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The study showed that patients in the high BUN groups were hospitalized and withdrawn from the study protocol at statistically significant higher rates.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.

I recently saw a patient in our peritoneal dialysis clinic who had been ultrafiltering about a liter a day but who was now consistently draining 100ml less than his instilled PD solution volumes despite extended drain times and multiple acrobatic contortions to try and recover additional fluid.

Peritoneal catheter outflow problems are common and many PD patients transfer to hemodialysis because of catheter related issues. Peritoneal outflow failure can be defined as the incomplete recover of instilled dialysate consistently within 45 minutes of beginning a drain.

So what are some of the things you can do when faced with a PD patient who is having difficulty recovering their dwells? Recently, an article in AJKD reviewed the topic and the salient points are outlined below.

1) Check for peritonitis – Start by looking for signs and symptoms then look at the dialysate to see if it’s overtly cloudy followed by a dialysate cell count and culture. During episodes of peritonitis the permeability of the peritoneal membrane to water, glucose and proteins is increased. This leads to rapid loss of the osmotic gradient as glucose moves from the dialysate into the blood resulting in reabsorption of fluid if dwell times are long enough.

2) Check a KUB – Useful for many reasons. The KUB can help you see catheter kinking, tip migration and constipation, which is very common culprit of outflow obstruction.

3) Examine the patient for signs of catheter leakage – Pericatheter leaks usually show up soon after catheter placement as wetness on the exit site dressing. Leakage of dialysate can also occur at any time into the abdominal wall, the pleural space (usually the right) and the genitals.

4) Is there resistance to dialysate or saline instillation? – If it’s tough getting fluid in in addition to getting fluid out something inside or outside the catheter is blocking it up. Inside kinks (which you might have seen on the KUB), fibrin and blood clots are potential culprits. Outside dilated stool filled intestine, and other intrabdominal organs in particular the omentum may be occluding the catheter. If fluid flows freely in, and the above options have been ruled out ultrafiltration failure should be considered.

In our patient, exam was unremarkable apart from trace lower extremity edema and saline was easily instilled into the peritoneal dialysis catheter by one of our RNs. The recovered PD dialysate was clear and cell count was zero. A KUB showed stable catheter position without kinking and copious stool. We started a trial of laxatives and were gratified to hear a few days later that our patient was now achieving his former ultrafiltration volumes.

The Classics: IDNT

September 2001 was a strong month for Nephrology in NEJM. RENAAL, IDNT and the IRMA 2 were all published in the same issue that month.

IDNT, the Irbesartan Diabetic Nephropathy Trial compared an ARB to a CCB and placebo in DMII patients with CKD and proteinuria.

1715 patients were randomized from multiple centers around the world.

To be included in the study patients needed to be between 30-70 years old, have DMII and HTN (greater than 135/85), proteinuria (at least 900mg/24 hours), Cr 1.0-3.0 mg/dl in women and 1.2-3.0 mg/dl in men.

The study drug Irbesartan was started at 75mg and titrated to 300mg while Amlodipine was started at 2.5mg and titrated to 10mg per day.

The primary endpoint was doubling of serum Cr, ESRD (dialysis, transplantation or a Cr of 6.0 mg/dl) or death.

The secondary endpoint was a composite of death from cardiovascular causes, nonfatal MI, CHF resulting in hospitalization, a permanent neurologic deficit caused by a cerebrovascular event, or lower limb amputation above the ankle.

Mean followup time was 2.6 years.

Apart from there being slightly more men in the placebo group baseline characteristics were similar.


The ACRs were higher than in RENAAL with median values of 1.9 g/24hrs. An interesting little tidbit was that 24 hr urinary albumin was roughly 2/3rds that of total 24 hr urinary protein (did not know that).


Crs were around 1.7 mg/dl lower than the 1.9 mg/dl in RENAAL. Using demographic data MDRD eGFRs were approximately 44 ml/min/1.73m2 for men.

Blood pressures were also higher in IDNT than RENAAL with rough mean values of 160/87 vs 152/82 respectively.

During treatment the MAP was significantly higher (3.3 mmHg) in the placebo group when compared to the ARB and CCB groups (which were similar in MAP control).

The primary composite endpoint showed a statistically significant ARR of 6.4% and 8.5% and RR reduction of 20% and 23% when ARB was compared to placebo and amlodipine respectively. According to the authors adjustment for difference in BP did not alter these results.


The breakdown of the composite was as follows...

ARB reduced the risk of doubling of serum Cr when compared with both CCB and placebo. There were no statistically significant differences in ESRD or death from any cause between the groups.

Again impressive was overall just how at risk diabetics with CKD and significant proteinuria are with 22% doubling their Cr, 17% reaching ESRD and 15% dying over just 2.6 years.


The secondary outcome did not differ significantly between groups.

Proteinuria was on average reduced by 33% in the ARB group and the rate of decline in eGFR was 5.5 ml/min/1.73m2 vs 6.8 ml/min/1.73m2 and 6.5 ml/min/1.73m2 in the CCB and placebo groups respectively.

So nutshell...

Big international muticenter ARB vs CCB vs placebo trial with intention to treat analysis of diabetic nephropathy with macroalbuminuria showing reduction in the ARB group in the combined endpoint of mortality, ESRD or doubling of serum Cr driven by the reduction in doubling serum Cr.

Very similar to RENAAL with the added information that ARB is superior to amlodipine in this population.

Digging Deeper: RENAAL Reexamined

So I stumbled across this KI paper while watching a great lecture on ukidney given by Phil Mcfarlane at last year's Prevention in Renal Disease Conference in Toronto.

It's a really nice post hoc analysis of the RENAAL data looking at albuminuria's predictive value for events (ESRD, doubling of serum Cr, death).

See the previous post for what RENAAL was all about, patients with DMII and nephropathy who were randomized to ARB or placebo.

Here, de Zeeuw and colleagues asked...

1) Whether baseline albuminuria was predictive of events
2) Whether the degree of reduction was predictive of long term risk reduction for these events and finally
3) Whether the amount of albuminuria remaining after therapy conveyed risk similar to baseline levels.

1) Baseline albuminuria.


No shocker here, the more albumin you had in your urine the more likely you were to reach either the renal end point (ESRD, doubling of serum Cr, death) or ESRD. HRs are multivariate adjusted and calculated using an ACR less than 1.5 g/g as the referent.

What really struck me was that if you had a ACR of greater than 3.0 g/g, almost 100% of folks reached the renal end point at four years and nearly 80% got to ESRD.

2) % reduction of albuminuria at 6 months.

Exciting stuff here and very elegant figures. In terms of reduction in the composite end point you see a drop in risk the greater the reduction in albuminuria.


Around a 60% reduction in risk for those who achieved a drop of 60% or more in their albuminuria at 6 months.

When looking at ESRD in isolation the risk of progression vs protection as predicted by albuminuria is more marked.


Those with greater than a 40% increases in their albuminuria were upwards of two and a half more times more likely to need dialysis or transplantation when compared to those whose values were unchanged.

Likewise those who achieved the most dramatic reductions saw their risk drop by roughly 75% compared to unchanged values.

3) Residual albuminuria.

This is fascinating.


The curves of risk for a renal event at baseline and after six months based on the amount of albuminuria are virtually superimposable with lower levels associated with fewer events.

Interestingly when you subdivide the degree of albuminuria based on whether someone was on ARB or placebo and look at risk both at baseline and at six months you see that at six months for a given amount of albuminuria those on ARB fared no better than those on placebo.


The authors suggest that these findings taken together point towards albuminuria as a specific target for renoprotective therapy and that consideration should be given to further reducing albuminuria in patients on ARBs who continue to have high levels.

I love the idea that we can potentially do more for RENAAL style patients by driving albuminuria down as far as possible. To further lower proteinuria in a patient already on a ARB one could 1) use high dose ARB 2) add an ACEI 3) Add an aldosterone blocker 4) add a renin inhibitor or 5) add a nondihydropyridine CCB.

This is not without some controversy so with that in mind the ONTARGET trial will be next under the spotlight.