Kt/V urea has served its purpose, so let us now move on

Editor's note: Two reviews were recently published in Kidney International, that analyzed the role of Kt/V_urea in determining dialysis dose. One, by Raymond Vanholder, MD et al, argued that it is too simple a concept for the complexities of uremia and of today’s dialysis. The other, by John T Daugirdas, MD, argued that it is still a useful metric to measure dialysis adequacy. Dr. Agar and Ms. Schatell wrote this article in response to the latter.

As Kt/V_urea has again been hailed as “a useful measure of hemodialysis dose,” with the apparent lack of outcome effect of long dialysis in the Frequent Hemodialysis Network (FHN) trials cited as a reason why more dialysis is not necessary for toxin removal,⁽¹⁾ it may be pertinent to share an alternate view.

Kt/V_urea has played a useful historical role: to set and deliver a minimum target for small solute clearance. However, it applies only to solutes that “behave” like urea, are soluble in water, and are un-troubled by trans-compartmental transport barriers, except perhaps the blood brain barrier. Kt/V_urea gives us “treaters,” a warm and fuzzy feeling that we have done our job well.

But, what about those on the business side of the membrane—our patients? Does Kt/V_urea cut their mustard? To be honest, no. With apology to my esteemed colleagues Frank Gotch, John Daugirdas, and many other supporters of Kt/V_urea, it never quite has.

Why do I believe that Kt/V_urea has failed patients?

Firstly, Kt/V_urea zeros in on “the toxin of the 60s”. Back then, we thought urea was the toxin that mattered … but, we were wrong. In the following decades, a great many more insidious substances have been identified: phosphate, calcium-phosphate product, parathyroid hormone, β₂-microglobulin, homocysteine, phenols and indoles, p-cresol, and many others. Some are protein-bound, some are not; some are water soluble, some are not … there is a soup of toxins well-characterised by Ray Vanholder,⁽²⁾ of which many likely matter more than urea, but most fail the “move and behave like urea” test. To think that urea or a mathematical model like Kt/V_urea, expressed as _spKt/V, _eKt/V (or whatever) can accurately represent “sufficient dialysis” and mirror clearance of all of the other unmeasured substances is, bluntly, naïve…a view acknowledged by Gotch.⁽³⁾ Thus, placing all our dialysis adequacy markers in the urea-only basket is also naïve.

While the proposal to scale Kt/V_urea to surface area may have merit in sustaining a role for Kt/V_urea as a valid indicator of dialysis adequacy, what is more likely to be of survival-predictive value would be the scaling of the rate of volume removal—the ultrafiltration rate (UFR)—to surface area or body weight. We have been late to recognize that what really matters is volume—not the notional volume of distribution of urea in the equation Kt/V_urea, but real volume—the salt and water volume that stretches hearts, raises blood pressure, and drowns lungs. Volume is the true bete noir that kills our patients, and a factor I have discussed elsewhere.⁽⁹⁾ Volume, and the rate at which we change it during dialysis (UFR), have been neglected for far too long.

To use the failed FHN₂ trial⁽¹⁰⁾—and fail it did, on almost every front, as I have described elsewhere⁽¹¹⁾—to argue that more dialysis is not better dialysis because additive quanta of Kt/V_urea add little benefit, is to miss the seminal impact of dialysis duration (time) on UFR and time-dependent, deep compartmental clearance. In my view, this denies common sense for, indeed, the true advantage of more intensive dialysis lies with the better deep compartmental removal of larger molecular weight toxins, and the markedly slower rate of removal of fluid. Kt/V_urea tells us nothing about these factors that clearly count most.

In my view, while Kt/V_urea has played an important role, it has had its time. There are now newer and bigger dragons to slay, more important measures—for example, regulation of the ultrafiltration rate to an agreed maximum, with or without scaling it to surface area or body weight—on which to focus. And while we unpick the malevolence of volume, we must also seek and define whether other Kt/V-like markers for complex solutes that urea does not represent show greater specificity for more effective and complete toxin clearance. Only by girding for a forward journey, rather than resting on a past laurel, will we achieve better future outcomes for those who sit stoically on the other side of the membrane. -by John Agar, MBBS, FRACP, FRCP, OAM; Dori Schatell, MS

References

Daugirdas JT. Mini Review: Kt/V (and especially its modifications) remains a useful measure of hemodialysis. Kidney Int. (July 2015); doi:10.1038/ki.2015.204

Vanholder R et al. (for: European Uremic Toxin Work Group). Review on uremic toxins: classification, concentration, and inter-individual variability. Kidney Int. 2003; 63(5): 1934-1943

Gotch FA, Levin NW. Daily dialysis: the long and short of it. Blood Purif. 2003;21(4-5):271-81

Gotch FA, Sargent FA. A mechanistic analysis to the National Cooperative Dialysis Study. Kidney Int. 1985; 28: 526-534

Lowrie EG, Laird NM, Parker TF, Sargent JA. Effect of the hemodialysis prescription on patient morbidity. N Engl J Med. 1981; 305:1176-81

Gutzwiller JP, Schneditz D, Huber AR, Schindler C, Gutzwiller F, Zehnder CE. Nephrol Dial Transplant. 2002; 17(6): 1037-44

Eloot S, Van Biesen W, Dhondt A et al. Impact of hemodialysis duration on the removal of uremic retention solutes. Kidney Int. 2008; 73: 765–770.

Saran R et al. Longer treatment times and slower ultrafiltration in hemodialysis: Associations with reduced mortality in the DOPPS. Kidney Int. 2006; 69: 1222-1228

Agar JWM Personal Viewpoint: Limiting maximum ultrafiltration rate as a potential new measure of dialysis adequacy. Hemodialysis Int. 2015; March 16^th. doi: 10.1111/hdi.12288.

Rocco MV et al. The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial. Kidney Int. 2011; 80(10): 1080-1091.

Agar JWM. A sad direction in home dialysis research: The FHN2 nocturnal survival analysis. To be found at: http://www.homedialysis.org/news-and-research/blog/97-a-sad-direction-in-home-dialysis-research-the-fhn-2-nocturnal-survival-analysis KidneyViews blog. Last accessed 23.07.2015.