What does effectiveness mean?


#1

My wife’s pre BUN is 45 +/- and creatinine is under 10, The other toxins are in normal ranges for dialysis patients. Her HHD nurse says those aren’t normal because the KT/V is too low. The nephrologist says numbers don’t mean anything. He’s happy as long as she feels ok.

I thought dialysis was about removing toxins and excess fluid. What exactly does Kt/V tell you that having toxins controlled doesn’t, The nurse doesn’t know. All she knows is that the Kt/V must be higher.


#2

This is a great question, Fornia. In the U.S., Medicare (which pays for most dialysis) uses Kt/V as a performance measure for clinics. They do not get paid as much if everyone does not hit their Kt/V targets. Kt/V DOES measure a “toxin” - though it is based on urea–a small molecule that does not behave like other toxins in the body. Urea is VERY easy to remove (and cheap to measure), though not all that toxic.

What this tends to mean is that if someone’s Kt/V is low, other toxins that are harder to remove may NOT be being removed effectively. What “other toxins” are “in normal ranges for dialysis patients”? My guess is that you’re talking about electrolytes–potassium, phosphorus, etc. But, in the U.S. we don’t tend to measure the kinds of toxins that can really matter in the longer term, like c-reactive protein (a marker of inflammation) or Beta-2-microglobulin (a protein that can cause painful amyloidosis). I’d want those measured to be sure there is no harm coming from a low Kt/V.

Another possibility–and this CAN happen with more frequent home HD–is that the difference between her pre-treatment BUN (blood urea nitrogen – UREA) and her post-treatment BUN isn’t all that high. So, the ratio looks bad, because there just wasn’t as much urea there in the first place to remove…


#3

Thanks Dori. Sometimes it’s just a matter of asking the right question.

As I understand it, a high flux membrane has holes that are larger and allow all the blood components whose molecular size is that of Beta 2m and smaller to pass freely between the water in the blood and the water in the dialysate.

Also, the larger molecule concentrations are much lower than urea and creatinine and their rebound rates are much longer. Is there any reason to assume these other toxins are less soluble than urea? Just because they take longer to move from the cell water in the muscles thru the inter cell water and the capillary walls into the blood doesn’t tell anything about how they move around in the waters of the blood and dialysate.

I’m thinking about that first pass of the blood thru the dialyzer. Isn’t it reasonable to assume that if all the urea is removed, then all the other toxins are also removed. Pass 2 ends up getting urea and not much else.


#4

– Yes, high flux membranes have larger holes, and they do remove more Beta-2 microglobulin and other toxins.
– I wouldn’t not necessarily say that the larger molecular concentrations are “much lower than urea,” mostly because I don’t know that anyone has quantified them, at least, not that I’ve seen.
– YES, large molecule wastes are MUCH less soluble than urea, mainly because they ARE larger. If you Google an image of urea vs. beta-2 microglobulin, you’ll see that urea is not only tiny, it’s also smooth and easy to pass through the membrane pores. Beta-2 microglobulin is large–and also TWISTY and difficult to get through (imagine it having to shake and shimmy to fit through). Some “small” wastes, like phosphorus ACT like larger ones, because they have a sort of water “jacket” around them. Dr. Agar has done terrific blogs on this topic, like these:–

– “Isn’t it reasonable to assume that if all the urea is removed, then all the other toxins are also removed. Pass 2 ends up getting urea and not much else.” NO. This is 100% backward, I’m afraid. Remember that urea is easy to remove and small, while other toxins are difficult to remove and large. Yes, you may get a lot of urea with the first pass, but you get almost none of anything else, with tiny incremental amounts more with each pass. TIME (what Dr. Agar calls “membrane contact time” is the ONLY way to remove these larger and more important wastes. Each pass counts. This is why nocturnal HD does so much better of a job removing toxins (AND water).


#5

Hi again, Sorry about the assumption on concentrations. I was looking at actual clinical trials like the following and noticed in that particular population the creatinine concentration was 10% of the urea and the phosphates were about 5% of the creatinine. Forgetting that urea nitro is only one of the ureas and extrapolating is always dangerous.

Nephrol Dial Transplant. 2014;30(1) 129-136. Which was “Phosphate, urea and creatinine clearances: haemodialysis adequacy assessed by weekly monitoring”

As for the Beta 2m, it looks like normal concentrations are more like 40 mg/L or 4 times the urea, so I was way off on that. Thank you for helping me understand solubility better too.
In the last week Bill Peckham has helped me understand membrane and dialyzer design.

I’m still wondering how to deal with our provider and their preoccupation with medicare’s preoccupation with Kt/V.

Our nephrologist and dislysis provider are not tracking most toxins because they think Kt/V tells them everything they need to know about efficacy. The nephrologist says he’s not into numbers, just wants to know how she feels, which, given all her other problems stemming from radiation and chemo is hard for her to quantify. But with a normally low BUN level (40 to 50) while getting 2 hrs, 4x/week at 200 mL/min BFR, my wife’s Kt/V is always low and creatinine, potassium and phosphates are all under control and that probably applies to all the other small molecule toxins.

I think a low blood flow rate is better because you can use smaller needles, there’s less damage to the blood and fistula from lower AV presures and each mL of blood gets to spend more time in the dialyzer during each pass. Faster blood flow does mean more passes per cycle BUT the total time each mL gets to spend is the same (5,000 mL +/- over 2 or 4 hours). More quick passes with more turbulence in the dialyzer vs fewer slower passes. I’ll take the latter unless we can come up with evidence to the contrary, related to middle molecule clearance. And then there’s the fact that different membranes have different pore size distributions and different toxins may have different affinities related to crossing through. I believe our nephrologist has the data on the dialyzer characteristics but I’m not sure he knows what to do with it as he seems to defer to the nurse when setting dialyzer parameters.

Any ideas how to deal with the provider’s queeziness with respect to their next medicare audit? I know we can complain to our ESRD Network but we are really complaining about Medicare and they don’t take kindly to criticism of themselves.


#6

In the last paragraph of your last reply you missed something that is fundamental to understanding the dialysis process. I’m looking at 2 papers that included actual data on the clearance of various toxins.

A 2008 study from Belgium found at

A 1999 study from the VA Med Ctr in Utah

The key take away is that most of the actual clearance for every blood toxin studied, happens in the first 5 to 15 minutes of a dialysis session. I believe it’s because the dialyzer clears all of the toxins in each mL of blood as it passes through and once all of the blood volume has passed one time the only toxins that are available to clear are what is called rebound.

In the 2008 study from Belgium, Fig 3 pg 767, showed no difference in the total clearance for urea, creatinine, phosphorus or Beta 2 micro between 4, 6 or 8 hour cycles. It may just be that any cycle time over 4 hours is just a placebo effect. Note that the flow rates for both blood and dialysate were kept equal and 350 mL/min for the 4 hr cycle, 250 for the 6 hr cycle and 180 mL/min for the 8 hr cycle, resulting in the same volume of blood and dialysate being processed in each. The curves are the same, just spread out. More time isn’t the same as more membrane exposure because slower flow results in longer exposure per pass with fewer passes. I believe slower is better in the first pass or two. This doesn’t show a difference between the 4 and 8 hour marks.

Of more interest to me is the clearance during the first 2 hours. Looking at the 4 hr cycle reduction ratio’s at 350 mL/min blood and dialysate flow:
mins urea creatinine Phosphorus Beta2m
5 12% 20% 20% 20%
15 21 26 27 28
30 26 33 35 35
60 37 41 42 42
120 52 53 50 50
240 70 64 50 50

All 4 showed more clearance in the first 5 mins than the next 10 mins or any sequence thereafter and the inferred rebound rates were steady after the first pass cleared all of the pretreatment toxins. Because the phosphates and Beta2m have been proven to be harder to dialyze it is reasonable to assume it took more than one pass to clear the pretreatment concentrations but note that very little was cleared after the first 30 minutes.

In the 1999 study, looking at Fig 3 pg 1575, using the low flux membrane, the Beta2m concentration went up as UF cleared fluids, weight went from avg 85 to 82 and it took 30 to 60 minutes post dialysis for the B2m to stabilize lower. I assume that is because fluid rebound from the inter&extra cellular compartments takes 30 to 60 minutes. 10 patients with BFR = 300 and DFR = 500 mL/min.

For the high flux dialyzer, B2m mg/L went from 39 to 32 at 60mins, 31 at 120m and 30.5 at 180m. Post measures were 30 mg/L immediate post & 10 & 20mins, then went to 32 at 30m and 33 at 60mins, full rebound was going to take 4 to 6 hours as it was still rising only very gradually.

The clearance from 60 to 180mins was 1.5 mg/L or 0.75mg/L/hr on avg. If the second 30mins was at that rate it was .38mg/L and the first 30min was at 6.6mg/L. I know I’m extrapolating but there really is no reason to assume the rebound rate would change between 30mins and 60 when it was the same from 60 to 180 mins. The dialyzer membrane flux certainly isn’t changing. The only stuff cleared after the first 30 mins is rebound and rebound happens between the cell water and the blood in a steady process that begins when the blood concentration drops with the first mL of cleaned blood returning.

I know you are not a clinician but it does make a difference when you are advising people about their options. There is nothing magic about dialysis. It follows certain basic laws. The dialyzers are designed to meet CMS standards for Kt/V which don’t actually apply to all patients the same way but are applied as if they do.

If BUN is under control (under 66 mg/dL on average over several months) it is reasonable to assume most of the other small molecules are too and Kt/V is irrelevant. If phosphates are under control you can assume one of the high flux membranes is being used and the middle molecule toxins are probably under control also. Kt/V tells you nothing about efficacy of dialysis for this last group. Each must be tested separately if there is any reason to suspect the membrane being used is not clearing them.


#7

Does your wife have any urine output. Has the dialysis clinic taken her native (natural) kidney function into consideration when looking at her Kt/V? The 2015 National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) Hemodialysis Adequacy Guideline 3 says this:

“Guideline 3: Measurement of Dialysis: Urea Kinetics
3.1 We recommend a target single pool Kt/V (spKt/V) of 1.4 per hemodialysis session for patients treated thrice weekly, with a minimum delivered spKt/V of 1.2. (1B)
3.2 In patients with significant residual native kidney function (Kru), the dose of hemodialysis may be reduced provided Kru is measured periodically to avoid inadequate dialysis. (Not Graded)
3.3 For hemodialysis schedules other than thrice weekly, we suggest a target standard Kt/V of 2.3 volumes per week with a minimum delivered dose of 2.1 using a method of calculation that includes the contributions of ultrafiltration and residual kidney function. (Not Graded)”

Here’s the link to the KDOQI HD guideline - https://www.ajkd.org/article/S0272-6386(15)01019-7/pdf

In addition to affecting Kt/V, the more urine output she has, the easier it is for her to manage fluids. Urine output usually declines the longer someone is on dialysis and patients have to adjust their fluid intake accordingly.


#8

Sorry to take so long to reply. I had to ask Dr. Agar, because this level of detail is over my head. Here’s what he said:

"I do know Sunny Eloot, and her work is seminal to the understanding of the influence of time and frequency on ‘deep compartmental cleaning’ … esp. of the harder-to-shift middle-molecule marker stuff like beta-2, methyl guanidine, guanidino-succinic acid, p-cresol, and l’il ole phosphate which, though seemingly small, has a naughty hydrophilic tendency and wraps itself in water which makes it (oddly) difficult to sieve.

Dialysis patients … and, dare I say it … dialysis professionals (docs and nurses) … have been ‘sold a pup’ and have been led to believe that urea is all that matters when, in truth, urea matters least of all.

It should be/is … urea? … who cares!

A simple reference to Ray Vanholder’s seminal list of ‘uraemic toxins’ … and a whole bunch more have been added SINCE this list was published … is a good way to start an enquiring patient to look away from urea.

NB: the internet is crap, here, so maybe you coukd add the reference by Googling Ray’s paper from the early 2000’s via Vanholder Uraemic Toxins … I think it was KI but maybe NDT …

People also need to understand that dialysis - 2018 style - simply provides an imperfect glomerulus. Stuff is dragged, pushed, jiggled and jaggled, beckoned, prodded, and persuaded across a far-from-natural artificial membrane with a pore size and slit structure design a universe away from the exquisite natural filter that comprises that glomerular slit diaphragm.

But … that’s all we can do. And that’s the easy part. We have never replicated the tubule … that extraordinary modifier of the relatively simpler pressure-driven glomerular filtrate that reabsorbs, secretes, and adjusts the final loss that is our urine.

Nor, when we talk ‘function’ by tossing around (so confidently) the eGFR concept as if its all that matters, do we measure, include, consider or attempt eTR+/-S (estimated tubular reabsorption and/or secretion) … that’s a step too hard. Yes, David Hume’s seminal work on artificial tubules is extra-ordinary, but I am not convinced Bill Fissell is as close as some think/hope … though he IS at least in-building Hume’s artificial tubule into the model.

All this is a long way of saying … people who think urea matters need to ‘get a life’. Nephrologists who spurn Kt/V or say they dont care about numbers, but ‘how the patient is’ are the ones who are on the right track.

Patients and their carers can also get too bogged down in the detail … and think more about the outcomes … work, play, life, pleasure, time, family … and forget ‘measures’."