eKt/V

As previously discussed on RFN, the single pool Kt/V was developed by Gotch and Sargent in a reanalysis of the NCDS data in an attempt to distinguish the dose of hemodialysis at which outcomes improved.


The spKt/V model assumes that the human body acts like a “single pool” that contains a certain concentration of urea. The model describes what happens when the dialysis cleaning machine is attached to the single pool and the urea containing fluid is brought into the machine, has a certain amount of urea removed, and then is returned to the body (figure 1).


Each time fluid comes in, has urea removed and returns it lowers the urea concentration in the pool so that the dialysis machine is fed fluid with a progressively lower urea concentration. This means that as the run proceeds less urea is removed for any given volume.


For example, at the start of the run if the machine is clearing 100 ml/min and the concentration of urea is 100 mg/dl, 100 mg of urea will be removed from the body in one minute. However, if towards the end of the run the concentration of urea is 40 mg/dl, only 40 mg of urea will be removed in one minute.


This constant fractional removal leads to a curvilinear decline in the urea concentration during the dialysis run as shown in figure 2 by the solid line. When the urea concentration is expressed as a logarithm the decline becomes linear (dotted line) with a slope of –K/V.


Using the starting BUN and the constant fractional decline for a set amount of time one can figure out what the final BUN will be…


Remember that K = clearance in ml/min, t = time in minutes, and V = the volume of distribution of urea in liters leading to the dimensionless ratio Kt/V.


Rearranging…


Kt/V = -ln(R)


R = (post dialysis BUN/pre dialysis BUN). Plug in the numbers and see that a post dialysis BUN/pre dialysis BUN of 0.37 gives you a Kt/V of 1.0. A spKt/V of 1.0 means that the entire of volume of the single pool has passed through the dialyzer once.


The fancy looking Daugardis equation, mentioned last time for spKt/V, contains additional adjustments for urea addition to the single pool that occurs from generation during the time the dialysis machine is operating and urea removal that occurs via convection during ultrafiltration.



The spKt/V predicts urea concentration change as shown by the dashed line in the figure 3. However, what actually happens on dialysis is shown by the dots. The BUN drops faster than predicted during dialysis and then rebounds more quickly than predicted afterward. The net impact is that spKt/V overestimates the amount of urea removed during a dialysis session.


The above occurs because the human body is not a single pool. Instead, it has multiple compartments across which urea moves at various rates. During dialysis the intravascular and interstitial spaces are cleared of urea quite rapidly while a smaller amount of urea is cleared from the intracellular space due to slower movement across membranes as diagrammed in figure 4. This leads to the more rapid decline in BUN than predicted by spKt/V seen as the dots in figure 3.


Additionally, there is rapid blood flow and clearance though some compartments of the body with slower flow and clearance through others as shown in figure 5. For example, the cardiopulmonary circuit cycles through the dialysis machine every 10-15 seconds while blood flowing through the slowest compartments may take several minutes to do the same.


After dialysis ends there is a rebound in urea concentration that is a combination of equilibration of intracellular urea stores and return of blood from poorly perfused areas.


The equilibrated Kt/V can be obtained by measuring the BUN 30-60 minutes after the end of dialysis. It provides a more accurate measure of dose by using a urea concentration that is more reflective of the concentration in the total body water as compared with spKt/V, which uses a concentration reflective of the interstitial and intravascular spaces.


Of course, having someone stay for an additional hour after their dialysis session ends is inconvenient. Luckily there are conversion equations from spKt/V to eKt/V as shown below (there are several available equations for doing this).


eKt/V = spKt/V [(t/(t + 35)]


Notice the importance of time for any given spKt/V. For example, with spKt/V held constant and varying the time from say 100 minutes to 200 minutes the eKt/V will go from 74% to 85% of the spKtV. The longer you run the closer eKt/V will be to spKt/V (figure 6).


In the Hemodialysis (HEMO) Study published in 2002, 1846 patients were randomized to either high or low flux dialysis membranes and standard or high dose 3x per week dialysis. The dose targets were in eKt/V calculated from spKt/V. As mentioned above, eKt/V was used because it is a more accurate reflection of dose.


The achieved mean eKt/Vs in the standard dose and high dose groups were 1.16 and 1.53 respectively with mean spKt/Vs in the same groups of 1.32 and 1.71. There were no differences between groups in the primary outcome of death from any cause.


As I’m sure you’ve noted NCDS and HEMO where both trails of 3x week hemodialysis schedules. What if we want to compare dose between more or less frequent dialysis? Up next, stdKt/V…

Measures of dialysis dose

As previously discussed on RFN, the urea Kt/V is a measure of dialysis dose that is related to patient outcome. There are several different Kt/Vs encountered in the dialysis literature.




spKt/V = single pool
eKt/V = equilibrated
stdKt/V = weekly standard


A nice way to think about each one is in the context of the major trials in which they were used.


spKt/V

The National Cooperative Dialysis Study (NCDS) published in 1981 examined four different 3x week dialysis prescription targets in 151 patients. The original paper did not use Kt/V. Instead, the prescription targets were high vs low time averaged BUN and long vs short dialysis treatment times.


The time averaged BUN and dialysis times achieved were approximately 90 mg/dl vs 50 mg/dl and 4.5 hours vs 3.25 hours in the high vs low and long vs short groups respectively. Protein intake was not randomized and was meant to be between 0.8 and 1.4 g/kg though some patients fell below this range.


The study showed that patients in the high BUN groups were hospitalized and withdrawn from the study protocol at statistically significant higher rates. Time was not a statistically significant variable for either of these outcomes though the p value for increased risk of hospitalization in the short time group was 0.06. The original NCDS paper did not sort out whether people in the each of the BUN groups were there because of their dialysis dose or because of their protein intake.


A subsequent reanalysis in KI by Gotch and Sargent in 1985 separated these variables out using the single pool Kt/V (for dose) and normalized protein catabolic rates (for protein intake). As seen below they showed that poor outcomes were associated with a spKt/V of less than 1.0 in 3x per week dialysis.



In practice the spKt/V is calculated for a single run of dialysis using known variables as inputs in any of several developed equations. The commonly used Daugirdas equation…


spKt/V = -ln(R - 0.008*t) + (4 - 3.5*R)(preBW-postBW/preBW)


Uses the know variables of…


R (post dialysis BUN/pre dialysis BUN)
preBW (pre dialysis body weight)
postBW (post dialysis body weight)
t (treatment time)


The spKt/V is used in most dialysis units to assess dose for patients on 3x week dialysis schedules. There are however, other versions of Kt/V that are seen in the literature and are useful in certain situations. On that note, stay tuned for eKt/V…

Try this in clinic…

It was the usual sort of day in clinic and the team was seeing a middle aged woman with stable diabetic nephropathy and subnephrotic proteinuria. Her blood pressure and blood sugars had been well controlled since the last visit and being good nephrologists her urine specimen was spun and the sediment examined.

The team was shocked to find a packed field shown top left… Which became stranger under polarized light shown to the right…


Some of these objects were sort of hexagonal like cystine crystals but the patient had never had a kidney stone, never had this finding before and was much older than one would expect for a cystinuria presentation. The maltese cross finding was odd as well. Cystine crystals don't have these. The objects didn’t really look like oval fat bodies and the crosses were not the clean symmetric looking ones typically seen in these fat droplets.


The team, perplexed, split up taking the slide to the urinalysis lab to ask the techs if they knew what the heck this was, hitting pubmed and back to the patient to see if there was any funny business with the specimen.


On reconvening the answer was clear: corn starch. The techs instantly said they see it all the time when their gloves contaminate a specimen. Pubmed, gave us a nice case report from NDT Plus and the patient noted having some vulvar irritation and was likely using a corn starch based baby powder which had dropped into the specimen cup.


This is the part you can try at clinic…


To confirm our discovery I dipped one of our powdered gloves in water and then prepared it like a regular urine specimen. Perfect match. Give it a try in clinic next time you have some housestaff or unsuspecting renal co-fellows around.

Alimentary Azotemia Redux: A Quantitative Approach

The issue of whether a marked elevation in the BUN when compared with the creatinine might represent gastrointestinal bleeding was nicely covered previously on RFN. One of our attendings recently had our group of first year fellows review the issue using a quantitative approach that highlighting the relevant physiology.

Consider a 72kg male in steady state eating 90grams of protein per day with a creatinine clearance of 120ml/min and a Urea clearance of 60ml/min.

Remembering that a male will produce 20mg/kg of creatinine a day, our 72kg male will produce 1440mg of creatinine in a day…

72kg x 20mg/kg = 1440mg

A person in steady state must excrete what they produce (a key nephrology concept). So if our man makes 1440mg of creatinine he must excrete 1440mg of creatinine (if he fails to excrete it all his plasma creatinine concentration will rise and he has fallen out of steady state).

We can additionally estimate the amount of BUN produced by remembering that urea nitrogen production is approximately 1/6th of protein intake. So our man eating 90grams of protein produces 15grams of urea nitrogen each day (90grams x 1/6 = 15grams) which in steady will be excreted.

With the above we can now calculate the plasma creatinine and BUN concentrations using the clearance equation…

clearance (C) = [urine concentration (U) x urine volume (V)] / plasma concentration (P)

C = UV/P

Plug in the numbers correcting the units along the way for Cr…

120ml/min = (1440mg/day) / P
P = (1440mg/day) / 120ml/min
P = (1440mg/day) / 172,800ml/day
P = 0.0083mg/ml
P = 0.83 mg/dl

Same deal for BUN…

60ml/min = (15g/day) / P
P = (15g/day) / 60ml/min
P = (15,000mg/day) / 86,400ml/day
P = 0.17mg/ml
P = 17 mg/dl

A final thing we can sort out from what was provided is the fractional excretion of urea which by convention is expressed in percent. This is just what it says it is, the fraction of filtered urea (we'll approximate GFR with CrCl) that gets excreted in the urine. As urea is freely filtered this is…

FeUr = (Urea clearance / GFR) * 100
FeUr = (Urea clearance / CrCl) * 100
FeUr = [(60 ml/min) / (120 ml/min)] * 100
FeUr = 50%

So here’s what we know in table form…


Now imagine that our man starts feeling unwell, stops eating and has a one liter bleed from a peptic ulcer into his GI tract. For arguments sake lets say this occurs with no drop GFR (the “it’s the blood not the renal function” argument).

His protein intake is now the protein content of 1L of blood. 40% is cells (mostly rbcs) and 60% is plasma. The major proteins in the cellular and plasma parts respectively are hemoglobin and albumin (there's a bit more protein around from globulins and so on but this will give us a rough estimate).

Normal hemoglobin and albumin concentrations would be 14 g/dl and 4 g/dl respectively. So from the above we can estimate the protein content of blood in the GI tract…

1L * 0.60 = plasma volume
0.6L = plasma volume

plasma volume * protein concentration = plasma protein content
0.6L * 4g/dl = plasma protein content
0.6L * 40g/L = plasma protein content
24g = plasma protein content

1L * 0.40 = cellular volume
0.4L = cellular volume

cellular volume * protein concentration = cellular protein content
0.4L * 14g/dl = cellular protein content
0.4L * 140g/L = cellular protein content
56g = cellular protein content

Total protein content = cellular protein content + plasma protein content
Total protein content = 24g + 56g
Total protein content = 80g

Using our previous calculations our table now looks like this…


Notice that in the above scenario the BUN drops a bit as the protein intake has decreased. What if we kept our man eating the same diet and had him bleed at the same time while holding kidney function stable?


If you almost double the protein intake you almost double the BUN (from 17 to 33 mg/dl). Now let’s try the stopped eating, 1 liter bleed scenario along with a 50% drop in GFR due to hypotension. Remember that in the volume depleted state the fractional excretion on urea is typically less than 35% and for arguments sake we’ll make it 20% in our man.


As compared with no renal dysfunction we now get an BUN/Cr ratio of 23 as compared to 18. How about we run scenario with continued eating, 1 liter bleed and now with 50% drop in GFR due to hypotension with the associated drop in urea clearance.


Pretty impressive, huh? With a bit of kidney dysfunction added into increased urea production we’ve now got a BUN/Cr ratio of 98 vs 40.

The point of all this is that the BUN and serum creatinine will vary based on:

1) Cr production
2) Cr clearance
3) BUN production
4) BUN clearance

The integration of these four things yields the BUN and serum creatinine values and the subsequent ratio between the two.

As noted by Ernest, the dog paper he reviewed and the math above the most impressive BUN/Cr ratio elevations are generated by a combination of increased urea nitrogen production and decreased urea clearance. The ratio is further accentuated by the proportionally greater drop in urea clearance vs creatinine clearance seen in volume depletion.

Intradialytic Hypertension

I’ve recently had a few calls from our outpatient dialysis unit about patient’s with rises in their blood pressure during and after dialysis. Intradialytic hypotension is a very common phenomenon and it’s been interesting to learn that intradialytic hypertension also occurs quite frequently with a reported prevalence of up to 15%.


The relationship between blood pressure and clinical outcome in hemodialysis patients is complex and both the most predictive type of measurement and optimal target value are unknown. As a matter of practicality, The Handbook of Dialysis recommends targeting pre dialysis blood pressures of <130/80 with less strict goals in patients with wide pulse pressures or at risk for orthostasis.


Intradialytic hypertension has been defined in a number of ways but basically refers to patient’s whose intradialysis or post dialysis BPs are higher than their starting values. It has been associated with increased hospitalization and mortality in hemodialysis patients.


Why it occurs is unknown but several theories have been put forward:

1) Volume overload – Animal chronic kidney disease models suggest that chronic sodium and volume overload can lead to sustained elevations in blood pressure though increases in peripheral vascular resistance. On the molecular level sodium leads to the release of digitalis-like factor which inhibits the Na/K ATPase on vascular smooth muscle leading to increases in both intracellular sodium as well as calcium. These rises in intracellular calcium then cause smooth muscle contraction with increases in vascular resistance. In addition, dialysis patients with little or no residual renal function are not able to urinate off excess volume leading to rises in preload and cardiac output.


So the above provides an explanation as to why sodium mediated volume overload might lead to hypertension but why would blood pressure rise further with ultrafiltration on dialysis?


Some studies suggest that as volume is removed in overloaded patients cardiac output and blood pressure rise, presumably as the heart is put in a more favorable portion of the starling curve though evidence for this is conflicting. Alternatively a recent review tied together the volume overload and endothelin hypotheses (see below) by suggesting that faster intravascular refilling in volume overloaded patients resulted in more mechanical stress triggered endothelin-1 release with subsequent rises in peripheral vascular resistance.


2) Endothelial cell dysfunction – In response to volume changes, mechanical stress and hormonal stimuli endothelial cells synthesize and release factors that contribute to BP homeostasis. Several studies to date have looked at this and have shown greater rises in the vasoconstrictor endothelin-1 in patients with intradialytic hypertension when compared with controls. The largest study supporting this hypothesis also showed that intradialytic rises in blood pressure were largely due to rises in peripheral vascular resistance rather than cardiac output. Of interest, there is a currently enrolling NIH trial looking at carvedilol's impact on intradialytic hypertension due to it's potential to suppress endothelin-1 release.


3) Dialytic removal of antihypertensives – Many blood pressure medications including multiple beta-blockers and ACE inhibitors are significantly removed during dialysis. Although removal of these agents is a potential contributor in some cases, intradialytic hypertension still occurs in patients who are off all BP meds.


4) Erythropoetin stimulating agents – Intravenous administration has been associated with elevations in blood pressure in dialysis patients and interestingly also with elevations in endothelin-1.


5) Sympathetic overactivity, RAAS activation, electrolytes – Volume removal followed by upregulation of homeostatic systems is often cited as a possible cause of intradialytic hypertension. However, a recent study that measured plasma catecholamines and renin in patients with and without intradialytic hypertension pre and post dialysis found that renin and norepinephrine were actually higher in controls post dialysis. Dialysis induced reductions in serum potassium and elevations in calcium have also been postulated as possible causes but in the same study no significant difference between groups in these electrolytes was found. Intradialytic sodium gain due to higher dialysate than plasma sodium has been suggested as a possible cause of intradialytic hypertension but has not been directly studied.


Interventions targeting improvements in intradialytic hypertension have not been evaluated in randomized prospective fashion and the optimal treatment approach and benefit, if any, is unknown.


When I get the phone call I’ve been making sure the patient is asymptomatic then depending on the details of the blood pressure, I ask the patient and nursing staff if I can extend the run and increase the ultrafiltration goal (two small case series support this approach). If the BP remains elevated after dialysis, I will ask the patient to take an additional dose of one of their antihypertensives and I make note to review their medications, epo dosing, labs, dialysis regimen and dry weight.


I’d be interested to hear how others deal with this dilemma.