Sunday, July 27, 2014

cJASN is building an open access renal physiology text book

One of the surprising things about nephrology fellowship is how far separated renal physiology is from the day to day work of nephrologists is. Kind of by definition we are called in when the kidneys aren't working so we don't get normal physiology thrown in our face. But that doesn't mean we don't need to know it. One of the important jobs of the nephrologist is to keep this knowledge alive and be experts in the internal workings of the kidney. I am a disciple of of Burton Rose, others carry the generation before me used Brenner and Rector and before that Guyton and before that Homer Smith. Who will the next generation of nephrologists look to enlighten them in the ways of the kidney?

CJASN is making the argument that they will. Mark L. Zeidel, Melanie P. Hoenig, and Paul M. Palevsky have started a renal physiology course that is open access and will come serially every month like Dickinson novel.

Take a look at the editorial describing the project and the first chapter which is just an introduction to the main course. The introduction is the subject of this month's eJC. Here is what I wrote in their forums:
I am so excited about this series. Fellowship application season is upon us and I have already heard rumblings that this year will be even worse than the devastating match results from 2014.  
The work-force task group from the ASN has been focusing on developing nephrology mentors to increase interest in nephrology. This is a great idea, but the mentor that inspired me to become a nephrologist was not made of flesh and blood but of ink and pulp. 
I am a nephrologist because I was inspired by the brilliant prose of Burton Rose in the yellow edition of Clinical Physiology of Acid Base and Electrolyte Disorders. But times have changed and residents no longer read books. I applaud this series and hope it will serve as a contemporary inspiration for medical students and residents to pursue the noble and fascinating field of nephrology. 
I also tip my hat to the editors of CJASN for making the series open access. A resource this valuable should be shared with the world.  
Bravo.

Monday, July 21, 2014

Hemo the Magnificent. A classic

Check out the complete video:



and part 2:



Wikipedia entry. 

This was the movie I was thinking about when I tweeted:




Hat tip to Dr. McIinnis for uncovering the video!




I had no idea this masterpiece was done by Frank Capra! Wow.

Monday, July 14, 2014

Richard Lehman is a medical treasure

Read this one paragraph and you will understand why.
Someone recently told me that the link between alcohol and reduced coronary disease is purely observational, and that therefore we should not recommend alcohol as part of the “Mediterranean” diet. I didn’t want to argue, but you could say much the same about smoking and cardiovascular disease. The evidence of benefit from alcohol is solid, robust, and repeatedly found wherever you look, but almost impossible to replicate experimentally for the very good reason that people who drink do so as part of their daily pleasure. Yet the several hundred authors of this paper have tried to do something even more impossible: make this evidence disappear by a Mendelian hat trick. I am completely baffled that they should (a) want to do it and (b) think this is good enough: “Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.” No it doesn’t.
Read him every week and your life will be better.,

Some twitter lover for Lehman








Unusual causes of non-anion gap metabolic acidosis: chlorine gas

Chlorine gas inhalation happened this week-end at a water park in Michigan. Link


Fact sheet on chlorine here.

Sunday, July 13, 2014

Great potassium links

Potassium Intake of the U.S. Population
What We Eat in America, NHANES 2009-2010
by Mary Hoy and Joseph Goldman

Link (PDF)

What we eat in America Individuals 2 years and over day 1 dietary intake data, weighted.
NHANES 2009-2010
National Research Council. Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate. Washington, DC: The National Academies Press, 2005.


Link (PDF)

Hypokalemic periodic paralysis - an owner's manual

Monday, July 7, 2014

#NephJC Preview: Hyperosmolarity drives hypertension and CKD

On Tuesday, July 8th, at 9 pm we are doing our sixth nephrology journal club and it is on Johnson et al's Perspective in July's Nature Reviews Nephrology.


The article begins with a discussion with the ongoing epidemic of CKD in Sri Lanka and Central America. Actually people in the know are calling it Mesoamerica, a term I had not heard before.

From Wikipedia
Mesoamerica is a region and cultural area in the Americas, extending approximately from central Mexico to Belize, Guatemala, El Salvador, Honduras, Nicaragua, and northern Costa Rica, within which a number of pre-Columbian societies flourished before the Spanish colonization of the Americas in the 15th and 16th centuries.[1][2] It is one of six areas in the world where ancient civilization arose independently, and the second in the Americas after Norte Chico (Caral-Supe) in present-day northern coastal Peru.

Characteristics of the CKD epidemic:
  • Men are predominant affected
  • Victims work and line in hot tropical agricultural communities
  • They are manual workers
  • Largely asymptomatic
  • Elevated creatinine without (significant) proteinuria
The second paragraph is critical to the rest of the review. It states that numerous of studies and researchers have looked for nephrotoxins like pesticides or heavy metals none have been found. This chart is from Dan Weiner's free and excellent CJASN review.

The Johnson editorial focuses on recurrent dehydration as the etiology. This explains the male:female mismatch and explains why high altitude appears to be protective. The article suggests that it is the hyperosmolality not the volume depletion that may be important in the disease:
In this Perspectives article, we present the hypothesis that changes in osmolarity induced by an imbalance in water and salt intake, rather than the amount of salt or water ingested per se, drives the development of dehydration-related hypertension and kidney disease.
This theory is in contrast to the more conventional view of repeated episodes of volume depletion causing pre-renal AKI and this resulting in CKD as described by Weiner et al:
Recently, a new paradigm has been gaining favor that AKI, even with apparent recovery in kidney function, may not be innocuous (27). In this paradigm, either repair attempts themselves or ongoing insults with subsequent repair at- tempts lead to a self-perpetuating cycle of inflammation and repair, resulting in kidney fibrosis and clinically recognizable CKD. Accordingly, we hypothesize that repeated ischemic insults to the kidney caused by severe volume depletion with or without hyperthermia and potentially in conjunction with other kidney insults result in progressive kidney fibrosis and ultimately, kidney failure.
The article then describes the body's defense against hyperosmolality, the first path is the familiar release of ADH and the concentration of urine and reclamation of water from the collecting tubules. The second limb is one I was not familiar with.
The second process involves activation of the polyol metabolic pathway, in which hyperosmolarity increases the activity of aldose reductase, which in turn converts glucose into sorbitol. Sorbitol is an osmolyte that protects tubular cells and interstitial medullary cells from the hyperosmotic environments that drive water reabsorption, especially under conditions of dehydration and plasma hyperosmolarity.
The rest of the article describes the science behind how these two pathways, when chronically activated, can promote  CKD.

ADH antagonists have been shown to prevent/decrease albuminuria in rat models of diabetic nephropathy. In another experiment, forced water drinking reduced a number of measures of diabetic kidney disease in rat models (e.g. proteinuria, nephrosclerosis, renin activity, etc). The article describes some potential mechanisms for this toxicity including the possibility that ADH drives hypertension, increased metabolic demand and mitochondrial dysfunction. The authors provide links to two reviews of ADH as a progression factor in CKD:

  1. Nature Reviews Nephrology: Vasopressin: a novel target for the prevention and retardation of kidney disease?
  2. Current Opinion in Nephrology and Hypertension: Vasopressin beyond water: implications for renal diseases

The article then turns to the aldose reductase pathway. Aldose reductase generates sorbitol which is used to protect the tubular and medullary cells from hyperosmolarity. The proposed toxicity comes from the metabolism of sorbitol to fructose and then the metabolism of fructose. Fructose kinase rapidly consumes ATP in the conversion of fructose to glyceraldehyde 3-P and the consumption of ATP can cause ATP depletion and ischemic damage.
A depiction of fructose metabolism alongside glycolysis. The first step of fructose metabolism is wholly unregulated so ATP will be consumed until either there is no ATP or fructose available.
The article points out that KHK-C, enzyme that burns ATP in the metabolism of fructose, is primarily located in the liver (hence all the liver disease associated with high sugar intake) but is also found in the proximal tubule. High fructose intake has been associated with renal disease in animal models.
So the purported chain of events is:
  1. increased osmolality leads to
  2. increased aldolase activity which leads to
  3. increased sorbitol
  4. Sorbitol is metabolized to fructose
  5. Fructose metabolism causes local ATP depletion and renal damage
This chain of events was demonstrated to occur in animal models in a recent KI article. The increased osmolality was created by heat exposure, further modeling the presumed injury in Mesoamerica. Renal dysfunction, from the increase in osmolality, was demonstrated via increases in creatinine, NGAL, blood pressure and histologic change. The experiment also used fructose kinase knock out mice and they were protected from these changes, implicating this enzyme as the bad actor.

Johnson et al, logically extends this data to one possible implication:
The observation that dehydration-induced hyperosmolarity results in renal injury mediated by endogenous fructose (which is produced by the polyol pathway) also raises the question of whether rehydration with fructose-containing drinks, or the chewing of sugarcane (which is rich in fructose), might exacerbate renal injury.
the aminoglycoside of our time?

The article then turns its attention to the pro-inflammatory aspects of hyperosmolality. This has been demonstrated with increased cytokine release form peripheral blood monocytes and increased TGF-beta from smooth muscle cells. Increased osmolality stimulates the sympathetic nervous system which in turn stimulates angiotensin 2. All of these could be important mechanisms in causing or extending CKD with increased osmolality.

The authors conclude by briefly reviewing some of the data on salt intake and hypertension. They suggest that some of the variable results may have been because we have been looking at salt intake and ignoring the possibility that the mechanism of hypertension may not be entirely due to increased extracellular volume and that increases in osmolality may be important. Would it be possible to replace the puritanical instruction to minimize sodium with a simpler instruction to wash that sodium down with a lot of water? Exploring this will require careful attention to be paid to the timing of water administration:
Specifically, plasma osmolarity will be affected by both the amount of salt ingested and the timing of ingestion. For example, drinking water followed by eating salty food might have worse consequences than the reverse. Eating salty foods and then drinking fluids to quench the resulting thirst might not be ideal, as the thirst response occurs after vasopressin is released.[ 82 , 83 ]

This is a fascinating and novel look at emerging models of renal failure and shows the how a remote epidemic can stimulate fresh looks at old problems.

Sunday, July 6, 2014

#NephJC this Tuesday, we dive into MesoAmerican Nephropathy

Readers of PBFluids know that I have been on the uric acid is the source of hypertension and hypertensive nephropathy beat ever since Richard Johnson came to the Townsend to speak at a gout symposium. Johnson's lecture on the link between uric acid and hypertension is the single best lecture I have ever seen.

Before that lecture I thought I was a pretty good lecturer, that lecture taught me that I was a baby. I knew nothing. If you ever get a chance to hear Dr. Johnson, move heaven and earth to hear him, he is amazing.

You can see some of my posts relating to uric acid, fructose and kidney disease here:
Though not covered extensively on PBFluids one of the most interesting stories in nephrology for the last year has been the emergence of a newly recognized epidemic of renal disease in Central America. I first learned about it following this tweet:


and I was recently reminded about this when this tweet crossed my stream:


Here is a close up of the only country in the world where Nephritis and nephrosis is the leading cause of death, Nicaragua.


The one time I blogged about this. Though I haven't been fastidious about the MesoAmerican Nephropathy beat, eAJKD has:
Interestingly, these two intrigues subjects, the toxicity of uric acid/fructose and MesoAmerican Nephropathy collided in a recent editorial by Richard Johnson et. al. This editorial is the subject of this week's NephJC on Tuesday, July 8th at 9:00 Eastern.

The article is a perspective review titled: Hyperosmolarity drives hypertension and CKD-water and salt revisited. (PMID: 24802066)

I was told that Nature Reviews Nephrology was going to make the article open access and it was a few weeks ago but for now it is closed. Make nice to your local medical librarian.

More background and a summary of the article tomorrow.

Thursday, June 26, 2014

Nephrology oscars

The Greatest Movie Scene (intravenous fluids division) goes to...Catch 22


Wednesday, June 18, 2014

Lowest potassium I have seen

The Story

A young woman loses consciousness at home and is unable to be revived. EMS brings her to the hospital with resuscitation in progress.

Initial ECG:



Initial labs:


What's the acid base disorder?


I look at the increased pCO2 and decreased pH and call it a respiratory acidosis. The HCO3 should go up to compensate for the increased CO2 but it is slightly decreased, so there is also a metabolic acidosis.

When there is a metabolic acidosis check the anion gap (and even when there is no evidence for a metabolic acidosis, you should check for an anion gap). Holy Ketones, the anion gap is 23!

A large anion gap in the face of only a modest drop in bicarb is unexpected. One expects the bicarbonate to fall 1 mEq/L for every 1 mEq/L the anion gap rises. So if this lady started with an anion gap of 12, her gap went up by 11, so the bicarb should have fallen by 11. In order for the bicarbonate to fall by 11 and end up at 22 it would need to start at 33, indicating a preexisting metabolic alkalosis (or compensated respiratory acidosis I suppose). The metabolic alkalosis is welcome because it fits with the hypokalemia rather well. Alaklosis and hypokalemia go together like macaroni and cheese.

So what is causing the increased anion gap? Well that is easy to determine in this case, her lactate was 12.4, almost a perfect match for an increase in the anion gap of 11. Remember the anion gap is quantifying an anion that is not in the chem-7 but is making its presence known by the unbalanced number of cations and anions. We expect the unbalance to be between 6 and 12, this is a normal anion gap. Her anion gap is 23, 11 over the limit. This means we need to find the anion that explains this gap of 11. A lactate level of 12.4 neatly explains the increased gap. If you are concerned about the difference between 11 and 12, remember that the calculation of 11 comes from assuming that prior to building up the lactic acid, her anion gap was 12, but it could have been 8 or 10 or 4.

What happens next will shock you (now I'm a real internet writer)


The potassium went down. It went way down...to 1.8, and that, my internet friends, is the lowest potassium I have ever seen. And it is the presumed cause of the cardiac arrest. The ECG normalized with correction of the potassium.
For the next 38 hours we give her potassium. A lot of potassium. Especially if you consider that she was anuric due to acute tubular necrosis.


Keep in mind that the entire extracellular compartment normally contains only 56 mmol of potassium. The entire plasma compartment normally contains only 12 mmol of potassium. Also keep in mind that after 810 mmol of potassium she was still hypokalemic.

So what happened after 38 hours?


We overshot, in fact we made her hyperkalemic and needed to start dialysis. The dialysis was inevitable, she remained anuric for days after we started the CRRT, and she was also becoming volume overloaded.

The cause of the hypokalemia is unclear. The one point that I am certain of, though, is this must be a chronic process. She had a documented potassium deficiency of 31 grams of potassium! No acute event could have caused her to lose that much potassium, the process that caused the hypokalemia and metabolic alkalosis must have been going on for weeks? Months? Years? Prior to her developing the cardiac arrhythmia. She has recovered her renal function and her electrolytes remain within normal limits, she does not seem to have any renal leak of potassium that I can detect. She denies vomiting. She does have a poorly documented incident of hypokalemia that happened years ago. Her magnesium when measured on the first hospital day was normal. Since recovering her kidney function her magnesium has been low normal. She denies salt-cravings. Just after she recovered her kidney function and her creatinine was normal, she developed slight hypokalemia, right around 3.2 mmol/L. I shot off a TTKG and it was an unremarkable 3.1.

So smart people on the internet, what do you think caused the hypokalemia. The family is understandably concerned that this could happen again. I have my theory, but I don't want to bias your thoughts. Please e-mail me or DM me on Twitter.

Blogged with patient permission. Release on file at PBFluids world headquarters.
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