I can’t post to Vimeo until next week. So google docs this time.
Part one is here
August is aPLA2R month
For decades we have known that membranous nephropathy was an antibody induced glomerulonephritis, we just didn’t know what the antigen was. Then, in 2009, Beck et al. rocked nephrology by discovering the antigen, Phospholipase A2 antibodies were detracted in 70% of patients with membranous nephropathy and no patients with either secondary membranous, other proteinuric glomerulonephritis or normal controls. Since then there has been a steady stream of positive trials showing tight association with aPLA2R antibodies and disease activity in idiopathic membranous nephropathy.
 |
| Panel H illus trates the domain structure of PLA2R, which is composed of an N-terminal cysteinerich domain (CysR), a fibronectin type II domain (FNII), eight CTLDs, a transmembrane domain (TM), and a short intracellular C-terminal tail (IC). The blocking fragment used in the experiments consists of CTLDs 4, 5, and 6 of a recombinant rabbit PLA2R. |
This month both CJSAN’s eJC and #NephJC will be going deep with studies that examine the state of the art in aPLA2R research.
This month CJASN’s online journal club is doing an interesting article looking at aPLA2R status at the beginning and end of therapy and its ability to predict long-term outcomes. It is a unique study with multiple titers of aPLA2r over the course of time matched with 5 years of follow-up. Though it is not the biggest trial of aPLA2R in some ways it is the best and it is an important step in understanding how to use this new tool in the management of membranous nephropathy.
Every month eJC has a sponsor, this month that sponsor is my home institution St John Hospital and Medical Center in Detroit. My fellow and I reviewed most of the key studies in aPLA2r and provided a helpful summary of this study. Check out our background post at Medium and then participate in the forum.
#NephJC will be shortly announcing its article for discussion and then have a twitter discussion on August 12th at 9pm EDT.
World’s Best Potassium Lecture part 1 of 3
Once agin I have the honor of teaching the second year medical students at Oakland University William Beaumont School of Medicine. I have 4 points of contact with the students:
- I get to run the first TBL of the renal section. It is on sodium and water
- I get to run an Acid-Base workshop
- I get to deliver a traditional Acid-Base lecture
- I get one hour to do potassium. Last year I tried to squeeze potassium, metabolic alkalosis and secondary/monogenic hypertension into that one hour. What a disaster. So this year I am going to flip the class took so that the students can learn the basics of potassium on their own and then do an interactive case based approach to the more advanced concepts. We’ll see if I get better ratings this year.
The lecture is mostly done, but not quite ready to be posted for download. However I did record the first segment. You can see that here.
I should have the other two segments online soon and when I do the lecture will be available as a PDF and a Keynote 2014 file.
Today’s lecture: Rapid Acid-Base Interpretation
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.
Hemo the Magnificent. A classic
Check out the complete video:
and part 2:
This was the movie I was thinking about when I tweeted:
Remember in 5th grade biology you were taught that the blood was like seawater? Total bullshit. Na in seawater is 469 mmol/L
— Joel Topf (@kidney_boy) July 21, 2014
Hat tip to Dr. McIinnis for uncovering the video!
@kidney_boy Are you telling me that Frank Capra and Ma Bell led us astray? http://t.co/uU5AXtgLzu @ 28:00 pic.twitter.com/QVA6ZCUGu4
— Mike McInnis MD (@DrMcInnisDIT) July 21, 2014
I had no idea this masterpiece was done by Frank Capra! Wow.
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
If you are a doctor on twitter and don’t follow @RichardLehman1 then you are doing it wrong.
— Joel Topf (@kidney_boy) August 27, 2013
Once again @RichardLehman1 shows why he is the smartest doc and best writer on twitter. http://t.co/NHs61hZIyb
— Joel Topf (@kidney_boy) January 6, 2014
“Richard Lehman’s journal review—14 July 2014” http://t.co/ucSWVTgATS #FOAMed one day this man will stop writing and I will be sad
— Andy Neill (@AndyNeill) July 15, 2014
Unusual causes of non-anion gap metabolic acidosis: chlorine gas
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
#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:
- Nature Reviews Nephrology: Vasopressin: a novel target for the prevention and retardation of kidney disease?
- 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:
- increased osmolality leads to
- increased aldolase activity which leads to
- increased sorbitol
- Sorbitol is metabolized to fructose
- 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.