Tag: dialysis

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New Tweetorial: Comparing diffusive versus convective clearance

I have been workshopping this one for awhile in my mind and today I carved out a few hours to create it.

It starts here

Part of the inspiration for this came from an epic message on the Channel Your Enthusiasm back channel by Roger Rodby

Here is the draft of the script.

Diffusive vs Convective clearance

I was teaching the third year medical students about acute kidney injury and the lecture begins with a brief history of extracorporeal dialysis for AKI. And I asked a student what extracorporeal dialysis was, and he correctly identified it as “dialysis outside the body.”

Since the ironclad law of the Socratic Method is that every correct answer is rewarded with another, harder, question, I replied, “Can you think of any example of intracorporeal dialysis?” The right answer is peritoneal dialysis, but he said , “The kidney?”

And off on a tangent we went…
Does the kidney even do dialysis? No. The kidney does not use diffusion to clean the blood. Clearance is provided by convection at the glomerulus. Plasma is squeezed through the slit diaphragms of the podocytes in the glomerulus but besides the lack of protein, the solute composition on both sides of that membrane is essentially identical.

The kidney does not clear the blood by diffusion, the defining characteristic of dialysis, but rather by convection. How does that work? Glad you asked. Take Creatinine. The creatinine on both sides of the podocyte is the same, 4.4 mg/dL in this example.

4.4 mg per dL x a GFR of 25 mL per minute x 1440 minutes in a day divided my 100 mL in a dL comes to 1584 mg of creatinine filtered.

That is just about the amount of creatinine produced by a typical person a day. 

So convective clearance can clear all of the creatinine produced everyday, the additional creatinine secreted in the proximal tubule is just gravy. 

What about sodium? 

138 mEq/L x a GFR of 25 mL per minute x 1440 minutes in a day divided by 1000 mL in a L comes to 4968 mE of creatinine filtered. 

This is a problem since we only consume around 100-200 mEq of sodium a day. So this where the tubules earn their stripes by reabsorbing all the excess filtered sodium to keep us from peeing ourselves to death.

So these two examples demonstrate an important principle of convective clearance, it is better for clearing things at a high concentration than at a low concentration. In fact, a GFR of 1 is enough to clear a typical sodium daily load.

138 x 1 ml/min x 1440 min/day divided by 1000 ml/L = 198 mEq/day

This why even a tiny residual renal function makes a huge difference in dialysis patients. 

But that same GFR of 1 would only clear 

4.4 x 1 ml/min x 1440 divided by 100 ml/dL = 63 mg of creatinine only about 4% of the daily creatinine load.*

*This calculation is highly dependant on the serum Cr concentration, which would be a lot higher than 4.4 if the GFR was 1, but since a GFR of 1 in incompatible with life, the patient would also be getting renal replacement therapy, so it is hard to know where the serum Cr would actually be.

So after explaining that the kidney didn’t actually do dialysis, or anything remotely close to dialysis. I asked if there was an organ that did do dialysis? Or, more specifrically, used diffusion for clearance.
Answers from the crowd: 

Liver > nope

Spleen > nope

Skin > nope

And finally, Lung? Yup.

The lung clears carbon dioxide from the body and absorbs oxygen by setting up a setting where the gasses move down their respective concentration gradients across a semipermeable membrane. You know, like dialysis.

A ventilator is not really like an artificial lung, in the way a dialysis machine replaces the core function of a kidney. It provides flow, but no clearance. We still are dependent on the alveolar membrane for oxygen absorption and carbon dioxide clearance. 

But ECMO is an artificial lung and fully replaces the alveoli and uses the principles of dialysis to clear carbon dioxide and move oxygen into the blood. So at some level, ECMO is closer to the lung than dialysis is to the kidney. 

One final note on this thread is in regards to dialysis and convection. The kidneys work by convective clearance but our primary means of replacing them is by diffusive clearance. However this summer we saw a randomized controlled trial of modifying dialysis to use convection rather than diffusion…and the result? Significant reduction in total mortality. 

We don’t get a lot of wins in dialysis, so when we get one, we pay attention.

The script isn’t exact because I have to do some edits to meet the character limits of tweets.

Here are the Keynote slides that I used to create the gifs.

Diffusion v Convection
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The future of nephrology

Super fun discussion on Twitter that has spilled out over the last few days. It began with this tweet about Nayan’s take on the latest MRI imaging during dialysis.

The original article is here and I’m a bit embarrassed about my sensationalization being a bit overwrought.

Forunaltely, it did trigger a great rolling conversation about the future of dialysis and by extension, nephrology. It may be difficult to recreate the discussion from that original tweet, so here are some key tweets:

In the midst of this discussion I broke the thread and added novel tweet asking people to place a bet on the future of transplant.

But this prognostication is focused on emerging transplant technologies and fails to capture the full breadth of nephrology transformation that we are seeing. With the emergence of Flozins, GLP1 agonists, MRAs (both steroidal and non-steroidal) as well as the increased interest and development of novel treatment targets, it is not a leap to say that nephrology in 10 years will look very different than it is today.

How will we mark that development? My poll of when will more than half of transplants come from non-human sources is a specific and quantifiable time that will represent a sea change in transplant. A marker that represents a change not in potential but in delivery. So how will we mark that moment in nephrology at large? I would argue that it happens when we see consistent year over year fall in the number of prevalent dialysis patients (in-center and home) for four consecutive years.

So how long until the combination of slower CKD progression, increased transplantation, and, unfortunately part of the equation, continued stagnation in dialysis longevity, result in consistently falling dialysis prevalence?

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The power of perspective

USRDS tracks the eGFR of patients starting dialysis, and from the mid 90s through the first decade of the 21st century there was a steady increase in the average GFR at the initiation of dialysis.

The average eGFR at initiation of dialysis went from 7.7 to 11.1 ml/min from 1995 to 2009.
From Li et al. 2017, Explaining trends and variation in timing of dialysis initiation in the United States.
Source

While the trend began before 1999, I suspect that the introduction and widespread adoption of the MDRD formula, which revealed that older people with relatively modest increases in creatinine had profoundly low GFRs, had a role in this. This recognition was further reinforced when KDOQI introduced the CKD stages in 2001 that called CKD Stage 5, “Kidney Failure” and implied that CKD stage 5 was a synonym for dialysis.

The trend of starting dialysis at earlier and earlier GFRs reversed following the publication of the IDEAL Trial in 2010. IDEAL showed no survival advantage for starting dialysis at a specific GFR compared to waiting for uremic symptoms that forced the patients to start dialysis. Dialysis is not a cosmetic procedure, we only do it when it is essential.

But deciding when to initiate dialysis is not as easy as waiting for a patient to become uremic, because guidelines, based on retrospective data, tell us to avoid central venous catheters and place arteriovenous access for hemodialysis. Grafts are pretty easy because they usually mature and are ready to use in less than a month. Fistulas, on the other hand, take time to mature and often fail to mature at all.

In this RCT of clopidogrel to assist in access maturation, two thirds of all fistulas were deemed inadequate five months after placement. A few more may have matured after that, but I don’t think it is likely and with a patient nearing dialysis, I suspect new plans for an alternative access will be sought out by that time.

So planning for hemodialysis, with a fistula really means trying to predict where a patient will be six in the future. Learning to do this is the art of taking care of patients with advanced CKD. During my career I have repeatedly been surprised by how long patients with advanced CKD can hold off and delay dialysis. Every time these patients come in I would bring up a list of their old GFRs and marvel how long they had been going with a sub-20 ml/min GFR. Often this would stretch for close to a decade. So when Navdeep Tangri published his Kidney Failure Risk Equation (KFRE) I felt validated as it showed that patients with low GFRs avoided dialysis longer than doctors (and patients) expected.

How the Kidney Failure Risk Equation (KFRE), physicians, and patients did at predicting the initiation of dialysis. Below the line of identity means over predicting dialysis, over the line of identity is under predicting.

On Wednesday I posted a typical case to twitter and asked people to decide between sending the patient for fistula creation now or to wait. It is the same patient in both polls, but in the first I provided the eGFR, while in the second I provided the KFRE result.

Same patient; wildly different results. I think it does a nice job of showing that people underestimate patients’ prognosis when they look at eGFR. I find I use the KFRE when talking with patients all the time. It helps reassure people with good kidney function when they are first diagnosed with kidney disease and it helps me when they have advanced CKD when trying to figure out the timing of access procedures and more detailed discussions of end-stage kidney disease.

I use QxMD to calculate the four variable KFRE

This web app by Amarnath Marthi allows you to play with the variables in nearly real time to get an idea of how the equation works (though I wished it would let me use mg albumin / g creatinine). Note that the risk of ESRD goes down as the patient’s age goes up. This is due to the competing risk of death becoming larger with advancing age.

Below are links to some of the great tweets that emerged from these posts. It always amazes me the breadth and depth of knowledge I find in my Twitter feed.

Real wisdom here. CVC catheters are probably not so bad, especially in people of advanced age.
Edgar always with a great reference.
The man himself!
Good thoughts wrapped in a dollop of hostility.
Fistula candidate means just that. Many other variables need to be accounted for to get a functioning fistula.
Was not aware of this data, though it seems a bit soft. But if it pans out, it would be practice changing, at least for me.
This last tweet is here because in my reply I post a reference that shows that the KFRE actually cover estimates need for dialysis in the elderly not underestimates.
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No! No! No! Never! Give a dialysis patient a Fleets Enema!

What is wrong with this picture?

Sevelamer and Fleet Enema. They go together like a honey baked ham and Chanukah. Fleets enemas have an obscene amount of phosphorous and sevelamer (Renvela) is a phosphorous binder. They should never co-mingle on the same MAR. So while some may see a couple of benign medications, I see a Chanukah ham.

A  Fleets enema, or any typical sodium phosphorous enema, is roughly 4 onces or 120 ml. The active ingredient is sodium phosphorous, to the tune of 26g of sodium phosphate per dose, some articles quote a phosphorous concentration of 13,000 mg/dL. Remember, a normal diet has about 1 gram of phosphate and only 700 mg of that is actually is absorbed; so we are talking about a potentially massive overdose.

I love that someone scanned the entire packaging

No patient with kidney disease or on dialysis should get this drug without talking to their doctor. Its written right on the damn package.

I guess, if you are in the hospital and the doctor orders it, that is essentially the same thing as asking your doctor. Too bad that over and over again doctors express their ignorance about dangerous this seemingly innocuous medication can be by ordering it in patients with kidney disease.

A rogues gallery of bad outcomes from the lowly Fleets Enema

The sodium phosphorous enema can be lethal to a patient with kidney failure.

Here is a case report regarding a patient who developed hypocalcemic tetany and coma following a single enema

My favorite quote in the case report is the hyperphosphatemia review of systems:

…the family denied that other drugs or unusual food such as star fruit was given by them- selves.

They gave the patient a couple of amps of calcium gluconate and then dialyzed him on hospital day 6, 7 and 8.

The situation is even more harrowing if you give the enema orally. This results in massive sodium and phosphorous absorption. In this case report the team gave it to the patient…twice:

They ran in to trouble while treating a toxic theophylline level. They gave activated charcoal to bind the theophylline. Subsequently, the patient developed an illeus and was given 120 mL of a sodium-phosphorous enema down the NG tube. The next day he received 4 liters of polyethylene glycol via the NG and finally another 120 ml sodium phosphorous enema enterally.

Then he arrested.

They resuscitated him. Here are his post-code labs:

  • Na 177
  • K 2.8
  • CO2 18
  • Cr 3.4
  • phosphate 59.6
  • calcium 5.2
  • Ca x Phos product: TFTC*
  • pH 7.12/37/40

* Too frightening to calculate

After resuscitation the patient was too hemodynamically unstable for dialysis and died during a subsequent arrest.

Look at that phosphorous! A phosphorous over fifty is like a traffic accident, can’t tear your eyes away.
Here’s a simple rule:

If the medicine is supposed to go in the butt, don’t feed it to your patient.

As high as the phosphorous is however, the symptoms are due to the low calcium. The high phosphorous complexes with the calcium driving the ionized calcium down.

JASN published a tight review in 1996. They discuss an unfortunate case where a gentleman was prescribed two enemas for a flexible sigmoidoscopy prep. The patient however, mistakenly ingested them orally rather than, you know, using them the right way. 191 mmol of sodium and 208 mmol of phosphorous down the hatch. The patient presented to the ER complaining of foot and hand pain along with diarrhea and difficulty swallowing and speaking. Data on presentation:

  • QTc 0.6 sec (prolonged)
  • ionized calcium 0.34 mmol/L
  • total calcium 4.5 mg/dL
  • Na 154 mmol/L
  • phosphate 44.8 mg/dl
  • anion gap 39

The patient was managed with insulin and dextrose, aluminum hydroxide and IV calcium gluconate along with IV fluids. Dialysis was delayed for 4 hours due to difficulty gaining IV access. He was dialyzed against a high (3.5 mg/dl) calcium bath

One of the points I tried to highlight in the graph is the rapid drop in the phosphorous prior to the dialysis. The conservative therapy of IV fluids, insulin, and aluminum hydroxide look highly effective. Also note how effective dialysis is at raising the calcium.

The authors make an excellent point regarding the acidosis. The patient had an initial pH of 7.28 and an anion gap of 39. The anion gap is from the high phosphorous. The authors point out that treating the acidosis with alkali will further drop the ionized calcium and is contraindicated until the calcium is corrected.

The discussion of the paper is delicious and addresses a situation I have found myself debating with fellows. The question is what to do when the phosphorous is really high and the patient has hypocalcemic symptoms. Does the administration of calcium lead to metastatic calcification to the detriment of the patient? The authors feel that calcium should be given to treat the symptoms of hypocalcemia and delay full treatment of hypocalcemia until the phosphorous is restored to normal levels.

In terms of personal experience, the MAR from the top of the post comes from a dialysis patient who did receive a Fleets enema while in the hospital. His phosphorous went from 3.5 to 11.7, overnight. He remained asymptomatic but the whole experience terrified me.

No. No. No Never. Give a fleets enema to a dialysis patient.

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Calling all nephrologists! If you care about anemia, you have until August 30th

The Centers for Medicare and Medicaid Services has proposed changes in the Quality Incentive Program (QIP) for 2013. The changes specifically involve anemia. The QIP was created to assure that even though the costs of providing dialysis care are born exclusively by the dialysis provider, there are specific quality goals that if not met result in financial penalties. The quality goals currently place are:

  • Percentage of Medicare patients with an average Hemoglobin < 10.0g/dL (Hemoglobin Less Than 10g/dL Measure)
  • Percentage of Medicare patients with an average Hemoglobin > 12.0g/dL (Hemoglobin Greater Than 12g/dL Measure)
  • Percentage of Medicare patients with an average Urea Reduction Ratio (URR) ≥ 65 percent (URR Hemodialysis Adequacy Measure).

Dialysis units that fail to hit the goals perscribed by the quality score receive a reduction in the Medicare payment by 0.5-2%. It should be apparent that the required hemoglobin targets ares problematic, especially given the recent action by the FDA (see my recent post Between a rock and a hard place). CMS is proposing the elimination of the floor on hemoglobin targets:

…Therefore, for the PY 2013 ESRD QIP, we propose to continue to use the following two measures previously adopted for the PY 2012 ESRD QIP:

  • Hemoglobin Greater Than 12g/dL Measure.
  • URR Hemodialysis Adequacy Measure.

This feels wrong to me. Creating an economic incentive that puts the cost of treating anemia on the provider but doesn’t provide any minimal goals may result in a race to the lowest hemoglobin. What’s to stop a rogue dialysis unit from removing ESAs from their formulary. We can all freely admit that ESAs have some previously under appreciated risks and that our enthusiasm for treating anemia was not entirely evidence-based, but our response to should not be to turn back the calendar to 1988.

After the release of Epo, the transfusion rate plummets. It falls by two thirds in a year and continues to fall so that the current rate of 0.3% per quarter represents a 98% reduction in transfusions. Revolutionary. And this doesn’t even begin to address the quality of life brought to dialysis patients by higher hemoglobins.

CMS states that they cannot add another unique quality indicator for 2013 and are looking toward 2014 to do this. In the absence of new quality guidelines they should keep the goal to maintain a hemoglobin over 10 g/dl but lower the target to 9 g/dL for 2013.

Patients deserve an incentive that keeps providers conscious of anemia. In study after study, low hemoglobins walk hand in hand with poor outcomes. The concern regarding anemia has been driven by attempts to normalize hemoglobin. It is clear that normalization is hazardous and without scientific support; however a failure of the experimental group does not mean we should abandon the therapy given to the control group. In every study the control group received ESA to maintain hemoglobins at least 9 g/dL.  Removing the hemoglobin floor from the quality measures would be giving a de facto license to withhold an important medication from dialysis patients.

The TREAT trial is the best study every done on outcomes in CKD with an ESA.
These dosing groups resulted in an effective separation in hgb with little profound anemia

I have copied this post to Regulations.gov as my comment on the latest guidelines.

The deadline for comments is August 30th.

A science liaison at Amgen told me that Amgen was advocating for a hemoglobin floor of 10 g/dl. The Renal Physician Association is also supporting a hemoglobin of 10 g/dL. [This paragraph was updated 8/22/11, after a complaint that I mis-interpreted Amgen’s position. My apologies.]

I have heard that CMS has received few comments from physicians. Embarrassing. Anemia is important and nephrologists should care how the governments crafts incentives that will change how our patients are treated. Go now and comment. Tell CMS what you think.

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Davita: is the vial half empty or half full

Early Tuesday, I caught half a headline about drugs being wasted at the expense of Medicare and to the benefit of some dialysis company. A few hours later I saw the first caustic tweets:

Just some of the angry tweets

Then I started getting direct messages asking for my thoughts. Recently, Davita has been getting more than its share of bad press recently and this seemed like more of the same. The facts of the news story, as far as I can tell, are as follows

  • A former medical director and nurse brought a whistle blower suit against Davita
  • They accuse Davita of using large vials to administer IV drugs during dialysis. The large vials resulted in excess medication being wasted
  • Medicare pays for the entire vial regardless of how much is wasted
  • The Justice department investigated this claim for more than two years and decided not to join the lawsuit
My first reaction was Davita had done a bad, bad deed here but the more I thought about it, the more that seemed to be a rush to judgment. The fact that the Justice Department, after investigating  for two years, did not join the lawsuit became the itch I could not ignore. My interpretation, is that the Feds looked into how Davita was handling the drugs and they did not find any unlawful activity.

So I was satisfied with the assumption that the way Davita was handling the drugs was legal. However, even when things are within the letter of the law we want our medical institutions to use resources efficiently. Clearly, intensionally pouring drugs down the biohazard drain, as the whistle blowers contend, is not the most efficient use of medical resources. The problem was the Medicare reimbursement system. For years, Medicare underpaid for the dialysis procedure so that dialysis providers had to turn themselves into high-end retail pharmacies that peddled Epo, and Zemplar in order to keep the lights on. With this type of system the providers were incentivized to use as much drug as possible. This perversion of fee-for-service has been at the root of almost all of the recent scandals in dialysis units. The recent anemia controversies were driven to the forefront largely because dialysis companies were payed for giving drugs not for patient oriented outcomes.

Its clear to me that retail pharmacy system was not the system we wanted. The laws need to change and you know what? This system is no longer the law. Bundling began earlier this year and removes these perverted incentives in order to better align provider and patient goals. In response to the new incentives you know what happened? The vials became right sized and Epo use plummeted. It’s too early to see how bundling effects patient outcomes but Davita and the other Large Dialysis Organizations are responding to the new incentives.

The lesson here is that incentives drive medical decision making. Incentives need to be implemented thoughtfully because small, seemingly minor holes can be blown wide open and introduce major distortions in the delivery of care. In terms of this whistle blower case, I think we shouldn’t dwell on the cows leaving the old barn that has been replaced by one with automatic and secure doors. The old reimbursement system was broken and has been fixed (or at least changed) and I don’t think there is much to be gained by dwelling on the previous system’s inefficiencies and errors.

So as I see it:
  • Davita administered and wasted dialysis drugs in a way that is uncomfortable, and inefficient but legal.
  • The Government realized the incentives were not aligned with better outcomes and changed the incentives
  • Davita and the other large dialysis organizations have changed their purchasing and administration procedures in response to the new incentives
  • A couple of former employees want to sue Davita for its legal, but opportunistic, drug handling behavior under the old incentives
Transparency: I am a part owner of a dialysis joint venture with Davita and one of my partners, Robert Provenzano, is Davita’s VP of Medical Affairs.
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The new definition of a rock and a hard place–Updated

The rock would be Amgen with their newest prescribing information for Epogen and Aranesp. The recommendations for dialysis patients can be summarized as:

Specifically, for patients on dialysis, the label advises physicians to initiate ESA therapy when the hemoglobin level is less than 10 g/dL and guides physicians to reduce or interrupt the dose when the hemoglobin approaches or exceeds 11 g/dL.  So target a hemoglobin higher than needed to prevent transfusions and no higher than 11 g/dL.

The hard place would be the federal government whose Quality Improvement Plan (QIP) for dialysis units states:

The intent is to control anemia and maintain optimum hemoglobin levels within the range of 10-12 g/dL (grams per deciliter).  Anemia management will be assessed by two separate measures: 

  1. CMS will assess the percentage of patients whose hemoglobin levels dipped under 10 g/dL.  The program assigns this measure the greatest weight in facility performance calculation, because numbers under 10 g/dL are highly undesirable.  (Weight = 50%)
  2. CMS will assess the percentage of patients whose hemoglobin levels exceeded 12 g/dL. Numbers greater than 12 g/dL could suggest unnecessary or excessive administration of certain drugs.  (Weight = 25%)

There is little air to breathe between 10 and 11 g/dL. Something has got to change and my guess is by the end of the year QIP will be suggesting hemoglobins between 9 and 10.

UPDATE: CMS has proposed new rules that remove the lower limit for hemoglobin as a quality measure. Here is some news coverage and here is the PDF.

I think its crazy to remove the lower hemoglobin limit. When CMS introduced the bundled payment system they turned anemia management from a profit center to a cost center for dialysis units. The Quality Incentive Plan was designed to prevent dialysis units from minimizing costs by denying patients adequate treatment. It seems that with the 2013 proposal, a Machiavellian dialysis unit could eliminate anemia management completely and reap financial rewards without penalty.

This can’t be right, at the least CMS should add minimizing transfusions as a quality measure, that would reconcile the prescribing information and the quality goals.

Hat tip to the anonymous first poster.

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Found an old lecture

In 2006 I had to give the fellows a lecture on nocturnal dialysis. I remember being delighted with how it turned out. It was a fellow-level lecture that would have little appeal to non-nephrologists. The lecture goes into the different ways to measure dialysis dose and deep-dives into the National Cooperative Dialysis Study and the HEMO trial.

A month or so after giving the lecture I had a hard drive crash. After that, I couldn’t find the lecture.

Well, today I was mucking through an old external hard drive and found the lecture! Yay me! I backed it up!

If you are interested the lecture is now resting safely under the Lectures Tab.