Improving Outcomes in Intensive Hemodialysis: An Expert Commentary

More: Cleveland Clinic Workshop on Innovation in Uremia Therapy
Improving Outcomes in Intensive Hemodialysis: An Expert Commentary With Philip A. McFarlane, MD

Philip A. McFarlane, MD, PhD

Medscape Nephrology. 2008; ©2008 Medscape
Posted 09/08/2008

Editor's Note:

Frequent intensive hemodialysis (short daily hemodialysis and nocturnal home hemodialysis) has recently gained increasing popularity as an alternative to conventional in-center hemodialysis because there is an emerging body of evidence providing that frequent intensive hemodialysis offers superior uremic toxin clearance, blood pressure control, and improved patient outcomes. Anne G. Le, PharmD, RPh, Editorial Director of Medscape Nephrology, spoke with Philip A. McFarlane, MD, from St. Michael's Hospital in Toronto, Ontario, about the impact of dialysis on uremia and the use of intensive hemodialysis and its impact on patient outcomes.

Introduction

Philip A. McFarlane, MD: So what we're talking about today is uremia and whether we can make an impact on that with more dialysis and whether we can understand the uremic state better. And to understand what its components are and what the important things that lead to people on dialysis feeling unwell and have poor outcomes are is important. Therefore, the title of the talk is "Improving Outcomes in Intensive Hemodialysis" and we'll talk about 3 things. First is the problems of dialysis as we are currently performing it; second we're going to talk a little bit about intensive hemodialysis; and then third, we're going to try to see if we can understand better why intensive hemodialysis seems to improve outcomes in people on dialysis.

Problems Associated With Dialysis

We'll start with the problems associated with dialysis. These are well-described and well known to people working in the area. Survival on dialysis is very poor in Canada and the United States; if you have a condition like diabetes, your average survival on dialysis is about 2.5 years. For most people, survival on dialysis is worse than most malignancies like breast cancer and colon cancer, and in addition to a short life, it's not an easy life for people on dialysis as these people report the lowest quality of life for any chronic medical condition. And along the way, providing dialysis is an expensive venture and typically costs around about close to $75,000, $80,000 per person per year. So in looking at all of this information, it's important to ask the question, why do people on dialysis feel sick? Why do the people on dialysis have such a short survival? And the answer that's given is that it's due to uremia, but of course that leads to the next question, which is what is uremia. It ends up that this is an area where people have been working to understand things better. There is a European uremia working group and they have a Web site, www.uremic-toxins.org, and if you go there, they have a number of their publications. They list over 90 individual toxins that have been described as putative potential uremic toxins, so obviously the condition of uremia is complicated and has a number of facets. But in addition to the small solutes and larger solutes that are described in the uremic-toxins Web site, in amongst all of that are the clinical conditions that have been associated with uremia such as hypertension, volume overload, heart disease, oxidative stress and the whole long list of other issues as well, so this is a complicated condition. And the one thing that's becoming clear is that the state of uremia is more powerful than dialysis, at least as is conventionally practiced in most of the world, 3 times a week up to 4 hours per treatment of hemodialysis. Those treatments are life-sustaining, but they certainly don't cure the uremic state.

Intensive Hemodialysis

So let's now move onto the second part and talk about what intensive hemodialysis may do to impact outcomes. First, in thinking if you were going to dialyze someone more intensively, how could you do it? Well, there's 2 main things you could do, you could increase the time on dialysis or you could increase the frequency of dialysis, or you could do both. And in thinking of some principles of how these more intensive regimens may work, first we will divide it up into low molecular weight solutes as the uremic group. These things are small solutes that should be very easy to dialyze -- they cross the dialysis membrane easily and the only exception to this is if they're protein bound. These are transferred between compartments rapidly so dialyzing them will not be particularly time dependent, but those that are transferred more slowly from one compartment to the other become very time dependent. To remove them effectively, you have to dialyze someone for longer, and an example of that would be phosphate. Larger molecules, higher molecular weight retention products, blood and dialysate flow is not important determinants of the clearance of these products as they've become time dependent. And again, it becomes frequency dependent only if the intercompartmental diffusion is the rate-limiting step.

So in thinking about the types of intensive dialysis that we can do, 1 popular method is short daily hemodialysis, done 2-3 1/2 hours, 4-7 times a week, typically 2 1/2 to 3 hours 5 times a week. This is an aggressive treatment done with high pump speed, high dialysate flows using conventional dialysate and does not necessarily require heparin. Instead of increasing frequency, you can increase the duration as they've done in Tassin, France for many decades now practicing 3 times a week dialysis but with long treatments, 6-8 hours during the day. The ultimate way of intensifying dialysis would be to do both, increase both the frequency and the duration. But it is not practical to do this outside of the home setting and so really we're talking about home nocturnal hemodialysis where people dialyze between 6 and 12 hours, 5-7 times a week.

Originally when this was first started in Toronto, this was done as a slow form of dialysis with dialysate flows of 100 mL/min and blood pump speeds around 200 mL/min, but as is currently practiced, it's practiced a little bit more aggressively with higher dialysate flows between 300 and 800 mL/min and a bit higher blood pumps speed at 300 mL/min. It does require heparin and often requires unconventional dialysate, high counts of dialysate with phosphate spikes and higher potassium levels and so on. Initially home nocturnal was practiced with just internal jugular lines; however, for many years Joyce Hunter has been using the buttonhole technique for cannulating fistulas. When we think about small solute clearance, we think about it in terms of what percentage of normal kidney function someone receiving these types of dialysis would achieve. For things like peritoneal dialysis and conventional hemodialysis, the small solute clearance is equivalent to what someone with about 15% of normal kidney function would achieve. But that's getting down near the threshold where if this is a person in a predialysis clinic, you would start to think about placing them on dialysis. Someone on dialysis actually does not receive a tremendously large amount of small solute clearance. Something like short daily hemodialysis provides around about 25% of normal kidney function, and that's around about the threshold where people start to develop clinical symptoms and signs of uremia. And so a short daily hemodialysis is a dose of dialysis big enough to get someone to the threshold where they might start to lose their uremic symptoms. Of course home nocturnal hemodialysis would achieve an even bigger dose of around 40% of normal kidney function and this is well above the level where you would expect someone to be free of the symptoms of uremia. And just for comparison, transplant typically provides around about 50% of normal kidney function. Now it's important to keep in mind that when we talk about those numbers, this is small solute clearance and clearly the kidney does more for a person than just simply clear small solutes, so this is a bit of a simplistic way of making an equivalent comparison between dialysis and normal kidney function.

Improving Outcomes With Intensive Hemodialysis

Now, there's a lot of literature now available for intensive hemodialysis and its impact on a variety of outcomes and positive benefits related to intensive hemodialysis have been described for blood pressure control, anemia, quality of life, left ventricular hypertrophy, sleep apnea, fertility, calcium phosphates and mineral disorders, potassium control, endothelial progenitors cell biology, and so on. I'm just going to briefly touch on a couple of areas.

One is quality of life and a study that our group published in Kidney International in 2003 showed that people on home nocturnal hemodialysis reported a much higher quality of life with the utility score of around 0.77[1] Similar people who are conventionally dialyzed had a utility score of about 0.53 and those folks on home nocturnal hemodialysis achieved a utility level close to what people who have a functioning kidney transplant report. And more recently, Bruce Culleton's report from JAMA in 2007, a randomized controlled trial comparing home nocturnal hemodialysis vs conventional dialysis again found that there is significant improvements in, in the domains of, of effects of kidney disease and burdens of kidney disease with people on nocturnal hemodialysis reporting significant improvements in those areas.[2]

Another area we could look at is mortality and we don't have a tremendous amount of head to head data looking at survival on these different modalities. But when we look at for example, the Tassin group reports, they have survival curves going out over many, many years, decades, and their survival curves look much, much better than what we would see in Canada or the United States for the typical dialysis patient.[3] Now, there was 1 randomized trial of course in this area and that was the HEMO study, which was published in The New England Journal of Medicine in 2002, and it compared 2 levels of intensity of hemodialysis, a single session eKt/V of 1.5 vs 1.45 and they showed absolutely no difference in survival in this 1846-person study.[4] Now, the major critique that those of us who perform intensive hemodialysis have of this study is that the method of intensification was primarily through increase in blood pump speed and dialyzing people a little bit more aggressively, and not necessarily for a tremendously larger number of hours of dialysis. And also, we would still consider the achieved level of dialysis in the high dose group to be a relatively low dose.

Now finally, we will discuss mechanisms of benefit; why does this work? Why might intensive hemodialysis have a more meaningful effect on uremia? And the answer in short is that I don't know and I would argue that it's very difficult if not impossible to know and the issue here relates to the concept of attributable risk. Attributable risk is a fraction of an outcome that's attributable to the exposure of interest. The classic example of this would be to think about lung cancer and say what percentage of lung cancers in North America are attributable to smoking and the answer ends up being about 85% of a person's lung cancer risk related to smoking, and so if you are a lung cancer investigator, you could arguably concentrate on smoking and leave all other factors behind. Now, how do we determine the attributable risk in dialysis patients? Well, where we run into difficulties is when you have many competing risk factors so for example, if we had to account for things like the effect of hypertension in diabetes on survival, well, we would do that, it would be not too difficult with those 2 factors. However, there are also interactions between these 2 factors, the interaction between hypertension and diabetes that would also need to be taken into account, and that would make things a little bit more complicated. If you add a third risk factor in like dyslipidemia, well now you've got the 3 primary effects: hypertension, diabetes, and dyslipidemia. You've got 3 second-order interactions: between hypertension and diabetes, between lipids and diabetes and lipids and hypertension, and of hypertension and dyslipidemia and diabetes together. So now suddenly any kind of statistical model to try to look at the independent effects of those 3 risk factors has become much more complicated.

The question becomes if you have 90 or more risk factors, how are you going to statistically model these things to determine which components of uremia are the ones that are impacting on outcomes, and the answer is it can't really be done. This has been described by Rabe and colleagues[5] and Rockhill and colleagues[6] and others -- the idea that the current statistical methods for partitioning attributable risk among multiple competing risk factors are flawed and they tend to overestimate the actual attributable risk for each of the components. So what we can say about intensive hemodialysis is that it broadly affects many of the listed components of the uremic syndrome. It is associated with clinical improvements in many areas and it is safe. How in fact it actually works and which of the factors the uremic factors are impacted the most and attribute to these improvements are unknown.

Concluding Remarks

I'll summarize by saying the following things, the poor quality life and survival of conventionally dialyzed patients is often a result of chronic exposure to the uremic milieu. There are many putative components of the uremic state. The attributable risk of individual component is unknown and likely to be unknowable. Intensive hemodialysis impacts broadly across the components of the uremic state and is associated with impressive improvements in most study parameters.
References

1. McFarlane PA, Bayoumi AM, Pierratos A, and Redelmeier DA. The quality of life and cost utility of home nocturnal and conventional in-center hemodialysis. Kidney Int. 2003;64:1004-1011. Abstract
2. Culleton BF, Walsh M, Klarenbach SW, et al. Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life. JAMA. 2007;298:1291-1299. Abstract
3. Charra B, Laurent G, Chazot C, Jean G, Terrat JC, Vanel T. Hemodialysis trends in time, 1989 to 1998, independent of dose and outcome. Am J Kidney Dis. 1998;32:S63-S70. Abstract
4. Rocco MV, Dwyer JT, Larive B, et al; for the HEMO study group. The effect of dialysis dose and membrane flux on nutritional parameters in hemodialysis patients: Results of the HEMO Study. Kidney Int. 2004;65:2321-2334. Abstract
5. Rabe C, Lehnert-Batar A, Gefeller O. Generalized approaches to partitioning the attributable risk of interacting risk factors can remedy existing pitfalls. J Clin Epidemiol. 2007;60:461-468. Abstract
6. Rockhill B, Weinberg C. Error in population attributable risk calculation. Epidemiology. 1996;7:453-454. Abstract

Philip A. McFarlane, MD, PhD, Staff Physician, University of Toronto, Toronto, Ontario, Canada; Medical Director, Home Dialysis, St. Michael's Hospital, Toronto, Ontario, Canada

Disclosure: Philip A. McFarlane, MD, PhD, has disclosed no relevant financial relationships.

Disclosure: Anne G. Le, PharmD, RPh, has disclosed no relevant financial relationships.

http://www.medscape.com/viewarticle/577246