Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • ASN Meeting Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
    • Reprint Information
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Reprint Information
    • Subscriptions
    • Feedback
  • ASN Kidney News
  • Other
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • ASN Meeting Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
    • Reprint Information
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Reprint Information
    • Subscriptions
    • Feedback
  • ASN Kidney News
  • Visit ASN on Facebook
  • Follow CJASN on Twitter
  • CJASN RSS
  • Community Forum
Perspectives
Open Access

Contextualizing the FHN Nocturnal Trial a Decade Later

How Nocturnal Home Hemodialysis Is Performed Matters to Outcomes

Robert P. Pauly and Brent W. Miller
CJASN November 2020, CJN.09160620; DOI: https://doi.org/10.2215/CJN.09160620
Robert P. Pauly
1Division of Nephrology, University of Alberta, Edmonton, Alberta, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Brent W. Miller
2Division of Nephrology, Indiana University, Indianapolis, Indiana
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Brent W. Miller
  • Article
  • Info & Metrics
  • View PDF
Loading
  • daily hemodialysis
  • Epidemiology and outcomes
  • chronic dialysis

Introduction

Long, frequent hemodialysis (HD) was thought to be a sound treatment because of improved clearance of uremic toxins and control of extracellular fluid volume. After all, no solute or volume control is tantamount to no dialysis, and whatever its shortcomings, dialysis does keep people alive. The question really is how much solute and volume control keeps people “more alive” (i.e., living longer and better).

With nocturnal HD, treatments occur three to seven times per week, typically lasting 6–9 hours. The last 2 decades have seen much observational evidence espousing its benefits, from mineral metabolism, exercise capacity, cardiovascular function, sleep, pill burden, diet, and health-related quality of life. Even the first randomized controlled trial comparing nocturnal HD with conventional dialysis (often called the Alberta trial) seemed to confirm the observational literature by demonstrating reduced left ventricular mass index, a surrogate of heart function and of mortality (1). These observations, that a large increase in dialysis dose was beneficial, were in stark contrast to the Hemodialysis (HEMO) trial, which failed to show any benefit in a small incremental increase in dialysis dose with thrice-weekly center-based HD.

The Frequent Hemodialysis Network Nocturnal Trial and Its Pitfalls

In April 2001, the National Institute of Diabetes and Digestive and Kidney Diseases convened a task force in Bethesda, Maryland, out of which the Frequent Hemodialysis Network (FHN) studies group emerged. A statistical model presented at the meeting suggested between 1622 and 3892 patients followed for 3 years would need to be enrolled to demonstrate a mortality difference; enrollment on this scale was not felt to be feasible.

The FHN consortium ultimately chose to study both daily and nocturnal dialysis in parallel but separate randomized controlled trials using a creative coprimary composite end point of mortality plus change in left ventricular mass and mortality plus change in the physical health composite score of the SF-36 (2). The requisite sample size of 250 patients would have had 80% power to detect reasonable changes in left ventricular mass and the physical health composite score after 1 year.

The center-based Short Daily trial achieved the recruitment target and demonstrated a benefit to more frequent HD (3). In contrast, the Nocturnal trial failed to reach statistical significance for either coprimary outcome (4). One possible explanation submitted by the authors for the lack of positive effect could be the greater proportion of participants on nocturnal HD who lost residual kidney function compared with conventional HD (5). Although compelling, especially given the association with residual kidney function and survival, this argument is predicated on accepting the Nocturnal trial as negative and that there are no other reasonable explanations for the loss in function.

With only 87 patients (of 118 ever recruited; 35% of the target sample size) ultimately randomized into the Nocturnal trial—and even then, only 72 had 12-month data for analysis—nocturnal HD would have needed to be nearly twice as effective as was hypothesized in order for the results to have been statistically significant—an optimistic expectation by any standard. This trial was not a negative study the way it is often portrayed; rather, it was an unsuccessful and inconclusive study because it was wholly underpowered for the primary outcome. Often overlooked is that nocturnal HD showed improvements in intermediate biochemical, hemodynamic, and quality of life outcome (6,7); even left ventricular mass was nearly significant with a P value of 0.09—all suggesting the generally positive effect of the modality.

The Nocturnal Trial Extension Study and Its Lessons

Published 4 years after the original investigation, the Nocturnal HD Extension study, with 5 years of follow-up, concluded that patients randomized to nocturnal HD had a higher mortality than those randomized to conventional dialysis (8). Case closed, right?

We suggest there are three critical, yet overlooked, aspects of the FHN Nocturnal trial worth re-examining. First, most patients randomized to conventional dialysis increased dialysis frequency to greater than thrice weekly, and many received >25 hours of dialysis per week after the initial 12 months of the trial. Given that the number of deaths in the extension phase far exceeded the number observed in the 12 months of the original study, it begs extreme caution attributing deaths to any given modality when the dialysis prescriptions of all patients became relatively homogeneous for a much longer period of time.

Second, there seems to be a pronounced difference in outcome depending on where patients received their care, with a mortality rate of 0.128 deaths per patient-year for those treated in the United States and a rate of 0.055 deaths per patient-year in Canada. Although not analyzed formally, it does raise the provocative question of whether the participating Canadian sites systematically conducted nocturnal HD differently than their American counterparts.

Third, centers were categorized as “experienced” with nocturnal HD if they had trained more than five patients for nocturnal HD prior to trial participation. This implies that a center having previously trained just six patients would be considered experienced. However, one could argue that meaningful experience with nocturnal HD might not be achieved until a program had trained 50, 60, or even 70 patients—certainly not five, 10, or 20. Thus, with respect to the Nocturnal trial, six sites (of nine participating centers) had virtually no real experience with nocturnal HD.

Keeping in mind that the logistics of performing home nocturnal HD with conventional dialysis machines (as were used in the FHN trials) involve a hundred or so steps (we have counted) and that there was certainly much variation in ancillary care that would never have been standardized between study sites, one can easily imagine dozens of cointerventions that could cumulatively affect outcomes. This is particularly worrisome considering that the majority of patients were American and that more than half of those were recruited from a single center. Thus, one center could have had a disproportionate influence (good or bad) on the trial, and even a small number of adverse events from inexperienced sites could have profoundly skewed results. For example, returning to the observation of more rapid loss of residual kidney function with nocturnal HD, for believers that the Nocturnal trial suggests increased mortality risk (we contend there is insufficient evidence to support this interpretation), this is often cited as a possible mechanism for that increased risk. However, could an overzealous emphasis on BP reduction have resulted in overly aggressive downward titration of postdialysis target weights and an accompanying loss of residual function, which has more to do with the approach of the prescriber rather than the modality itself?

We speculate that practice patterns and experience with home dialysis among participating centers were important and likely underappreciated determinants of the trial’s outcome. Drawing from the peritoneal dialysis experience, it is recognized that important clinical outcomes, such as peritonitis, can be mitigated with increased patient training time, greater nurse experience with peritoneal dialysis, and periodic patient visits to evaluate dialysis in the home setting. Why would processes of care, such as these and others, have any less bearing for nocturnal HD?

How It Is Done Matters

Is there any evidence that practice patterns in nocturnal HD influence outcomes? To address this question, let us consider nocturnal HD delivery in Canada. Many, if not all, of the early adopters of nocturnal HD in Canada visited Dr. Andreas Pierratos’s units in the late 1990s and early 2000s to learn from, adopt, and adapt his program’s protocols and procedures. Although an outsider may be excused for assuming that Canadian nocturnal HD delivery is homogeneous, there is, in fact, considerable heterogeneity in almost all aspects of home dialysis care provision across the country (9). This led to the hypothesis that home HD disposition is influenced not only by patient mix but also by the treatment center, and a detailed analysis of the seven largest and most established home HD programs in Canada revealed a significant center effect for both technique failure and mortality (10).

This highlights that processes of care between centers are important determinants of that care: where patients are evaluated, trained, and followed up makes a difference to their clinical course. One can view a center effect as the cumulative result of all program policies, procedures, resourcing, and philosophy of care that influence a patient’s experience. Interestingly, four of the seven centers included in this multicenter cohort study were also four of the nine centers involved in the Nocturnal trial, further underscoring the critical influence any given center may have had on the trial’s outcomes.

Conclusions

Since the publication of the FHN Nocturnal trial and the Nocturnal Extension study, there has been waning interest in nocturnal HD. However, the Nocturnal trial was underpowered, inconclusive, and conducted by largely inexperienced centers. Home nocturnal HD is not an easy modality to deliver, and there is much left to learn about how best to train, monitor, and care for patients who opt for this therapy. However, our message is simple: the FHN Nocturnal trial should not dissuade providers from offering this modality. What we do and how we do it actually matter to the success of nocturnal HD. Ignoring this denies patients the opportunity to benefit from a potentially important treatment and slows progress toward developing best practices around nocturnal HD.

Disclosures

B.W. Miller reports consultancy agreements with Fresenius Medical Services; receiving honoraria from DaVita, Fresenius Renal Therapies Group, University of Southern California, and UpToDate; and serving as a scientific advisor or member of NxStage Medical Scientific Advisory Board. The remaining author has nothing to disclose.

Funding

None.

Acknowledgments

The content of this article reflects the personal experience and views of the author(s) and should not be considered medical advice or recommendation. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or CJASN. Responsibility for the information and views expressed herein lies entirely with the author(s).

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

  • Copyright © 2021 by the American Society of Nephrology

References

  1. ↵
    1. Culleton BF,
    2. Walsh M,
    3. Klarenbach SW,
    4. Mortis G,
    5. Scott-Douglas N,
    6. Quinn RR,
    7. Tonelli M,
    8. Donnelly S,
    9. Friedrich MG,
    10. Kumar A,
    11. Mahallati H,
    12. Hemmelgarn BR,
    13. Manns BJ
    : Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life: A randomized controlled trial. JAMA 298: 1291–1299, 2007pmid:17878421
    OpenUrlCrossRefPubMed
  2. ↵
    1. Suri RS,
    2. Garg AX,
    3. Chertow GM,
    4. Levin NW,
    5. Rocco MV,
    6. Greene T,
    7. Beck GJ,
    8. Gassman JJ,
    9. Eggers PW,
    10. Star RA,
    11. Ornt DB,
    12. Kliger AS
    ; Frequent Hemodialysis Network Trial Group: Frequent Hemodialysis Network (FHN) randomized trials: Study design. Kidney Int 71: 349–359, 2007pmid:17164834
    OpenUrlCrossRefPubMed
  3. ↵
    1. Chertow GM,
    2. Levin NW,
    3. Beck GJ,
    4. Depner TA,
    5. Eggers PW,
    6. Gassman JJ,
    7. Gorodetskaya I,
    8. Greene T,
    9. James S,
    10. Larive B,
    11. Lindsay RM,
    12. Mehta RL,
    13. Miller B,
    14. Ornt DB,
    15. Rajagopalan S,
    16. Rastogi A,
    17. Rocco MV,
    18. Schiller B,
    19. Sergeyeva O,
    20. Schulman G,
    21. Ting GO,
    22. Unruh ML,
    23. Star RA,
    24. Kliger AS
    ; FHN Trial Group: In-center hemodialysis six times per week versus three times per week [published correction appears in N Engl J Med 64: 93, 2011]. N Engl J Med 363: 2287–2300, 2010pmid:21091062
    OpenUrlCrossRefPubMed
  4. ↵
    1. Rocco MV,
    2. Lockridge RS Jr..,
    3. Beck GJ,
    4. Eggers PW,
    5. Gassman JJ,
    6. Greene T,
    7. Larive B,
    8. Chan CT,
    9. Chertow GM,
    10. Copland M,
    11. Hoy CD,
    12. Lindsay RM,
    13. Levin NW,
    14. Ornt DB,
    15. Pierratos A,
    16. Pipkin MF,
    17. Rajagopalan S,
    18. Stokes JB,
    19. Unruh ML,
    20. Star RA,
    21. Kliger AS,
    22. Kliger A,
    23. Eggers P,
    24. Briggs J,
    25. Hostetter T,
    26. Narva A,
    27. Star R,
    28. Augustine B,
    29. Mohr P,
    30. Beck G,
    31. Fu Z,
    32. Gassman J,
    33. Greene T,
    34. Daugirdas J,
    35. Hunsicker L,
    36. Larive B,
    37. Li M,
    38. Mackrell J,
    39. Wiggins K,
    40. Sherer S,
    41. Weiss B,
    42. Rajagopalan S,
    43. Sanz J,
    44. Dellagrottaglie S,
    45. Kariisa M,
    46. Tran T,
    47. West J,
    48. Unruh M,
    49. Keene R,
    50. Schlarb J,
    51. Chan C,
    52. McGrath-Chong M,
    53. Frome R,
    54. Higgins H,
    55. Ke S,
    56. Mandaci O,
    57. Owens C,
    58. Snell C,
    59. Eknoyan G,
    60. Appel L,
    61. Cheung A,
    62. Derse A,
    63. Kramer C,
    64. Geller N,
    65. Grimm R,
    66. Henderson L,
    67. Prichard S,
    68. Roecker E,
    69. Rocco M,
    70. Miller B,
    71. Riley J,
    72. Schuessler R,
    73. Lockridge R,
    74. Pipkin M,
    75. Peterson C,
    76. Hoy C,
    77. Fensterer A,
    78. Steigerwald D,
    79. Stokes J,
    80. Somers D,
    81. Hilkin A,
    82. Lilli K,
    83. Wallace W,
    84. Franzwa B,
    85. Waterman E,
    86. Chan C,
    87. McGrath-Chong M,
    88. Copland M,
    89. Levin A,
    90. Sioson L,
    91. Cabezon E,
    92. Kwan S,
    93. Roger D,
    94. Lindsay R,
    95. Suri R,
    96. Champagne J,
    97. Bullas R,
    98. Garg A,
    99. Mazzorato A,
    100. Spanner E,
    101. Rocco M,
    102. Burkart J,
    103. Moossavi S,
    104. Mauck V,
    105. Kaufman T,
    106. Pierratos A,
    107. Chan W,
    108. Regozo K,
    109. Kwok S
    ; Frequent Hemodialysis Network (FHN) Trial Group: The effects of frequent nocturnal home hemodialysis: The frequent hemodialysis network nocturnal trial. Kidney Int 80: 1080–1091, 2011pmid:21775973
    OpenUrlCrossRefPubMed
  5. ↵
    1. Daugirdas JT,
    2. Greene T,
    3. Rocco MV,
    4. Kaysen GA,
    5. Depner TA,
    6. Levin NW,
    7. Chertow GM,
    8. Ornt DB,
    9. Raimann JG,
    10. Larive B,
    11. Kliger AS
    ; FHN Trial Group: Effect of frequent hemodialysis on residual kidney function. Kidney Int 83: 949–958, 2013pmid:23344474
    OpenUrlCrossRefPubMed
  6. ↵
    1. Chan CT,
    2. Greene T,
    3. Chertow GM,
    4. Kliger AS,
    5. Stokes JB,
    6. Beck GJ,
    7. Daugirdas JT,
    8. Kotanko P,
    9. Larive B,
    10. Levin NW,
    11. Mehta RL,
    12. Rocco M,
    13. Sanz J,
    14. Schiller BM,
    15. Yang PC,
    16. Rajagopalan S
    ; Frequent Hemodialysis Network (FHN) Trial Group: Determinants of left ventricular mass in patients on hemodialysis: Frequent Hemodialysis Network (FHN) Trials. Circ Cardiovasc Imaging 5: 251–261, 2012pmid:22360996
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Garg AX,
    2. Suri RS,
    3. Eggers P,
    4. Finkelstein FO,
    5. Greene T,
    6. Kimmel PL,
    7. Kliger AS,
    8. Larive B,
    9. Lindsay RM,
    10. Pierratos A,
    11. Unruh M,
    12. Chertow GM
    ; Frequent Hemodialysis Network Trial Investigators: Patients receiving frequent hemodialysis have better health-related quality of life compared to patients receiving conventional hemodialysis. Kidney Int 91: 746–754, 2017pmid:28094031
    OpenUrlCrossRefPubMed
  8. ↵
    1. Rocco MV,
    2. Daugirdas JT,
    3. Greene T,
    4. Lockridge RS,
    5. Chan C,
    6. Pierratos A,
    7. Lindsay R,
    8. Larive B,
    9. Chertow GM,
    10. Beck GJ,
    11. Eggers PW,
    12. Kliger AS
    ; FHN Trial Group: Long-term effects of frequent nocturnal hemodialysis on mortality: The Frequent Hemodialysis Network (FHN) nocturnal trial. Am J Kidney Dis 66: 459–468, 2015pmid:25863828
    OpenUrlCrossRefPubMed
  9. ↵
    1. Pauly RP,
    2. Komenda P,
    3. Chan CT,
    4. Copland M,
    5. Gangji A,
    6. Hirsch D,
    7. Lindsay R,
    8. MacKinnon M,
    9. MacRae JM,
    10. McFarlane P,
    11. Nesrallah G,
    12. Pierratos A,
    13. Plaisance M,
    14. Reintjes F,
    15. Rioux JP,
    16. Shik J,
    17. Steele A,
    18. Stryker R,
    19. Wu G,
    20. Zimmerman DL
    : Programmatic variation in home hemodialysis in Canada: Results from a nationwide survey of practice patterns. Can J Kidney Health Dis 1: 11, 2014pmid:25780606
    OpenUrlCrossRefPubMed
  10. ↵
    1. Pauly RP,
    2. Rosychuk RJ,
    3. Usman I,
    4. Reintjes F,
    5. Muneer M,
    6. Chan CT,
    7. Copland M,
    8. Lindsay R,
    9. MacRae J,
    10. Nesrallah G,
    11. Pierratos A,
    12. Zimmerman DL,
    13. Komenda P
    : Technique failure in a multicenter Canadian home hemodialysis cohort. Am J Kidney Dis 73: 230–239, 2019pmid:30392981
    OpenUrlPubMed
PreviousNext
Back to top

In this issue

Clinical Journal of the American Society of Nephrology: 16 (1)
Clinical Journal of the American Society of Nephrology
Vol. 16, Issue 1
January 07, 2021
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in CJASN.
Enter multiple addresses on separate lines or separate them with commas.
Contextualizing the FHN Nocturnal Trial a Decade Later
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Contextualizing the FHN Nocturnal Trial a Decade Later
Robert P. Pauly, Brent W. Miller
CJASN Nov 2020, CJN.09160620; DOI: 10.2215/CJN.09160620

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Contextualizing the FHN Nocturnal Trial a Decade Later
Robert P. Pauly, Brent W. Miller
CJASN Nov 2020, CJN.09160620; DOI: 10.2215/CJN.09160620
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Introduction
    • The Frequent Hemodialysis Network Nocturnal Trial and Its Pitfalls
    • The Nocturnal Trial Extension Study and Its Lessons
    • How It Is Done Matters
    • Conclusions
    • Disclosures
    • Funding
    • Acknowledgments
    • Footnotes
    • References
  • Info & Metrics
  • View PDF

More in this TOC Section

  • Reducing the Burden of CKD among Latinx
  • Social Determinants of Health in People with Kidney Disease
  • Personal Experiences of Patients in the Interaction of Culture and Kidney Disease
Show more Perspectives

Cited By...

  • No citing articles found.
  • Google Scholar

Similar Articles

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Keywords

  • daily hemodialysis
  • epidemiology and outcomes
  • chronic dialysis

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Trainee of the Year
  • Author Resources
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • CJASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About CJASN
  • CJASN Email Alerts
  • CJASN Key Impact Information
  • CJASN Podcasts
  • CJASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe

© 2021 American Society of Nephrology

Print ISSN - 1555-9041 Online ISSN - 1555-905X

Powered by HighWire