Tuesday, September 16, 2014

New neph blog: UC Kidney Stone Program

Fred Coe and the crew from University of Chicago have started a kidney stone blog. This is the most prominent nephrology scientist to stick his toe in the blogging world. Dr. Coe was one of my teachers when I was at the University of Chicago (I blogged about him here and here). Dr. Coe has been instrumental in establishing the foundations of kidney stone science and continues to move field forward. He was a category in 2014's NephMadness:
(5) Dr. Charlie Pak versus (4) Dr. Fred Coe 
Charlie Pak and Fred Coe are the Bob Knight and Dean Smith of kidney stones. Not only did they dominate the field and do the pioneering work establishing the fundamental discoveries of the field, but they also trained the next generation of stone scientists that are currently leading the field. 
To this day the centers where Pak and Coe worked are world leaders in the field. In a plot twist, that would most likely happen in a comic book origin story, they were classmates at the University of Chicago Medical School, class of ‘61, and then were residents together at U of C. 
Dr. Coe remained at University of Chicago but Pak went elsewhere to established the Clinical Research Center and a new Division in Mineral Metabolism at University of Texas Southwestern Medical Center at Dallas. 
They even jointly won the Belding Scribner Award from the ASN in 2000.  
Intellectually they have staked out differing areas of excellence, Dr. Coe has focused on the the importance of the earliest stones to be anchored to the kidney. The location for these tiny early stones is Randall’s Plaques. The theory is that these tiny crystals form in the interstitium adjacent to the thin limb of the loop of Henle, they grow and eventually erode into the renal papilla. There, they are in contact with  supersaturated urine which can deposit calcium oxalate (or other other types of stones?). The plaques can be seen on cystoscopy and their presence predicts stone formers. Stone formation correlates with the degree of plaque coverage.
The blog is full of scientific and practical advice about kidney stones. His first post about why a blog is particularly insightful. 
A blog post is not a book chapter, a review article, a scientific article, or even a newsletter but something else entirely. It is the exact right size to convey one point and no more. It has no room for ornament or circumlocution, for fuzziness or indirection or even for two different points. You cannot avoid that moment when the main point must ring out clearly.
And this paragraph is just so Coe:
Being a singular, real, and immediate focus of attention, a point is something to work with. We can debate it, dissect it, even dismiss it if evidence permits or its logic is flawed. If a point appears to be sound, people can accept it as true for the moment, as an element that can be put together with like elements to make a picture of reality for this one disease. It is a picture that is true for the moment, arising as it does from science, just as the moment caught up in the pointillist net of Georges Seurat’s exquisite Sunday Afternoon on the Island of La Grande Jatte, being great art, will be true forever.

Welcome to the blogosphere Dr. Coe, we look forward to your posts. Your blog has earned a spot on my list of Notable Nephrology and Medical Blogs.

Sunday, September 14, 2014

Lecture on modern strategies to keep up to date in the medical literature. #FOAMed at Work.

I love it when fellows turn the tables on their attendings and school them on how the kids do it today.



Kamran Boka is currently a critical care fellow at Henry Ford Hospital but when he was a wee resident he worked with me at St John Hospital. This is an excellent lecture, make sure you check it out. Boka is fully engaged in the 21st century medical infosphere:


Check it out. He has important lessons for everyone.


Thursday, September 4, 2014

Urine specific gravity, not that great at estimating osmolality

I have a clinic patient with SIDAH and until the FDA regains some sanity and Otsuka provides a more rational price this will continue to be a frustrating battle. This patient had some pretty typical labs for a patient with SIADH, except for the specific gravity. I don't remember seeing such a discrepancy between the Sp Grav and osmolality before.




One of the sharpest nephrologists on twitter, Christos Argyropoulos, replied with this reference:




The conclusions from the abstract:
RESULTS: This study demonstrated that USG obtained by both reagent strip and refractometry had a correlation of approximately 0.75 with urine osmolality. The variables affecting the correlation included pH, ketones, bilirubin, urobilinogen, glucose, and protein for the reagent strip and ketones, bilirubin, and hemoglobin for the refractometry method. At a pH of 7 and with an USG of 1.010 predicted osmolality is approximately 300  mosm/kg/H(2)O for either method. For an increase in SG of 0.010, predicted osmolality increases by 182  mosm/kg/H(2) O for the reagent strip and 203  mosm/kg/H(2)O for refractometry. Pathological urines had significantly poorer correlation between USG and osmolality than "clean" urines.

Here is a table I made from the conclusions:

Tuesday, September 2, 2014

Sodium, in the spotlight for next week's #NephJC

In August, the NEJM pushed out three articles examining the role of sodium in human disease. These are the subject of September 9's #NephJC.

The first article is the Association of Urinary Sodium and Potassium Excretion with Blood Pressure. This question used the large epidemiologic study, Prospective Urban Rural Epidemiology (PURE) to answer the question.

PURE enrolled 157,543 adults age 35 to 70 from 18 low-, middle-, and high-income countries on 5 continents.

The study collected 102,216 fasting first morning urines. The authors used the Kawasaki formula to extrapolate 24 hour urine sodium and potassium from the samples. They collected 24-hour samples on 1,000 patients and found that they over estimated sodium intake by about 7%:


The mean sodium excretion was 4.9g and the mean potassium excretion was 2.1 grams.
It was difficult for me to understand the difference between the Observed excretion and Usual excretion but the authors seemed to reference the Usual excretion as the definitive curve.

Sodium excretion was higher in rural areas and in lower income countries. The reverse was true for potassium, higher in cities and higher in higher income countries.

The meat of the paper was the positive association between sodium intake and blood pressure. For every additional gram of sodium excretion the systolic blood pressure went up 1.46 mm Hg and the diastolic rose 0.54 mm Hg (P less than 0.001). Statistical mumbo jumbo increased those numbers to 2.11 systolic and 0.78 mm Hg diastolic. This relationship was non-linear with increased blood pressure effect as the sodium excretion rose over 5 grams.

Potassium had the opposite effect with systolic blood pressure falling 0.75 systolic (1.08 after statistical adjustment) and diastolic dropping 0.06 (0.09 adjusted) mm Hg for every gram increase in potassium excretion. 

Older people showed larger changes in blood pressure with increased sodium excretion.

The sodium effect on blood pressure was a lot larger that the 0.94 mmHg systolic and 0.03 mmHg diastolic found in the landmark INTERSALT study but still seems like a pretty small effect given the difficulty in getting to a low a salt diet. Look at the bell curve showing only 0.2% of samples hitting the WHO goal of less than 2.3 g a day.

Sodium, in the spotlight for next week's #NephJC, part 2

The second article in the NEJM package was Urinary Sodium and Potassium Excretion, Mortality, and Cardiovascular Events.

This is an interesting study because so much of the arguments based on salt focus on the intermediate end-point of blood pressure, one can lose sight on the big daddy, total mortality. Previous studies have shown that low sodium diets have paradoxically been associated with higher rates of cardiovascular disease and death. These studies have often been dismissed by sodium puritans by pointing out that including patients with pre-existing cardiovascular disease will pollute the results because these, obviously, high risk patients are told to maintain a low sodium diet.

This study was performed using the same international cohort as the previous trial, The PURE study. This study enrolled 101,945 patients and analyzed early-morning fasting urine samples. They used the same Kawasaki formula that over estimated sodium excretion as in the other PURE study.

They used multiple models to analyze the data.

Patients with pre-existing cardiovascular disease, cancer or events in the first two years of follow-up were excluded from the analysis. They also did an additional analysis using propensity scoring to further reduce imbalanced confounders.

The most important letter in the PURE acronym is P for prospective. In this case it allowed them to match the cross sectional sodium excretion data with long-term follow data. Mean follow-up was 3.7 years. The primary outcome was death or a major cardiovascular event. Over the period covered by the study they recorded 3,317 outcomes. The risk from changes of sodium intake was seen at the edges of intake:
Increased mortality at sodium excretion over 7 grams and below 3 grams

Green indicates an association with sodium excretion. Red indicates no significant association.
The U-Shaped curve seen with sodium was not seen with potassium. The more potassium excretion the lower the risk of the primary outcome.


The results were essentially the same in the propensity-score-matched analysis.

I found this paragraph from the discussion to be particularly salient:
Current guidelines, which recommend a maximum sodium intake of 1.5 to 2.4 g per day, are based on evidence from largely short-term clinical trials showing that reducing sodium intake from a moderate to a low level results in modest reductions in blood pressure. The projected benefits of low sodium intake with respect to cardiovascular disease are derived from models of data from these blood-pressure trials that assume a linear relationship between sodium intake and blood pressure and between blood pressure and cardiovascular events. Implicit in these guidelines is the assumption that there is no unsafe lower limit of sodium intake. However, sodium is known to play a critical role in normal human physiology, and activation of the renin–angiotensin–aldosterone system occurs when sodium intake falls below approximately 3.0 g per day.
The authors make it clear that an epidemiologic association between mortality and sodium excretion is not the same as finding increased mortality or lack of benefit from patients lowering their sodium intake. Advice that the authors of the third study should have taken the time to internalize.
Finally, our study provides an epidemiologic comparison of groups that consume different levels of sodium, and it does not provide information on the effect on clinical outcomes of reducing sodium intake. Therefore, our findings should not be interpreted as evidence that the intentional reduction of sodium intake would alter the risk of death or cardiovascular disease. 

Sodium, in the spotlight for next week's #NephJC, part 3

The last article in NEJM's remarkable sodium package is an extraordinary analysis attempting to estimate the number of deaths that can be attributed to excess sodium intake.

Global Sodium Consumption and Death from Cardiovascular Causes.

The authors reviewed 205 studies of dietary sodium consumption:
  • 142 studies that used 24-hour urine collections
  • 91 with estimates of dietary intake
  • 28 with both methods
These studies came from 66 countries representing 74.1% of the adult population. It is appropriate to whistle and say wow, at this point.

Inorder to translate the sodium intake into mortality the authors first needed to estimate sodium's effect on blood pressure. They employed two Cochrane meta-analysis looking at the effect of reduced sodium intake on blood pressure (Meta 1, Meta 2). They used these meta-analysis to discover sources for there own meta-analysis. They needed age and gender specific effects of sodium on blood pressure which is why they needed to do their own analysis.

After estimating the effect of sodium on blood pressure, they then used the blood pressure data to estimate cardiovascular mortality based on the work done in two large studies (Study 1, Study 2).

Estimated global sodium intake was 3.95 g per day, quite a bit lower than the 4.4 grams measured in the PURE studies. They pointed out that 99.2% of the countries surveyed had mean sodium intakes higher than the WHO level of 2 grams a day. An astounding 88% of the world had sodium intake more than 50% over the WHO recommendation.

Their meta-analysis found that systolic blood pressure fell 3.8 mm Hg for every 2.3 grams sodium intake was reduced. This translates to a more interpretable 1.6 mm Hg for every gram reduction in sodium. This is quite close to the 1.5 mm Hg found in the PURE analysis. They used 2.3 grams because that is equal to 100 mmol of sodium, for people who like to speak like a chemist.

They then ran the blood pressure data into the mortality data from blood pressure and concluded that consuming more than 2 grams of sodium a day results in 1.65 million deaths from cardiovascular disease a year. This is 9.5% of all cardiovascular deaths in the world and nearly 20% of all premature deaths.

However, despite a very through analysis this is an exercise in somewhat meaningless statistical gymnastics. The authors fail to consider the possibility that lowering the blood pressure too far could have negative consequences, (Hello ACCORD Trial. Nice to meet you.) Or the possibility that low sodium diets could be harmful.

Note that, these figures come from a 2011 prospective trial published in a little known journal called JAMA. This signal that low sodium diets may not be beneficial is not new or unknown. It was picked up by the Institute of Medicine in their summary and recommendations to avoid very low sodium diets:
However, the evidence on health outcomes is not consistent with efforts that encourage lowering of dietary sodium in the general population to 1,500 mg/day. Further research may shed more light on the association between lower—1,500 to 2,300 mg—levels of sodium and health outcomes.
This becomes even more concerning when looked at through the lens of the PURE studies in the same issue of The Journal that show average sodium intake to be associated with the lowest mortality and danger rising on either side of the sodium consumption curve.

This is a study best taken with a grain of salt. Couldn't resist.

Monday, August 25, 2014

OUWB Acid base question

The e-mail:

Hi Dr. Topf,
We were going through the acid-base study guide and Prince Harry has us all out of sorts. His scenario is this: 
Your first mistake. It is Prince William not Harry. Know your Royals. (Though I do not think royal genealogy is a board eligible topic.)
7.42 | 32 | 76
Na - 148
Cl - 98
K - 5.8
HCO3 - 28 
For the primary acid-base disturbance, I would think it is respiratory alkalosis because the pH is elevated, the PCO2 is decreased, and the HCO3 is elevated.  
You are correct
Then for the second acid base disturbance, I thought it would be metabolic alkalosis. His PCO2 is 32, which is down about 10. So, his bicarb should go down either 2 if acute or 4 if chronic, to either 22 or 20. Instead it is 28 which means he has excess HCO3 (base) and so has an additional alkalosis. 
Correct again
I tried doing the anion gap (22) and the bicarb before (38) but my understanding is that a bicarb before of 38 would also be metabolic alkalosis.  
Yes
In the answers, it says that if you have an AG with alkalosis or a primary acid-base disorder, that it would be an acidosis.  
If you have time, can you help me understand why his primary disorder is metabolic alkalosis, and how to apply the anion gap and bicarb before formulas to this case?  
Thanks for your time. 
Best regards,
This refers to this question in the handout:


There is an error in the ABG. Using the Henderson Hasselbalch equation it is obvious that this ABG is impossible, as pointed out by +MedCalc on twitter:



So the actual pH should be 7.51. But that doesn't change the rest of the answer or the calculations.

To get this problem right, it breaks one of the rules I established and uses another rule that was not discussed. This is failure on my part and I will fix this.

The rule that it breaks is the rule that compensation is always in the same direction as the primary disorder. Obviously with a pCO2 of 32 and bicarbonate of 28 the two independent Henderson-Hasselbalch variables are moving in discordant directions.

This is a great guideline, it just isn't always true. In cases where patients have two primary disorders the pCO2 and bicarbonate can move in opposite directions. This is not the typical finding but when it occurs it is simple to interpret:


If the pCO2 falls it is respiratory alkalosis and if it rises it is respiratory acidosis. If the bicarbonate falls it is metabolic acidosis and if it rises it is metabolic alkalosis. So in the case of Prince William, his bicarb is up and pCO2 is down so he has both a metabolic and respiratory alkalosis. The reason I do not include this is that it is an additional complexity that if you follow the algorithm that I taught you will get the right answer without knowing this exception. I choose to streamline the teaching rather than teach this shortcut.

The rule that was not discussed is in regards to the anion gap. In my booklet I never discuss that the presence of an anion gap regardless of the pH or serum bicarbonate always indicates a metabolic acidosis. The hierarchy of acid interpretation that I showed in the booklet should include that right at the top and has been updated to reflect that:



So Prince William is rocking an anion gap of 22, this means he has an anion gap metabolic acidosis. If you use the bicarbonate before formula you see that his bicarbonate was 38 excluding his anion gap metabolic acidosis indicating a truly wicked metabolic alkalosis.

Tuesday, August 19, 2014

OUWB School of Medicine Materials 2014

The Potassium and Metabolic Alkalosis lecture:

The Acid Base Lecture
  • Keynote (480 MB)
  • PDF (51 MB)
  • Extra lecture only about non-anion gap metabolic acidosis

The Potassium lecture (on your own)

The Sodium and Water Handout

The Electrolyte and Acid Base Companion

Acid Base Workshop

Monday, August 18, 2014

Sodium is hard

Of all the concepts in fluids and electrolytes by far the most difficult is sodium, water and volume regulation. I think the problems stem from multiple angles, one of which is the confusion between total body sodium (reflected in volume status) and sodium concentration (the primary determinant of osmolality). When writing the sodium chapters I kept thinking about that exchange on Dagobah:



I lead a TBL exercise for second year medical students last week tackling this difficult subject and they ran in to all of the problems that befuddle students when they first try to grock this. On Friday I received this e-mail (only medical students include bibliography in their e-mails):

Good Afternoon Dr. Topf, 
I am a student at OUWB and you ran our TBL this past week. I’ve been struggling with this material and I was previewing for lectures next week. I apologize for emailing over the weekend, but I am confused over a concept that we went over in TBL - that is, the impetus for release/action of the RAAS system and ADH. 
From our discussion and our physiology class prior in the week, I am understanding that ADH primarily regulates osmolarity and that aldosterone primarily regulates blood volume. However, it seems that as I go over review books, I’m being told that ADH, “…also responds to low blood volume, which takes precedence over osmolarity,” (First Aid), and from our physiology text book (Costanzo), it indicates that ADH has 3 functions including: 
1. increasing H2O permeability of principal cells (which the text indicates is the primary function)
2. increasing activity of the Na+/K+/2Cl- cotransporter
3. increases urea permeability 
Upon my own research, a neuroscience text book source (from the University of Texas) indicates that there are angiotensin II receptors located in the subfornical organ which, upon binding of angiotensin II, cause a release of ADH from the posterior pituitary. I feel like I’m getting different information on what ADH’s role is a response to. 
In the case of isotonic volume loss (eg. hemorrhage, diarrhea), you would get activation of the RAAS system as a response to low blood volume/BP. My confusion rests in - does ADH get released as a result solely of the volume loss (not in response to a change in osmolarity) via the angiotensin II - subfornical organ - posterior pituitary pathway? (implying its importance and precedence in preserving blood volume over osmolarity?) 
OR is the production of aldosterone in this situation which leads to increased Na+ absorption, which in turn increases blood osmolarity leading to ADH release the mechanism for ADH release in relation to preservation of blood volume?


Thank you kindly in advance.

Best,

[Name withheld]

Sources: Physiology 4th ed. Linda S Costanzo pg. 291
First Aid for the USMLE Step-1 2013 Tao Le, Vikas Bhushan pg. 485
http://neuroscience.uth.tmc.edu/s4/chapter02.html Patrick Dougherty, Ph.D

Here was my reply

[Name withheld],

The goal of medical physiology is to build a model of how the body works so that the student can predict how the body will respond to various inputs. The more advanced the model the more situations the model will accurately predict the outcomes. Of course the down side of the more complex model is it becomes more and more difficult to remember and keep accessible for use.

Every concept in physiology that is taught should be taught as a step in building an accurate model. Any student that tries to memorize the avalanche of physiology facts without fitting them into a model will be lost. Additionally, students that confuse the model for reality will be disappointed because no model can adequately describe the wonderful complexity of the human body. The sweet spot is adopting a model that is accurate enough to describe the clinical scenarios you encounter in medicine without being so complex to confuse the user

This is especially appropriate for renal physiology.

Short answer is you have it right.:
RAAS is for volume (BP and perfusion) regulation and ADH is for osmoregulation.

Additionally the statement that ADH also responds to volume is also correct and essential in understanding why heart failure and volume depletion leads to hyponatremia. In both CHF and hyponatremia the perfusion is compromised so much that ADH is released (not because of high osmolality but because of the low perfusion signal for ADH). This ADH concentrates the urine and lowers urine output. Then even modest amounts of water will exceed intake and sodium is diluted.

The additional statement that it takes precedence over osmolality is critical. When there is simultaneous low osmolality (suppresses ADH) and low blood pressure (stimulates ADH), the volume stimulus wins. In the hierarchy of need, maintaining perfusion takes precedence over osmoregulation.

a page from the best book I ever wrote

Regarding Costanzo’s three functions:

  1. Increase water permeability. Yes this is the primary and most important function of ADH with regard to osmoregulation.
  2. Increase activity of the NaK2Cl this is likely true because the NaK2Cl is the pump needed to maintain the concentrated medullary interstitium that drives the reabsorption of water in the collecting ducts in response to ADH. Having ADH stimulate this receptor helps maintain that concentrated interstitium so it doesn’t get diluted by the reabsorbed water. However I would recommend you ignore this fact. This complicates the model of osmoregulation and will lead you down false roads.

    If you believe this is an important function of ADH you will assume that SIADH, a condition of unregulated over production of ADH will cause sodium accumulation (due to stimulation fo NaK2Cl pump) when in reality the most important aspect of SIADH to understand is that SIADH is a sodium neutral state (sodium in = sodium out) and only causes hyponatremia due to the over reabsorption of water (due to the ADH)
  3. Increased urea permeability. I have no idea if this is important and why it might be important. It likely is also important in maintaining the concentrated medullary interstitium. That is one of the strangest tissues in the body and ADH induced water reabsorption dilutes it so my guess is that many of the subtler renal affects of ADH are designed to maintain and restore this briny Superfund site in the middle of the kidney. Ignore the italics, that is only to impress other nephrologists that read this far.

In regards to the neuroscience textbook indicting AT2 receptors as a critical signal for ADH release. This is likely the trigger for the volume dependent release of ADH we discussed above. But again this is a fact that can be safely ignored because if you focus on AT2's role in ADH release you may falsely assume that ACE inhibitors (and angiotensin receptor blockers and renin blockers) will block these receptors, decrease ADH and cause a diabetes insipidus picture. This does not happenKeep it simple.

AT2 is for volume 
ADH is for osmolality 
don't conflate the two

Your final question is about isotonic volume loss, the answer is: you are clearly describing a perfusion related release of ADH. Do not use an overly complex Rube Goldberg system of increasing osmolality to release ADH.

I also would recommend my book. You can download the whole thing for free (PDF). It is long and Adobe Acrobat did a shitty job of rendering much of the text but it is excellent and it is free.


Wednesday, August 13, 2014

Recipe for IV Fluids

Normal Saline

1 tsp salt = 2,300mg sodium = 100 mmol sodium
1 gallon = 3.78 liters
1 liter of NS has 154 mmol of sodium
1 gallon need 582 mmol of sodium (154 * 3.78)
582/100 = approx 6 tsp of sodium

3% Saline

1 tsp salt = 2,300mg sodium = 100 mmol sodium
1 gallon = 3.78 liters
1 liter of 3% has 513 mmol of sodium
1 gallon need 1,939 mmol of sodium (513 * 3.78)
1,939/100 = approx 20 tsp of sodium

D5W

1 tsp sugar = 4.2 g sugar
1 gallon = 3.78 liters
1 liter of D5W has 50 g of sugar (glucose)
1 gallon needs 189 g of sugar (50 * 3.78)
189/4.2 = approx 45 tsp of sugar or 15 tablespoons

Anyone want to check my math?

IV fluid taste testing at McLaren Macomb Hospital





Monday, August 11, 2014

Just saw a heart failure patient in follow-up

We had a patient, who had been healthy until he ran into some a-fib. He then began a months long descent into the depths of decompensated heart failure. His dry weight prior to decompensation was 208. On admission to the hospital he was 262.

It took over a month of acute and sub-acute care, a failed cardioversion, a pacer, and a cardiac ablation, but he ultimately emerged from his heart failure. He is now back to his dry weight. He went from 208 to 262 pounds to 208 pounds'  That is 54 pounds of water weight. My understanding of heart failure is this excess fluid is almost entirely extracellular.

Think about how much water and sodium that is:

  • 54 pounds = 24.5 kg of 24 liters of water
    • Total body water of an average adult is 42 liters
    • Extracellular volume is a third of that, or 14 liters
    • at 208 pounds his total body water is only 47 liters
  • 24.5 kg of water with a sodium concentration of 140 = 3,430 mmol of sodium. 
    • For comparison the total body sodium for a 70 kg man is around 2,200 mmol
Incredible.
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