Wait Wait… Don’t Tell Me - Is More Dialysis Better?
Ajay K. Singh, MBBS, FRCP, MBA
Brigham and Women's Hospital/Harvard Medical School
In the United States, on National Public Radio there is a cute little radio show called Wait Wait Don’t Tell Me. It pits your knowledge against some of the best and brightest in the news and entertainment world while figuring out what's real news and what's made up. Well, in the world of kidney failure, the real news is that dialysis dose does matter and that more is better. In my view, what’s made up is that a urea reduction ratio (URR) of >65% or kT/V>1.2 is "adequate dialysis".
Could shortening the interdialytic interval by adding one or more dialysis treatments to the schedule make a difference? Yes, the evidence from Foley and co-workers (1) that was published in the New England Journal of Medicine presents a compelling case for changing the way we currently schedule dialysis. The authors discuss the importance of more frequent dialysis. Perhaps abrupt volume changes (going from too much volume to perhaps too little) and/or solute (changes in potassium or middle or small molecules) might be important after all. I discussed this paper here a few days ago.
Treatment of pregnant patients with more dialysis is better for both maternal and fetal outcomes. Both nocturnal dialysis and daily dialysis seem to result in better outcomes compared to thrice weekly dialysis; and a higher dose of dialysis does seem to make a difference. Two recent papers make this point (2,3) [discussed on this site yesterday], and the standard of care is now to provide 20 to 24 hours each week of high flux dialysis to pregnant patients – whether it’s regular or nocturnal delivery of dialysis (4). Of course, like Johnson and Johnson baby oil, one could also argue that if it’s good for babies it can’t be half bad for adults.
The paper in the New England Journal of Medicine by Glen Chertow and colleagues (5) provides strong evidence that greater frequency of dialysis improves outcomes. Chertow and colleagues published the Frequent Hemodialysis Network’s Daily Dialysis Trial. This was a prospective, multicenter, parallel-group clinical trial randomized of 245 dialysis-dependent adults who were randomized to either frequent (6 times per week) or standard (3 times per week) in-center hemodialysis for one year. What did they find? Frequent dialysis was significantly superior for both co-primary outcomes: The composite of death or change in left ventricular mass (“death/LVM”; Hazard ratio 0.61, 95%CI 0.46-0.82), as well as the composite of death or change in RAND Physical Health Composite from the SF-36 (“death/PHC”; HR 0.70, 95%CI 0.53-0.92). Secondary outcomes of hypertension and hyperphosphatemia were also improved, although patients in the frequent hemodialysis arm were more likely to undergo vascular access interventions (HR 1.71, 95%CI 1.08-2.73).
Of course you should ask how much evidence is there to indicate that more dialysis is better? Cited in the References section are a handful of studies that suggest exactly that (6-9), and I’ve only scratched the surface in reviewing what is out there.
What about the results of the HEMO study? It was also published in the New England Journal of Medicine (10); 1846 patients undergoing thrice-weekly dialysis were randomly assigned (using a two-by-two factorial design) to a standard or high dose of dialysis and to a low-flux or high-flux dialyzer. In the standard-dose group, the mean (±SD) urea-reduction ratio was 66.3±2.5 percent, the single-pool Kt/V was 1.32±0.09, and the equilibrated Kt/V was 1.16±0.08; in the high-dose group, the values were 75.2±2.5 percent, 1.71±0.11, and 1.53±0.09, respectively. The primary outcome, death from any cause, was not significantly influenced by the dose or flux assignment: the relative risk of death in the high-dose group as compared with the standard-dose group was 0.96 (95% CI, 0.84,1.10; P=0.53), and the relative risk of death in the high-flux group as compared with the low-flux group was 0.92 (95% CI, 0.81,1.05; P=0.23). However, the HEMO study evaluated the intensity of dialysis not its frequency and not total duration of dialysis. In fact, as Chertow and colleagues mention in their paper in NEJM: “solute removal can be dramatically augmented by increasing the frequency of hemodialysis sessions” (11).
The truth is that many nephrologists are adding their support to the idea of longer and/or more frequent dialysis (12,13). An excellent review by JR Lacson and Mike Lazarus published in March 2011 makes a persuasive case (14).
About 8 years ago, I visited Andreas Peirratos in his dialysis unit at Humber Hospital in Toronto Canada and interviewed several of his patients on nocturnal dialysis. While not a scientific study, I came away convinced that longer dialysis makes a difference, and should be offered to patients, and most importantly, should be reimbursed. Andreas Peirratos is a spectacular kidney doctor, and his 14 year experience is published elsewhere (15).
Naysayers of nocturnal dialysis will point to the results of the Nocturnal Hemodialysis trial published in Kidney International in July 2011 (16). Rocco and colleagues randomized 87 patients to three times per week conventional hemodialysis or to nocturnal hemodialysis six times per week. The 45 patients in the frequent nocturnal arm had a 1.82-fold higher mean weekly stdKt/V(urea), a 1.74-fold higher average number of treatments per week, and a 2.45-fold higher average weekly treatment time than the 42 patients in the conventional arm. However, the study's results for the two co-primary end-points: death or left ventricular mass were null. But surely, by any objective measure, we should agree that the study sample was too small, and the study was under-powered to observe a significant difference.
Do you remember Isaac Asimov? He was a Russian-born American author and professor of biochemistry who died in 1992. Growing up in England, I read a few of his science fiction books – I’m sure you did too. He wrote in I Robot: “It is the obvious which is so difficult to see most of the time. People say 'It's as plain as the nose on your face.' But how much of the nose on your face can you see, unless someone holds a mirror up to you?”
Bottom-Line: For years we’ve squandered the opportunity to make a real difference in the lives of our dialysis patients by doing the bidding of payors or policy makers in prescribing a minimally acceptable dose of dialysis, rather than doing the bidding of our patients and finding ways to maximize dialysis dose. The narrative has been about the high cost of dialysis. Perhaps costs are higher because of under-dialysis. Data supports the notion that under-dialyzed patients' are more likely to be hospitalized, and more likely to need higher dosages of drugs like epo and vitamin D, which cost a lot of money. By increasing the dialysis dose through higher frequency and/or duration of dialysis, costs may actually come down as patient's have improved outcomes, a reduced need for drugs, better quality of life, and lower hospitalization rates. Although we do need additional trials - with larger sample sizes and harder end-points, we also need to manage patients with the information that we have now. Therefore, increasing the frequency and/or duration of dialysis seems sensible. So the answer to the Wait, Wait...Don't Tell Me question is: Yes, more dialysis is better.
References
1. Foley, Robert N., Gilbertson, David T., Murray, Thomas, Collins, Allan J. Long Interdialytic Interval and Mortality among Patients Receiving Hemodialysis. New England Journal of Medicine 2011 365:12, 1099-1107
2. Luders C, Castro MC, Titan SM, De Castro I, Elias RM, Abensur H, Romão JE Jr. Obstetric outcome in pregnant women on long-term dialysis: a case series. Am J Kidney Dis. 2010 Jul;56(1):77-85. Epub 2010 Apr 10. PubMed PMID: 20382457.
3. Barua M, Hladunewich M, Keunen J, Pierratos A, McFarlane P, Sood M, Chan CT.Successful pregnancies on nocturnal home hemodialysis. Clin J Am Soc Nephrol. 2008 Mar;3(2):392-6. PubMed PMID: 18308997; PubMed Central PMCID: PMC2390936.
4. Hou S. Pregnancy in women treated with dialysis: lessons from a large series over 20 years. Am J Kidney Dis. 2010 Jul;56(1):5-6. PubMed PMID: 20620681.
5. Chertow GM, Levin NW, Beck GJ, et al. In-center hemodialysis six times per week versus three times per week. N Engl J Med 2010;363:2287-2300[Erratum, N Engl J Med 2011;364:93.]
6. Owen WF Jr, Lew NL, Liu Y, Lowrie EG, Lazarus JM. The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis. N Engl J Med 1993;329:1001-1006
7. Held PJ, Port FK, Wolfe RA, et al. The dose of hemodialysis and patient mortality. Kidney Int 1996;50:550-556
8. McClellan WM, Soucie JM, Flanders WD. Mortality in end-stage renal disease is associated with facility-to-facility differences in adequacy of hemodialysis. J Am Soc Nephrol 1998;9:1940-1947
9. Lowrie EG, Laird NM, Parker TF, Sargent JA. Effect of the hemodialysis prescription on patient morbidity: report from the National Cooperative Dialysis Study. N Engl J Med 1981;305:1176-1181
10. Eknoyan G, Beck GJ, Cheung AK, et al. Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med 2002;347:2010-2019
11. Depner TA. Daily hemodialysis efficiency: an analysis of solute kinetics. Adv Ren Replace Ther 2001;8:227-235
12. Suri RS, Nesrallah GE, Mainra R, et al. Daily hemodialysis: a systematic review. Clin J Am Soc Nephrol 2006;1:33-42
13. Walsh M, Culleton B, Tonelli M, Manns B. A systematic review of the effect of nocturnal hemodialysis on blood pressure, left ventricular hypertrophy, anemia, mineral metabolism, and health-related quality of life. Kidney Int 2005;67:1500-1508
14. Lacson E Jr, Lazarus M. Dialysis time: does it matter? A reappraisal of existing literature. Curr Opin Nephrol Hypertens. 2011 Mar;20(2):189-94. Review. PubMed PMID: 21178614.
15. Ouwendyk M, Pierratos A. Reflecting on 14 years of nocturnal home hemodialysis in Canada. CANNT J. 2008 Jul-Sep;18(3):55-7. PubMed PMID: 19010027.
16. Rocco MV, Lockridge RS Jr, Beck GJ, et al The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial. Kidney Int. 2011 Jul 20. doi: 10.1038/ki.2011.213. [Epub ahead of print] PubMed PMID: 21775973.
Ajay K. Singh, MBBS, FRCP, MBA
Brigham and Women's Hospital/Harvard Medical School
Could shortening the interdialytic interval by adding one or more dialysis treatments to the schedule make a difference? Yes, the evidence from Foley and co-workers (1) that was published in the New England Journal of Medicine presents a compelling case for changing the way we currently schedule dialysis. The authors discuss the importance of more frequent dialysis. Perhaps abrupt volume changes (going from too much volume to perhaps too little) and/or solute (changes in potassium or middle or small molecules) might be important after all. I discussed this paper here a few days ago.
Treatment of pregnant patients with more dialysis is better for both maternal and fetal outcomes. Both nocturnal dialysis and daily dialysis seem to result in better outcomes compared to thrice weekly dialysis; and a higher dose of dialysis does seem to make a difference. Two recent papers make this point (2,3) [discussed on this site yesterday], and the standard of care is now to provide 20 to 24 hours each week of high flux dialysis to pregnant patients – whether it’s regular or nocturnal delivery of dialysis (4). Of course, like Johnson and Johnson baby oil, one could also argue that if it’s good for babies it can’t be half bad for adults.
The paper in the New England Journal of Medicine by Glen Chertow and colleagues (5) provides strong evidence that greater frequency of dialysis improves outcomes. Chertow and colleagues published the Frequent Hemodialysis Network’s Daily Dialysis Trial. This was a prospective, multicenter, parallel-group clinical trial randomized of 245 dialysis-dependent adults who were randomized to either frequent (6 times per week) or standard (3 times per week) in-center hemodialysis for one year. What did they find? Frequent dialysis was significantly superior for both co-primary outcomes: The composite of death or change in left ventricular mass (“death/LVM”; Hazard ratio 0.61, 95%CI 0.46-0.82), as well as the composite of death or change in RAND Physical Health Composite from the SF-36 (“death/PHC”; HR 0.70, 95%CI 0.53-0.92). Secondary outcomes of hypertension and hyperphosphatemia were also improved, although patients in the frequent hemodialysis arm were more likely to undergo vascular access interventions (HR 1.71, 95%CI 1.08-2.73).
Of course you should ask how much evidence is there to indicate that more dialysis is better? Cited in the References section are a handful of studies that suggest exactly that (6-9), and I’ve only scratched the surface in reviewing what is out there.
What about the results of the HEMO study? It was also published in the New England Journal of Medicine (10); 1846 patients undergoing thrice-weekly dialysis were randomly assigned (using a two-by-two factorial design) to a standard or high dose of dialysis and to a low-flux or high-flux dialyzer. In the standard-dose group, the mean (±SD) urea-reduction ratio was 66.3±2.5 percent, the single-pool Kt/V was 1.32±0.09, and the equilibrated Kt/V was 1.16±0.08; in the high-dose group, the values were 75.2±2.5 percent, 1.71±0.11, and 1.53±0.09, respectively. The primary outcome, death from any cause, was not significantly influenced by the dose or flux assignment: the relative risk of death in the high-dose group as compared with the standard-dose group was 0.96 (95% CI, 0.84,1.10; P=0.53), and the relative risk of death in the high-flux group as compared with the low-flux group was 0.92 (95% CI, 0.81,1.05; P=0.23). However, the HEMO study evaluated the intensity of dialysis not its frequency and not total duration of dialysis. In fact, as Chertow and colleagues mention in their paper in NEJM: “solute removal can be dramatically augmented by increasing the frequency of hemodialysis sessions” (11).
The truth is that many nephrologists are adding their support to the idea of longer and/or more frequent dialysis (12,13). An excellent review by JR Lacson and Mike Lazarus published in March 2011 makes a persuasive case (14).
About 8 years ago, I visited Andreas Peirratos in his dialysis unit at Humber Hospital in Toronto Canada and interviewed several of his patients on nocturnal dialysis. While not a scientific study, I came away convinced that longer dialysis makes a difference, and should be offered to patients, and most importantly, should be reimbursed. Andreas Peirratos is a spectacular kidney doctor, and his 14 year experience is published elsewhere (15).
Naysayers of nocturnal dialysis will point to the results of the Nocturnal Hemodialysis trial published in Kidney International in July 2011 (16). Rocco and colleagues randomized 87 patients to three times per week conventional hemodialysis or to nocturnal hemodialysis six times per week. The 45 patients in the frequent nocturnal arm had a 1.82-fold higher mean weekly stdKt/V(urea), a 1.74-fold higher average number of treatments per week, and a 2.45-fold higher average weekly treatment time than the 42 patients in the conventional arm. However, the study's results for the two co-primary end-points: death or left ventricular mass were null. But surely, by any objective measure, we should agree that the study sample was too small, and the study was under-powered to observe a significant difference.
Do you remember Isaac Asimov? He was a Russian-born American author and professor of biochemistry who died in 1992. Growing up in England, I read a few of his science fiction books – I’m sure you did too. He wrote in I Robot: “It is the obvious which is so difficult to see most of the time. People say 'It's as plain as the nose on your face.' But how much of the nose on your face can you see, unless someone holds a mirror up to you?”
Bottom-Line: For years we’ve squandered the opportunity to make a real difference in the lives of our dialysis patients by doing the bidding of payors or policy makers in prescribing a minimally acceptable dose of dialysis, rather than doing the bidding of our patients and finding ways to maximize dialysis dose. The narrative has been about the high cost of dialysis. Perhaps costs are higher because of under-dialysis. Data supports the notion that under-dialyzed patients' are more likely to be hospitalized, and more likely to need higher dosages of drugs like epo and vitamin D, which cost a lot of money. By increasing the dialysis dose through higher frequency and/or duration of dialysis, costs may actually come down as patient's have improved outcomes, a reduced need for drugs, better quality of life, and lower hospitalization rates. Although we do need additional trials - with larger sample sizes and harder end-points, we also need to manage patients with the information that we have now. Therefore, increasing the frequency and/or duration of dialysis seems sensible. So the answer to the Wait, Wait...Don't Tell Me question is: Yes, more dialysis is better.
References
1. Foley, Robert N., Gilbertson, David T., Murray, Thomas, Collins, Allan J. Long Interdialytic Interval and Mortality among Patients Receiving Hemodialysis. New England Journal of Medicine 2011 365:12, 1099-1107
2. Luders C, Castro MC, Titan SM, De Castro I, Elias RM, Abensur H, Romão JE Jr. Obstetric outcome in pregnant women on long-term dialysis: a case series. Am J Kidney Dis. 2010 Jul;56(1):77-85. Epub 2010 Apr 10. PubMed PMID: 20382457.
3. Barua M, Hladunewich M, Keunen J, Pierratos A, McFarlane P, Sood M, Chan CT.Successful pregnancies on nocturnal home hemodialysis. Clin J Am Soc Nephrol. 2008 Mar;3(2):392-6. PubMed PMID: 18308997; PubMed Central PMCID: PMC2390936.
4. Hou S. Pregnancy in women treated with dialysis: lessons from a large series over 20 years. Am J Kidney Dis. 2010 Jul;56(1):5-6. PubMed PMID: 20620681.
5. Chertow GM, Levin NW, Beck GJ, et al. In-center hemodialysis six times per week versus three times per week. N Engl J Med 2010;363:2287-2300[Erratum, N Engl J Med 2011;364:93.]
6. Owen WF Jr, Lew NL, Liu Y, Lowrie EG, Lazarus JM. The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis. N Engl J Med 1993;329:1001-1006
7. Held PJ, Port FK, Wolfe RA, et al. The dose of hemodialysis and patient mortality. Kidney Int 1996;50:550-556
8. McClellan WM, Soucie JM, Flanders WD. Mortality in end-stage renal disease is associated with facility-to-facility differences in adequacy of hemodialysis. J Am Soc Nephrol 1998;9:1940-1947
9. Lowrie EG, Laird NM, Parker TF, Sargent JA. Effect of the hemodialysis prescription on patient morbidity: report from the National Cooperative Dialysis Study. N Engl J Med 1981;305:1176-1181
10. Eknoyan G, Beck GJ, Cheung AK, et al. Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med 2002;347:2010-2019
11. Depner TA. Daily hemodialysis efficiency: an analysis of solute kinetics. Adv Ren Replace Ther 2001;8:227-235
12. Suri RS, Nesrallah GE, Mainra R, et al. Daily hemodialysis: a systematic review. Clin J Am Soc Nephrol 2006;1:33-42
13. Walsh M, Culleton B, Tonelli M, Manns B. A systematic review of the effect of nocturnal hemodialysis on blood pressure, left ventricular hypertrophy, anemia, mineral metabolism, and health-related quality of life. Kidney Int 2005;67:1500-1508
14. Lacson E Jr, Lazarus M. Dialysis time: does it matter? A reappraisal of existing literature. Curr Opin Nephrol Hypertens. 2011 Mar;20(2):189-94. Review. PubMed PMID: 21178614.
15. Ouwendyk M, Pierratos A. Reflecting on 14 years of nocturnal home hemodialysis in Canada. CANNT J. 2008 Jul-Sep;18(3):55-7. PubMed PMID: 19010027.
16. Rocco MV, Lockridge RS Jr, Beck GJ, et al The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial. Kidney Int. 2011 Jul 20. doi: 10.1038/ki.2011.213. [Epub ahead of print] PubMed PMID: 21775973.
Thank you thank you thank you thank you thank you thank you thank you thank you thank you.
ReplyDeleteTHANK YOU for having the guts to *unambigously* state the obvious, and the COURAGE to take the flak you will inevitably receive from your colleagues.
ReplyDeletePLEASE don't now act like a politician and now go and hedge or re-state your position in weaker wording later: "What I really meant to say was . . ."
Too often this debate has been couched in cautious language and dissembling; instead of owning up to what is in reality just plain intellectual cowardice. We rationalize to ourselves that we are just being "good scientists" --by not having the guts to say anything at all. It is shameful how we have allowed fear of criticism from colleagues, financial self-interest, and a "don't rock the boat" mentality to entrench practices which have caused so much needless, *preventable*, suffering and death. This is not about good versus bad science. It is about right versus wrong.
Still, until organizations such as ASN, NKF and RPA meet their moral obligation to take a clear and firm position on this issue, which they have not, even the most *influential* bloggers, or the most *highly regarded* scientists, will have little or no impact. (And NO, calls for "we need more research" do NOT constitute a clear and firm position by an organization.)
"If you are neutral in situations of injustice, you have chosen the side of the oppressor." Desmond Tutu.
It seems obvious that more dialysis would be better. However, after working in dialysis for over 30 years I have found that it is the patients that object to longer or more frequent treatments. In the very few cases that patients felt they would like more HD we have provided it, but the much more frequent (multiple times daily) request for less dialysis requires constant education reinforcement. The "numbers" are not the only outcome to consider. Patients that feel well and are active are not likely to accept more dialysis. The ESRD patients that we see posting their good experiences and outcomes with frequent or extended dialysis, and that offer encouragement to other patients are to be complimented; but, they are in the minority.
ReplyDeleteWhen patients are left uninformed, or even lied to by their providers, i.e., told there is little or no benefit, they are steered into poor choices.
ReplyDeleteThis need not be the case, as Australia and New Zealand clearly have demonstrated. When the truth is laid out, that better dialysis with both KEEP YOU ALIVE longer, and make you FEEL BETTER, the decisions change. American nephrologists' continued shirking of their responsibility to fully and accurately inform their patients regarding what is now KNOWN--is merely being complicit in perpetuating the problem.
So, instead, we BLAME our patients, We create a fictitious universe where somehow American patients are so much less "compliant" than their counterparts in other countries that they are THREE TIMES as likely to die, or contrive even more fanciful allegations that European populations are intrinsically "different" in some drastic way from the United States.
The FHN trials found recruitment challenging, but they still found NEARLY HALF of potential subjects being willing to participate, a far cry better than the 1% we are currently achieving.
Still, so long as American nephrologists continue to fail in their personal ethical and professional obligations for informed consent, patient advocates will continue having to fill the void.
Wait Wait . . . Don't Tell Me!
ReplyDelete1. The vast majority of our patients are poorly informed.
2. WE are the ones who are supposed to have been been informing them.
3. It's still somehow THEIR fault?
What percentage of patients who do standard in-clinic hemo thrice weekly "feel well and are active"? How many dialysis patients even remember what it is like to feel well and be active? So, how do you/they define these concepts? Do you think they feel as well as you and are as active as you?
ReplyDeleteIt is irrelevant that those in the ESRD community who want more dialysis are in the minority. If 10 patients don't want more dialysis but I do, their choices shouldn't affect me. But just make sure that those 10 patients have been fully informed of the consequences of their choice.
It is always valuable to use your imagination and envisage what kind of treatment you would choose for yourself if you happen to have ESRD. Is there any nephrologist in this country who would chose SHD? If there is, speak up and tell us why you think this would be the optimal treatment for you and the way you want to live your life.
PS: Why am I the only one not posting anonymously on here?
Beyond the practical recruitment, time and expense hurdles for any contemplated future randomized clinical trials of extended or more frequent dialysis. I believe there are two serious ethical barriers.
ReplyDeleteFirst, the principle of equipoise requires the investigator to be "substantially uncertain" about which arm of the study would be in his patients' best interest. It is difficult to believe that any qualified investigator could now honestly meet that standard.
Second, the principle of informed consent would require disclosing to prospective research subjects that either more frequent or extended treatment (or both) are readily available in most parts of the United States and be provided with an unbiased summary of the hundreds of studies over three decades on these issues. It is hard to believe that, given this information, more than a few altruistic subjects could be recruited -- themselves hardly a sample of the U.S. dialysis population.
I suggest it is time to end the debate and take action in the interest of the length and quality of the lives of dialysis patients with Dr. Singh's conclusion -- "More dialysis is better."
I am amazed by the number of dialysis children and their parents, I come across who know no other choice but thrice weekly dialysis treatments. They do not know what other modalities exist!!! Why is that??? So now not only do I have to do the job of the social worker & dietician, but I need to research ALL my choice options as well!? (oh and advocate to receive the best treatment too?) My golly it is exhausting having end stage renal disease.
ReplyDeleteYou shouldn't need some huge research study to make an informed opinion. Your kidneys work 24/7-365 days a year....more dialysis the better...all we ask for is to have options. I would of loved doing daily hemo at a center...