Hanly PJ: The prevalence of restless legs syndrome across the full spectrum of kidney disease. J Clin Sleep Med 9: 455–459, 2013
48. Aritake-Okada S, Nakao T, Komada Y, Asaoka S, Sakuta K, Esaki S, Nomura T, Nakashima K, Matsuura M, Inoue Y: Prevalence and clinical characteristics of restless legs syndrome in
chronic kidney disease patients. Sleep Med 12: 1031–1033, 2011
49. Calviño J, Cigarrán S, Lopez LM, Martinez A, Sobrido MJ: Restless legs syndrome in non-dialysis renal patients: Is it really that common? J Clin Sleep Med 11: 57–60, 2015
50. Hedayati SS, Finkelstein FO: Epidemiology, diagnosis, and management of
depression in patients with CKD. Am J Kidney Dis 54: 741–752, 2009
51. Palmer SC, Vecchio M, Craig JC, Tonelli M, Johnson DW, Nicolucci A, Pellegrini F, Saglimbene V, Logroscino G, Hedayati SS, Strippoli GF: Association between
depression and death in people with CKD: A meta-analysis of cohort studies. Am J Kidney Dis 62: 493–505, 2013
52. Watnick S, Kirwin P, Mahnensmith R, Concato J: The prevalence and treatment of
depression among patients starting dialysis. Am J Kidney Dis 41: 105–110, 2003
53. Davison SN, Levin A, Moss AH, Jha V, Brown EA, Brennan F, Murtagh FE, Naicker S, Germain MJ, O’Donoghue DJ, Morton RL, Obrador GT; Kidney Disease: Improving Global Outcomes: Executive summary of the KDIGO controversies conference on supportive care in
chronic kidney disease: Developing a roadmap to improving quality care. Kidney Int 88: 447–459, 2015
54. Tong A, Sainsbury P, Chadban S, Walker RG, Harris DC, Carter SM, Hall B, Hawley C, Craig JC: Patients’ experiences and perspectives of living with CKD. Am J Kidney Dis 53: 689–700, 2009
55. Rettig RA, Levinsky NG, editors: Kidney Failure and the Federal Government, Washington, DC, National Academic Press, 1991
56. Galla JH: Clinical practice guideline on shared decision-making in the appropriate initiation of and withdrawal from dialysis. The Renal Physicians Association and the American Society of
Nephrology. J Am Soc Nephrol 11: 1340–1342, 2000
57. Mathew A, Obi Y, Rhee CM, Chen JL, Shah G, Lau WL, Kovesdy CP, Mehrotra R, Kalantar-Zadeh K: Treatment frequency and mortality among incident hemodialysis patients in the United States comparing incremental with standard and more frequent dialysis. Kidney Int 90: 1071–1079, 2016
58. Awuah KT, Gorban-Brennan N, Yalamanchili HB, Finkelstein FO: Patients initiating peritoneal dialysis started on two icodextrin exchanges daily. Adv Perit Dial 29: 1–3, 2013
59. Finkelstein FO: Performance measures in dialysis facilities: What is the goal? Clin J Am Soc Nephrol 10: 156–158, 2015
60. Pellicano R, Strauss BJ, Polkinghorne KR, Kerr PG: Longitudinal body composition changes due to dialysis. Clin J Am Soc Nephrol 6: 1668–1675, 2011
61. Burton JO, Jefferies HJ, Selby NM, McIntyre CW: Hemodialysis-induced cardiac injury: Determinants and associated outcomes. Clin J Am Soc Nephrol 4: 914–920, 2009
62. Grodstein GP, Blumenkrantz MJ, Kopple JD, Moran JK Coburn JW: Glucose absorption during continuous ambulatory peritoneal dialysis. Kidney Int 19: 564–567, 1981
63. McCormick BB, Bargman JM: Noninfectious complications of peritoneal dialysis: Implications for patient and technique survival. J Am Soc Nephrol 18: 3023–3025, 2007
64. Vascular Access Work Group: Clinical practice guidelines for vascular access. Am J Kidney Dis 48[Suppl 1]: S248–S273, 2006
65. Segal JH, Messana JM: Prevention of peritonitis in peritoneal dialysis. Semin Dial 26: 494–502, 2013
66. Foley RN, Guo H, Snyder JJ, Gilbertson DT, Collins AJ: Septicemia in the United States dialysis population, 1991 to 1999. J Am Soc Nephrol 15: 1038–1045, 2004
67. Sinnakirouchenan R, Holley JL: Peritoneal dialysis versus hemodialysis: Risks, benefits, and access issues. Adv
Chronic Kidney Dis 18: 428–432, 2011
68. McIntyre CW, Harrison LE, Eldehni MT, Jefferies HJ, Szeto CC, John SG, Sigrist MK, Burton JO, Hothi D, Korsheed S, Owen PJ, Lai KB, Li PK: Circulating endotoxemia: A novel factor in systemic inflammation and cardiovascular disease in
chronic kidney disease. Clin J Am Soc Nephrol 6: 133–141, 2011
69. Margetts PJ, Churchill DN: Acquired ultrafiltration dysfunction in peritoneal dialysis patients. J Am Soc Nephrol 13: 2787–2794, 2002
70. McIntyre CW, Goldsmith DJ: Ischemic brain injury in hemodialysis patients: Which is more dangerous, hypertension or intradialytic hypotension? Kidney Int 87: 1109–1115, 2015
71. Brown MC, Simpson K, Kerssens JJ, Mactier RA; Scottish Renal Registry: Encapsulating peritoneal sclerosis in the new millennium: A national cohort study. Clin J Am Soc Nephrol 4: 1222–1229, 2009
72. Palmer BF, Henrich WL: Recent advances in the prevention and management of intradialytic hypotension. J Am Soc Nephrol 19: 8–11, 2008
