Saudi Journal of Kidney Diseases and Transplantation

: 2009  |  Volume : 20  |  Issue : 1  |  Page : 1--11

Short daily and nocturnal hemodialysis: New therapies for a new century?

Micheal V Rocco 
 Nephrology Section, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA

Correspondence Address:
Micheal V Rocco
Section on Nephrology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina, 27157-1053


The National Institutes of Health (NIH) sponsored HEMO Study did not demonstrate that an increase in dialysis dose was associated with an improvement in patient mortality rates. Despite this negative result, there is ongoing interest in determining if still higher doses of dialysis may be of benefit to patients receiving chronic hemodialysis therapy. Testing this hypothesis requires the use of more fre­quent hemodialysis and/or a much longer duration for each dialysis session. «DQ»Short daily hemodialysis«DQ», actually six times per week hemodialysis for 1.5 to 3 hours per session, provides a significant increase in small molecule clearance as measured by urea kinetics. «DQ»Long nocturnal daily hemodialysis«DQ», actually six times per week hemodialysis for 6-8 hours per session, provides a significant increase in both small and large molecular weight clearance and often alleviates the need to take phosphate binders. Both forms of more frequent dialysis have been shown to improve control of blood pressure. One small randomized trial of nocturnal versus conventional home dialysis showed a decrease in left ventricular (LV) mass at 6 months in the nocturnal arm only. Most clinical trials conducted in these dialysis modalities have been observational trials and have enrolled small numbers of patients. The National Institutes of Health is sponsoring two clinical trials via the Frequent Hemodialysis Network to determine the effect of these two more frequent dialysis modalities on intermediate outcomes. In the short daily study, 250 patients will be randomized to receive either six times per week HD, with a session length of 1.5 to 2.75 hours, or conventional in-center hemodialysis. In the nocturnal study, 150 patients will be randomized to receive either six times per week overnight dialysis, with a session length of at least 6 hours, or conventional home hemodialysis.

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Rocco MV. Short daily and nocturnal hemodialysis: New therapies for a new century?.Saudi J Kidney Dis Transpl 2009;20:1-11

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Rocco MV. Short daily and nocturnal hemodialysis: New therapies for a new century?. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2021 Jan 20 ];20:1-11
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The effect of a higher dose of dialysis on pa­tient mortality and morbidity has been studied in the National Cooperative Dialysis Trial and the HEMO Study. The latter trial, conducted from 1995-2002 and the largest conducted to date in chronic hemodialysis patients, was de­signed to determine if a higher dose of dialysis, as provided by a three times per week schedule, or the use of high flux dialyzers decreased mor­tality and morbidity in chronic hemodialysis patients. Those patients randomized to the high dose arm (mean equilibrated Kt/V [eKt/V] of 1.53 ± 0.09, mean single pool Kt/V [sp Kt/V] of 1.71 ± 0.11) had a mortality rate that was no different than patients randomized to the stan­dard dose arm (mean eKt/V 1.16 ± 0.08, mean sp Kt/V of 1.32 ± 0.09; relative risk [RR] = 0.96, 95% confidence interval [95% CI] = 0.84­1.10; p = 0.53) [Figure 1]. [1],[2] Similarly, those patients randomized in the high flux arm (beta 2 microglobulin [132M] clearance of > 20 mL/min) had a mortality rate that was not different from patients randomized to the low flux arm (12M clearance [3] In addition, mean cumulative predialysis serum [32M levels were associated with all-cause mor­tality (relative risk = 1.11 per 10-mg/L increase in [32M level; 95% CI 1.05 to 1.19; p = 0.001), after adjustment for residual kidney urea clea­rance and number of pre-study years on dia­ lysis. [3]

There are several possible explanations for the negative results for the primary and secondary outcomes of the HEMO Study. First, the in­crease in the weekly clearance of small mole­cules, such as urea, in the high dose arm of the trial was only about 20%, as the standard or weekly Kt/V urea was about 2.4 in the high dose group and 2.0 in the standard dose group. In addition, the clearance of middle molecules is dependent on the total time on dialysis. Pa­tients in the high dose group received dialysis for about 90 more minutes per week than pa­tients in the standard arm, an increase of about 15%. When the HEMO Study results are viewed in the light of this modest increase in dose in the high dose arm, it is not quite as surprising that the study results for dialysis dose were negative. With current technology, it will be difficult to significantly further increase the weekly clearance of small and middle mole­cules with three times per week hemodialysis. Thus, to determine if still higher doses of dia­lysis may result in improved patient outcomes, patients will need to receive hemodialysis more than three times per week and/or for a much greater duration than 3 to 5 hours per session.

 General information on more frequent hemodialysis therapies

The negative results of the HEMO Study have intensified research efforts in the area of more frequent hemodialysis. Regimens for more fre­quent hemodialysis regimens include "short daily" hemodialysis and "long slow nocturnal daily" hemodialysis. Short daily hemodialysis is typically performed 6 to 7 days per week and each session usually lasts from 1.5 to 3.0 hours. These sessions are usually performed using dia­lyzers of large surface area (~ 2 m 2 ) with high blood flow (400-500 mL/min) and dialysate flow (500-800 mL/min) rates. The dialysis ses­sions can be performed either in-center or at home, although the cost of performing this the­rapy in-center may be prohibitive. Most studies have been conducted using a weekly time on dialysis that is similar to that prescribed to pa­tients receiving conventional three times per week hemodialysis. Thus, although there is a modest increase in urea clearance with short daily dialysis, there is little difference in middle molecule clearance between these two moda­lities.

Nocturnal home hemodialysis is performed 3­6 nights per week with each dialysis session usually lasting between 5 and 8 hours. Dialyzers of a smaller surface area are often used, with low blood (200-300 mL/min) and dialysate (200- 300 mL/min) flow rates. Additional monitoring devices are often used during the dialysis ses­sion to help identify any potential problems that may occur during the dialysis treatment. There measures include the use of moisture detectors around the site of cannulation and under the dialysis machine to detect blood leaks and ma­chine leaks, respectively, and the use of auto­mated blood pressure cuffs that will provide alarms if the patient's blood pressure falls out­side of pre-specified ranges. Some centers will use single needle instead of double needle dia­lysis for these sessions to minimize the number of fistula cannulations. Many centers train their patients to use the buttonhole technique for fis­tula cannulation. With this technique, a sharp needle is used to cannulate the access in the exact same location each time until a fibrous track is created. Once this track has developed, then blunt needles can be used to access the track and thus the fistula. Most patients find cannulation easier with the buttonhole tech­nique and some report less discomfort during cannulation. There are no data to suggest if either single needle hemodialysis or the use of a buttonhole technique for fistula access reduces the rate of vascular access complications.

 History of more frequent dialysis therapies

Both short daily and nocturnal hemodialysis have their origins in the early days of chronic hemodialysis therapy. Daily in-center hemodia­lysis was first performed in the late 1960s and early 1970s in both the United States and in Europe. [4] (reprint in: Semin Dial 1999;12:406- 409) [5] (reprint in: Nephrol Dial Transplant 1998; 13:2774-2778). Bonomini noted in 1972 that in six patients who had uremic type symptoms despite an increase in their time on dialysis from 22 to 30 hours per week, that changing patients to short daily dialysis (3-4 hours for five days per week) resulted in resolution of severe anemia, polyneuropathy, insomnia, pru­ritus, restless leg syndrome, anorexia, ameno­rrhea and impotence. Similar improvements in these and other areas, such as blood pressure control and left ventricular hypertrophy, have been noted by many other investigators since that time in both Europe and North America. [6],[7],[8],[9]

Nocturnal home hemodialysis was developed in the 1960s, and was performed three nights per week, [10],[11],[12],[13] although there was at least one report from 1968 that described a patient re­ceiving nocturnal hemodialysis 5 times per week. [14] A variation on the theme of overnight dialysis was developed by Dr. Charra and his group from Tassin, France. This group dialyzed patients in-center overnight for 8 hours three times per week. Their groundbreaking article in 1992 described a survival rate of 87% at 5 years, 75% at 10 years, 55% at 15 years, and 43% at 20 years; a rate much higher than that from any other chronic hemodialysis registry [Figure 2]. [15] Drs. Udall and Pierratos in Toronto, Canada modified these forms of nocturnal dialysis by combining three concepts - more frequent HD, longer duration of HD and home HD - into today's version of nocturnal home hemodialysis where patients perform hemodialysis at home for 5 to 8 hours per night for 5 to 6 nights per week. [16],[17]

 Clearance of small and middle molecules with more frequent therapies

Both forms of more frequent dialysis provide a higher quantity of solute removal and a more physiological modality of solute removal than conventional thrice weekly HD. Short daily hemodialysis takes advantage of the increased removal of small solutes in the first 120 mi­nutes of hemodialysis compared to the subse­quent 120 minutes on hemodialysis [Figure 3]. [18] This initial, rapid removal of urea is due to both a higher diffusion rate (driven by the large ini­tial concentration difference between blood and dialyzer) and to the multicompartment structure of the human body. Therefore, although a short hemodialysis treatment of 2 hours will decrease the removal of low-weight solutes, such as urea, by 30-40% per session, the increase in the number of sessions per week from 3 to 6 results in an increase in the weekly removal of urea by 20-40%. [19] Short daily hemodialysis provides an increased clearance of other non-protein bound solutes such as creatinine, uric acid and some protein bound solutes, including indole-3-acetic acid, indoxyl sulfate, and p-cresol. [20] There does not, however, appear to be an increase in the clearance of beta-2-microglobulin with short daily hemodialysis, [21] suggesting that middle molecule clearance is not significantly in­creased by short daily hemodialysis. The degree of phosphorus removal using short daily dialysis is dependent on the dialysis prescription. By performing daily dialysis for three hours six times per week, Ayus reported that weekly mean phosphorus removal was 2452 ± 720 mg/ week compared to 1572 ± 366 mg/week in conventional 3 times per week hemodialysis. The percentage of patients using phosphate bin­ders decreased from 77 to 40% among subjects on daily hemodialysis, whereas these parame­ters did not change (76 vs 77%) in the patients receiving conventional hemodialysis [22] Most studies that perform dialysis for shorter periods of time per dialysis session, have not been able to demonstrate this decrease in phosphate bin­ ders prescribed. [23]

In nocturnal dialysis, there is a significantly increased clearance of both small and larger molecules, as well as charged molecules. For example, the plasma concentration of beta-2­microglobulin declines by about 50% in pa­tients on nocturnal hemodialysis six nights per week. [24] The estimated clearance for phosphorus is equivalent to or exceeds the phosphorus intake in most patients. [25] Thus, most patients who perform nocturnal hemodialysis using a two needle system do not require the use of phosphate binders and some patients need to add phosphate to the dialysate in order to pre­vent hypophosphatemia. In this latter instance, phosphorus, in the form of Fleet enema® or Fleet phosphosoda® (oral), is added to the acid bath of the dialysate. [26],[27]

The removal of larger molecules such as beta­2-microglobulin is mostly dependent on time; [18] thus the much longer duration of nocturnal dialysis (30 or more hours per week) compared to either conventional hemodialysis (9-15 hours/ week) or short daily hemodialysis (9-18 hours per week) accounts for the higher clearance of these middle molecules with nocturnal hemo­dialysis. In comparison to conventional three times per week dialysis, the mass of mass of beta-2-microglobulin removed in one study was significantly higher with nocturnal hemodia­lysis (585 ± 309 mg versus 127 ± 48 mg, res­pectively, with predialysis beta-2-microglobulin levels at the end of one week of therapy 26.2 ± 5.2 mg/dL versus 19.8 ± 3.8 mg/dL with con­ventional hemodialysis. [24] Serum beta-2-micro­globulin pre-dialysis levels progressively dec­lined from 27.2 ± 11.7 mg/dL at initiation of nocturnal hemodialysis to 13.7 ± 4.4 mg/dL by 9 months, and then remained stable thereafter on nocturnal hemodialysis.

 Outcomes with more frequent hemodialysis therapies

Despite the growth of both daily and nocturnal hemodialysis programs, there is a paucity of data on outcomes with these modalities. A review of published daily in-center hemodia­lysis programs, published in 2006, was able to identify only 25 manuscripts that met the follo­wing criteria: 1) Five or more adult patients, 2) Follow-up of at least 3 months, 3) Prescription of 1.5-3 hours 5-7 days/week, 4) Published after 1989. [23] A total of 14 cohorts with 268 unique patients were described in these publications, with only one cohort enrolled in a randomized trial. A review of these studies, in toto, showed a clear benefit of daily in-center hemodialysis to improve the control of hypertension, by either reducing the number of antihypertensive medications required and/or improving systolic and diastolic blood pressures. Less clear was the benefit of this modality on anemia, with 7 of 11 studies showing an improvement in the treatment of anemia, either by a reduction in erythropoietin dose or an increase in hemo­globin levels. The findings for both serum albu­min levels and quality of life were mixed, with 5 of 10 studies demonstrating an improvement in these areas. Improvement in phosphate control, as determined by either serum phos­phate levels or a decrease in the utilization of phosphate binders, was seen in only 2 of 8 studies. The Ayus study discussed above [22] was not included in this review. Finally, there was no change in the rate of vascular access dys­function in 5 of the 7 reported studies. The small number of patients enrolled in these studies (the largest cohort was 42 patients) and the lack of dialysis prescription information in 8 of the 14 studies reviewed make it difficult to conclude that these results are definitive.

A smaller number of studies have been pub­lished in nocturnal hemodialysis and a recent review was able to identify only 10 manuscripts and 4 abstracts that met the following criteria: 1) Prescription of at least 5 nights per week and 6 hours per session, 2) Reported on at least one of four outcomes of interest, 3) Follow-up of at least 4 weeks, 4) Included a comparator group (case-control or pre/post within patient com­parison). [28] A total of 4 cohorts with 4-63 patients per cohort were identified, with follow­up ranging from 6 weeks to 3.4 years; none of the studies were randomized trials. There was a clear benefit of daily nocturnal hemodialysis in improving the control of hypertension, by both reducing the number of antihypertensive medi­cations required and improving systolic and diastolic blood pressures. Nocturnal dialysis was shown to improve anemia parameters, either by a reduction in erythropoietin dose or an increase in hemoglobin levels. Improvement in phos­phate control, as determined by either serum phosphate levels or a decrease in the utilization of phosphate binders, was seen in 1 of 2 studies. The importance of the dialysis prescription is important in interpreting this finding. In the study showing a benefit in phosphate control, all patients were receiving double needle hemo­dialysis while in the negative study, most patients were receiving single needle hemo­dialysis. Other studies not included in this re­view have also shown a benefit of nocturnal dialysis on phosphorus removal and a decrease in the number of binders needed to achieve normal phosphorus levels. [29] Quality of life was measured by different methods in these cohorts, so it was not possible to provide a summary statistic in this area; however, in each of the studies, there was an improvement seen in quality of life. In observational studies, im­provements have also been described for pa­tients with sleep apnea. [30]

Since the time of the review, a randomized trial of three times per week versus nocturnal six times per week hemodialysis conducted in 52 patients in Alberta Canada has been con­cluded. [31] The primary outcome, change in LV mass, was measured at baseline and at 6 months of follow-up in 35 patients. LV mass decreased in the nocturnal group but not in the con­ventional HD group (-17.8 ± 24.8 g versus +1.8 ± 26.7 g, respectively, p = 0.03). Antihyperten­sive medication use was reduced or discon­tinued in 16 of 26 patients randomized to noc­turnal hemodialysis and in 3 of 25 patients ran­domized to conventional hemodialysis (p [32] In the Lynchburg cohort, 34 nocturnal home hemo­dialysis patients were using tunneled internal jugular catheters (930 patient months of follow­up), 10 were using arteriovenous fistulas (190 patient months) and 1 was using an arte­riovenous graft (20 patient months). Mean ca­theter life was 8.5 months, with a range from 0.2 to 66.7 months. Exit site and infection rates for catheters were 0.35 and 0.52 episodes per 1000 patient days. The AV fistula and graft exit-site and sepsis infection rates were 0.16 and 0 episodes per 1000 patient days, respec­tively. Catheter complications included one epi­sode of disconnect due to patient's failure to use the locking device, one episode of central ste­nosis, and one episode of intracranial hemo­rrhage, due to prolonged INR, with resolution of symptoms. [33]

Finally, additional data on short daily and noc­turnal dialysis patients are being collected via an international registry. As of February 2006, 229 patients from the United States and Canada were entered into the registry and ethics appro­val was submitted for programs in Australia, New Zealand, France, Sweden, the United Kingdom, Finland and Hong Kong. [34]

Despite the research performed thus far in these more frequent hemodialysis modalities, more data are needed before more frequent dialysis regimens can be routinely recom­mended for chronic hemodialysis patients. The workgroup for the 2006 National Kidney Foun­dation's Kidney Disease Outcomes Quality Initiative (KDOQI) Update in Hemodialysis recognized the lack of definitive evidence in this area and thus did not provide any guide­lines, only clinical practice recommendations or opinions.

In this update, it was noted that, in the opi­nion of the work group, more frequent hemo­dialysis should be considered in those patients with hyperphosphatemia (nocturnal hemodia­lysis), chronic fluid overload or those who are either malnourished or losing weight. Frequent hemodialysis may be helpful for improving: quality of life, quality of sleep, reducing sleep apnea (nocturnal hemodialysis) and improving the sensitivity to erythropoietin stimulating agents. [35]

 Ongoing research in more frequent hemodialysis therapies

The NIH sponsored Frequent Hemodialysis Network (FHN) is designed to provide addi­tional information on more frequent hemo­dialysis therapies in a larger cohort of patients. Two trials in six times per week or "daily" dialysis are being performed through the FHN consortium. In the daily dialysis study, 250 patients will be randomized to receive either in­center hemodialysis six times per week or conventional in-center hemodialysis three times per week. Patients in the daily arm of the trial will be on dialysis for 1.5 to 2.75 hours, with the individual prescription designed to achieve a median eKt/V of 0.92 per session (range 0.74 to 1.02). In the nocturnal study, 150 patients will be randomized to receive either six times per week nocturnal or overnight hemodialysis or conventional three times per week home hemodialysis. [36] Patients in the nocturnal arm of the trial will receive dialysis for a minimum of 6 hours of dialysis six times per week. The typical dialysis prescription and estimated clea­rances for patients in the FHN nocturnal study are shown in [Table 1]. Similar data for the FHN Daily Study are shown in [Table 2]. In sum, the daily in-center arm of the trial provides a modest but significant increase in the weekly clearance of small molecules, while the noc­turnal arm of the trial will provide for markedly higher clearances of both small and middle molecules. Both of the daily arms will allow for a shorter interdialytic interval and a lower inter­dialytic weight gain than conventional three times per week therapies.

The small sample size for these two trials does not allow for sufficient power to detect diffe­rences in either mortality rates or clinically significant differences in hospitalization rates. Therefore, a number of intermediate outcomes, that are the same for both trials, have been chosen for primary and secondary endpoints. The two co-primary outcomes are a composite of mortality with the change over 12 months in left ventricular mass as measured by cardiac magnetic resonance imaging and a composite of mortality with the change over 12 months in the SF-36 RAND physical health composite. Secondary outcomes include cardiovascular structure and function (change in left ventri­cular mass), health-related quality of life/phy­sical function (change in the physical heath composite), depression/burden of illness (change in Beck Depression Inventory), nutrition and inflammation (change in serum albumin level), cognitive funtion (change in the Trail Making Test B), mineral metabolism (change in average predialysis serum phosphorus), survival, and hospitalization. In addition, hypertensive status and anemia have been designated as main out­come domains, but without single first priority outcomes. Vital status, hospitalizations and access procedures will be monitored throughout the 12 month follow-up period.

It is anticipated that the FHN Daily trial will be completed in early 2010 and the FHN Nocturnal trial will be completed in early 2011. The results from these trials should help to determine if providing patients with more frequent volume removal and a higher level of solute clearance from dialytic therapies will re­duce the unacceptably high mortality and hospi­talization rates in patients receiving chronic hemodialysis therapy.


The author thanks Laura Harvey for her exce­llent secretarial assistance. Dr. Rocco is sup­ported by grant # 5 U01 DK066480 from the National Institute of Diabetes and Digestive and Kidney Diseases.[37]


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