Countdown to #xBio 2014

Apr 11 2014 Published by under EB2014, Societies and Meetings

Two weeks from today I leave my home and head to glorious San Diego for Experimental Biology 2014, the annual gathering of the organizations that comprise the Federation of American Societies for Experimental Biology, AKA FASEB. My favorite of these groups, the American Physiological Society, once again asked me to blog the meeting. I have finally gathered scheduling information and abstracts to organize my activities.

I will be attending and summarizing Saturday's session on storytelling for scientists, presented by Randy Olson. He has followed that traditional career trajectory from tenured professor to film school, and he wrote two books about scientists and communication skills (or, more accurately, lack thereof). I heard him speak at a screening of his film, Flock of Dodos, a few years back. His latest book, written with Dorie Barton and Brian Palermo, is Connection: Hollywood Storytelling Meets Critical Thinking. I am looking forward to seeing how his message has morphed over time. Obviously, I love communications, so this session is right up my alley.

Saturday also starts more traditional fare, including the Cannon Memorial Lecture. James M. Anderson of the NIH will present his talk, The Contribution of Paracellular Transport to Epithelial Homeostasis. As someone who teaches renal pathophysiology, this topic will be relevant. Look for some live tweets during this session.

Of course I will also attend and discuss the Gottschalk Award Lecture for the Renal Physiology Section on Monday afternoon. Susan Wall of Emory University will present her work on The Role of Pendrin the the Pressor Response to Aldosterone.

I have selected a number of abstracts that interest me; next week I will contact authors about coverage, either through email interviews, conversations on site, or perhaps even videos of them at their posters. See something in the program you think I should explore? Drop me a line via twitter (@phlane) or email (pascalelane [at] gmail...you know the rest).

Be sure and follow me on twitter as well as @expbio, and track the official meeting hashtag (#xBio) while you're at it. You may not be gazing on San Diego harbor in the sunshine, but you can still get a feel for the science at the meeting.

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My Arch Enemy

Apr 08 2014 Published by under [Medicine&Pharma]

Oklahoma is recovering from an outbreak of Escherichia coli which has kept me away from the blog recently.

E. coli, as we usually call it, lives all around and in us. A good chunk of that microbiome we keep hearing about includes this bacteria. Most strains happily thrive in our guts, living a perfectly benign coexistence with us. At times they may find their way into our urine or other problematic place, but they can usually be rapidly dispatched.

Some strains produce a toxin first noted in the bacteria Shigella, thus named Shiga Toxin. Autocorrect on my iPhone wants to change "shiga" to "shiva." This may not be an error. This toxin causes incredible inflammation within the bowel. When the gut gets inflamed, it lets water and other material flow on through, producing diarrhea. In this case, the inflammation is so intense that the gut bleeds. A bloody gut produces bloody diarrhea. Nausea, vomiting, and intense cramping complete the clinical picture. This is a case of the runs you will never forget.

Click to Enlarge

Click to Enlarge

In a small number of cases of hemorrhagic colitis, the toxin enters the blood stream and produces a systemic response called a thrombotic microangiopathy (TMA for short). In tiny blood vessels throughout the body (capillaries), the toxin damages the inside. Platelets (oblong lavender thingies in the diagram) activate on these areas of damage to begin repairs. These tiny clots get bigger over time and form a mesh or halt blood blow to an organ, impairing or shutting down its function.

Not all organs seem as prone to TMA damage. The kidneys seem to provide a playground for the toxin and platelets; kidney involvement ranges from the trivial to irreversible infarction or scarring of the kidneys. This is why we call this TMA hemolytic uremic syndrome (HUS), uremia being another term for kidney failure. Other organs can be involved, including the brain, pancreas, liver, and heart.

Obviously the kidney provides a major clotting magnet, or I would not be discussing this entity. We do not really know why one child gets colitis and develops HUS while another gets just a horrible case of diarrhea. Using antibiotics and anti-diarrheal drugs during the colitis can increase the risk of HUS, but they do not explain it all.

Since this syndrome was described in the 1950's mortality has fallen from ~50% to <5% just with supportive care. Mortality generally is confined to patients with significant central nervous system involvement. Apparent kidney recovery occurs in 95% of survivors, although most will develop other signs and symptoms of chronic kidney disease over the decades.

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Saturday Night #Thunder

Feb 24 2014 Published by under Uncategorized

Saturday evening I attended a very special event that I was banned from discussing until now.

In a children's hospital, you get used to celebrities doing things. Local personalities hand out goodies, making our patients and themselves a little happier in the process. Most of the time, they seem to target two patient groups. Premature babies get a lot of love, as do the kids with cancer. Other patients with chronic diseases receive less media attention. Kids with cancer might DIE! Children on dialysis will get transplants and be cured, right?

Not always. And a kidney transplant is hardly a cure, given life-long risks of immunosuppression.

I was delighted a few weeks back to hear that a local star wanted to do a party with our dialysis kids. Not only were they (finally) getting some special attention, but the celebrity would be my favorite OKC Thunder player, Serge Ibaka. My excitement was tempered by the fact that at first we nephrologists were not invited to the party.

Click to enlarge

Click to enlarge

I pouted a bit, but accepted my missed opportunity.

A few days later, I got the call that I could come. None of my family could come with me, but I was welcome to watch my patients interact and have some fun. I also was not to bring a phone or camera, although being on call meant I had to bring the phone. This loophole allowed me to take my completely unofficial illicit photo of the shot blocker at right. That's just the kind of rebel I am, folks.

The event took place in the hospital play zone. Each patient and their immediate family spent about 15 minutes alone with Serge (I shook his hand, I can call him that now, right?) and the kids got personalized Thunder jerseys, autographed in most cases. Then we all came together and he answered questions from the patients. After a group photo, he then shot baskets against the kids on an arcade basketball game (one girl even beat him; she is still glowing). Afterwards, he even posed for selfies with some of the teens. I have never seen such big smiles on the faces of these children; dialysis appointments rarely make you happy.

Things I learned or confirmed?

  1. Standing next to a 6'10" guy makes me feel even smaller than usual.
  2. During the games, Serge looks fierce, like he would not mind breaking your nose. In real life he is charming and quite attractive (and roughly the same age as my children; I have already heard all the Mrs. Robinson jokes this weekend, thanks).
  3. He speaks 5 languages, including his Congo tribal tongue, French, Spanish, Catalan, and English. Many of our patients and families have Spanish as their first language, so this was another delight.

Saturday's event left me with such a happy feeling. I am hoping others will take on the fight for kids with less publicly emphasized disorders, including the drive to raise money for research and treatment. All children deserve to have their health struggles acknowledged.

Thanks, Serge. Now go block some shots.

 

 

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Nutcracker musings

Dec 03 2013 Published by under Kidney Function

December has arrived, bringing chilly weather and thoughts of nutcrackers...

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No, not this practical kind.

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Not even this decorative kind.

More like the dancing kind!

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Did you know that there is another kind of nutcracker?

A kidney kind of nutcracker?

Click here to read about this unusual condition, the nutcracker syndrome, at my other home online!

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Shameless Bragging: A Student's Paper

Aug 19 2013 Published by under Journal Club

Last week my former grad student started her post-doc in another time zone. In her honor, I am blogging her first first-author paper which recently came out in PLoS ONE. It's my first open access paper as well!

Irsik DL, Carmines PK, Lane PH (2013) Classical Estrogen Receptors and ERα Splice Variants in the Mouse. 

doi: 10.1371/journal.pone.0070926

When I started exploring the role of puberty and hormones in the kidney disease of diabetes mellitus (DM), two schools of thought drove the relationship between traditional sex steroids and the kidney:

  1. Estrogen good
  2. Testosterone bad

From epidemiological studies, we know that men fare less well than women with many kidney disorders, at least until after menopause. Over time, we have discovered that the world is far more complicated than what we thought. The hormone balance specific for each sex may determine the risk or rate of progression of DM kidney disease. But I am getting ahead of myself.

My hypothesis fell into the "bad testosterone camp." I came upon an opportunity to acquire estrogen receptor alpha knock-out mice, and I conceived an experiment. I  would make them diabetic for 2 weeks. Over that time, if estrogen were protective, the knockout mice should get really bad glomerular enlargement, an early marker of DM glomerulopathy. If they did not, then we could feel comfortable rejecting the "estrogen good" hypothesis.

Click to enlarge

This study appeared in 2004 (freely available here) with the surprising finding that the mice lacking estrogen receptors (ER) seemed to be protected from glomerular enlargement. Lack of the full-length ER alpha had no discernible effect in the boys, but the girls had no change in glomerular size with DM, even though their wild-type sisters did (See figure).

WTF?

This observation led to a lot of reading about estrogen. Two major families of ERs had been identified at that time, designated alpha and beta. Our mouse lacking ER alpha was known to lack hypothalamic feedback, leading to high levels of gonadotropins and circulating estrogen. The existence of ER beta in the kidney was unconfirmed, with many doubting its expression in post-natal life. Undaunted by this supposition, we hypothesized that elevated circulating estrogen, through interactions with ER beta, could lead to the protective effects we demonstrated.

Funding agencies generally agreed that our findings and thoughts were interesting. Not interesting enough to send money, but interesting.

I had almost given up ever finding the answer when Debra Irsik came into my lab, eager to study sex differences in the kidney. We settled on this project, and then I went to a conference given by Zhao-Yi Wang of Creighton University Medical Center. He studied the role of ER alpha splice variants in cell signaling in breast cancer. Splice variants? That do stuff? Did our knock-out have those?

Turns out, they sure could. The initial ER alpha null mouse, created by Lubahn and Korach, did not eliminate these splice variants, further complicating out potential explanations for the initial observation.

We decided our first step would be to find out what ER variants were expressed in normal wild-type mice. After all, Wang's experiments were in breast cancer cell lines; we might not find these in normal cells. Our first paper represents a survey of normal male and female mice for these receptors, with special attention to the kidney.

The full length ER alpha 66  was mainly present in female reproductive tissues but was also found in non-reproductive tissues at lower levels. ER alpha 46 was most highly expressed in the heart of both sexes. ER alpha 36 was highly expressed in the kidneys and liver of female mice but not in the kidneys of males. ER beta was most abundant in non-reproductive tissues and in the ovaries.

Because ER alpha 36 has a unique C-terminus, Wang was able to create an antibody specific for this variant. No antibody for the ER alpha 46 variant can be made. We were able to use an N-terminus antibody to localize ER alpha 66 by immunofluorescent confocal microscopy.

ER alpha 36 localization; Click to enlarge

In female mice, ER alpha 66 showed up in blood vessels, glomeruli, proximal tubular brush border, and the cortical collecting duct. ER alpha 36 localized to the mesangial cells, tubular epithelia, and podocytes (see the pretty immunofluorescent pictures in the figure). ER beta also localized in mesangial cells and podocytes. The boys showed little staining for ER alpha 66; the guys did stain for ER alpha 36 in measangial cells and tubular epithelia. Male mesangial cells also demonstrated ER beta staining.

So what is the bottom line here? First, estrogen receptors are much more complicated that initially thought, with at least two known functional splice variants for the alpha receptor. Makes you wonder how many more of those "junk bands" on western blots may be doing something in vivo! Also, estrogen is far more than a "sex hormone." Sure, its receptors are expressed at far higher levels in female reproductive tissues, but they are still hanging out in other organs, just waiting for that hormone to come around. And those are only the receptors we have identified so far!

Now we have a much more complicated story to tease out; can we possibly isolate the role of splice variants in an in vivo model? Stay tuned for Deb's next paper!

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Real Family Values

Aug 12 2013 Published by under Access

Stay of Hope Foundation

Imagine your happy life with a loving partner, some happy children, and perhaps a pet or two. You have comfortable careers with healthcare coverage. You are not rich - losing a paycheck would be a big problem - but you do not feel insecure.

Now one of your children gets sick. Their kidneys have failed! In addition to learning about new drugs and diets and dialysis, you find out that your insurance has restrictions on specialty care. If you want them to pay for the surgery, then your child has to move to a contracted center in another state. Sure, your state has a hospital that can do it just 2 hours from home, but this is not the "preferred provider" so only 80% of costs will be covered. That means more than $20,000 out-of-pocket.

So how bad would living at the out-of-state center be? Since we are talking about a child, there will have to be a guardian of some sort with them. You will need to relocate to a strange location for weeks to months, leaving behind your support system. Of course, you cannot continue to work during this time, nor can you contribute to the maintenance of your family in non-monetary ways. Who will feed the dog? To top it off, your insurer will reimburse you for living expenses while out-of-town, but you have to pay to move and start a second residence out of your own pocket. Where do you get that money?

Well, Medicare also covers patients with end-stage kidney failure. You have worked and paid into the system, so your child is eligible...if you start paying Medicare premiums. There goes $800 each month to make sure your kid gets covered some way.

It's enough to break a family apart. Or enough to inspire a mother start a charitable organization.

The Stay of Hope Foundation will provide a number of services for children and families facing these medical and financial pressures. Beginning in Oklahoma (charity starts at home, folks) the foundation will offer advocacy in dealing with insurers and financial support for living expenses, Medicare premiums, and other out-of-pocket expenses. The group just got its LLC papers; as soon as we raise the application fee ($850) we will start the long and winding road to 501(c)(3) status! Eventually, we hope to offer services throughout the USA.

This scenario has occurred on a few occasions during the decades I have practiced, so when I heard about Heather MacDonald's new work I volunteered for their board. Forcing families under the stress of chronic disease to split geographically or face financial disaster seems unkind at best (mean, wicked, and grinchy come to mind).

I am supporting this group with my time and treasure and pride. More information can be found on the website, as can a Paypal donation button and an address for old-fashioned checks. As I noted, we do not have that 501(c)(3) status yet, but we are working on it.

So spread the word. Give if you can. And help families deal with that spot between the rock and the hard place.

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You Cannot Know Until You Know

May 29 2013 Published by under Research issues

Last night I received an interesting query via twitter:

Tweet

Many patients in nephrology present with 50-60% of normal kidney function. Even if we can stop the insult that produced this much loss of kidney, at this point the vicious cycle of progression occurs. The kidney tries to adapt to its losses with processes that cause more loss of tissue. In trying to get back to normal, the kidney commits suicide. Over the years, we have discovered ways to slow this process, but we cannot stop it. This is particularly unfortunate, because most people have no symptoms of kidney failure with minimal medication at half of normal function. If we could halt the process at that point, most adults would have relatively normal lives without needing dialysis or transplant! (Since we cannot do this yet, I do not yet know if we could get children to grow and develop acceptably at half of normal function.)

Thus, my answer:

AnswerTweet

Of course, this is a really broad answer that is likely more clinically oriented than whatever spawned the question. Kidney researchers have been working on progression for as long as I can remember, resulting in our current strategies that slow it down; however, we still do not fully understand the process despite at least two decades of research! And, while I can identify this as a really clinically important area of inquiry, I HAVE NO IDEA WHERE THE BIG BREAKTHROUGH WILL ULTIMATELY COME FROM. If more incremental work in the existing areas will do it, then we may get there in a few years. I suspect the real breakthrough will come out of left field, from completely unexpected directions.

You know, the risky, out-there research that will have more trouble getting funded right now.

It may also come from studies of other organ systems! Other diseases! Other organisms!

I believe this is true for most clinical problems facing us today. We really cannot know what particular basic science piece will lead to therapeutic insights and cures. Who would have thought that studying cilia would help us understand polycystic kidney disease?

That's the real tragedy of the current funding climate. As paylines drop, funding tends to get more conservative with projects having the best chance of "success," defined as fulfilling their hypothesis. This can result in incremental studies which may be valuable, but rarely shift paradigms. Those weird, unexpected results that can impact other fields may be missed completely.

Patch-clamping fruit fly neurons may sound like a ridiculous waste of  money to the general public (and congress), but from a basic science standpoint it could be quite important. If we want cures for diseases, we have to support scientific inquiry, not just clinically-directed research. Our current "best treatments" for the problem of progression arose from studies of South American vipers; I would guess that those investigators had no idea that there would be such practical outcomes from their research.

Let's put it this way: I am a physician-scientist with more than 20 years of experience in the field, and I have no idea what specific basic science questions may lead to the next big breakthrough. Our best hope is to fund as much as we can, all of it if possible. We then need to keep scientists and clinicians engaged, so those random sparks of imagination come together.

The process is messy and disorganized and unpredictable. You cannot script discovery.

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Deep in the Kidney: Gottschalk Lecture at #EB2013

Apr 23 2013 Published by under EB2013

The highest award of the APS Renal section went to Jeff Sands, MD, a clinician and physiologist and former editor of American Journal of Physiology Renal Physiology. My tweets from his lecture follow.

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A Starling Is Born: #EB2013

Apr 22 2013 Published by under Kidney Function

keep-calm-and-talk-science.pngMany awards in science give one the chance to deliver a lecture. These awards are usually named for famous dead guys, such as Ernest Starling. Here is his biography from the APS Website:

Ernest Starling (1866-1927) was pre-eminent in the golden age of British Physiology. His name is usually associated with his Law of the Heart, but his discovery of secretin (the first hormone whose mode of action was explained) and his work on capillaries were more important contributions. He coined the word 'hormone' one hundred years ago. His analysis of capillary function demonstrated that equal and opposite forces move across the capillary wall--an outward (hydrostatic) force and an inward (osmotic) force derived from plasma proteins. Starling was much more than a gifted scientist. He held passionate views on many subjects -- education, London University, Germany and the British Government, etc. -- and was not slow to voice them. Time has shown most of his views to be right, but their publication may have hampered his worldly success. Working on defense against poison gas during WWI, he crossed swords with the war officer. After resigning his commission as colonel, he became chairman of the committee supervising British nutrition and successfully introduced food rationing.

If he were around today, I just know he would have blogged. But on to an excellent presentation by Donald Kohan, MD, PhD, a professor at Utah who studies the role of the collecting duct in control of blood pressure. He has teased out the role of a number of substances by creating mice that overexpress or lack these substances only in the collecting duct cells. Just creating that many mice over a career blows my mind! His talk flowed so logically and told the story so clearly, I am afraid all subsequent lectures for the near future will falter in comparison.

I live-tweeted the session, and I have collected my thoughts below. Some abbreviations pop up now and then, including CD for collecting duct, AC for adenyl cyclase, and PRA for plasma renin activity. If something is unclear, ask in the comments.

I also enjoyed when he acknowledged the support of his spouse and family by pointing out how professionally-accomplished his wife was as well.

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Sweet 16 for #Nephmadness: My Thoughts

Mar 27 2013 Published by under [Medicine&Pharma]

The editors of eAJKD have narrowed the field from 32 to 16. Here are their picks:

Glomerulus

  • Medicare ESRD Benefit (1) vs PD First (14): Medicare ESRD Benefit (also my pick)
  • KDIGO (5) vs USRDS (7): KDIGO, the favorite, won, besting my pick of the USRDS.
  • Epigenetics (8) vs Propensity Scoring (6): Editors went with a bit of an upset here; I picked propensity scoring, a proven technique, over epigenetics, a promising but as yet unproven contender
  • Real Time PCR (4) vs Randomized Clinical Trial (2): RCT is the gold standard, and it wins. (also my pick)

Proximal Tubule

  • HEMO Trial (1) vs TREAT Trial (3): HEMO wins this one (also my pick)
  • ALLHAT Trial (5) vs IDEAL Trial (7): This was a tough choice, but I went with the underdog while the favorite, ALLHAT, moved on.
  • FGF23 (8) vs Anti-PLA(2)R (6): Anti-PLA(2)R is really important in membranous nephropathy, a common disease in adults. Not so common in pediatrics, so I missed this one as well.
  • HIVAN (13) vs APOL1 (2): I could not believe HIVAN won the first round; glad to see APOL1 take this match-up (also my pick)

Loop of Henle

  • Captopril (1) vs Mycophenolate Mofetil (3): ACE inhibitors rule nephrology; Captopril wipes the floor with MMF (also my pick)
  • Eculizumab (5) vs Tolvaptan (10): Seriously, what do these people see in Tolvaptan? I hope Captopril annihilates this newbie.
  • Renal Fellow Network (9) vs UpToDate (6): UpToDate takes it (also my pick)
  • ASN Kidney Week (4) vs NephSAP (2): Kidney Week for the win (also my pick)

Collecting Tubule

  • MDRD eGFR Equation (1) vs 24-hour Cr Cl (3): Equation beats collection is like the fast break taking down a half-court game, yet when in doubt we still get a 24-hour urine
  • Winter's Formula (5) vs FeNa (7): Glad to see FeNa take this round (also my pick)
  • Kidney Biopsy (8) vs Citrate Anticoagulation (11): Like anticoagulation could beat the ultimate diagnostic test (also my pick)
  • Scribner Shunt (4) vs Kidney Transplant (2): While the shunt was revolutionary and lifesaving in its time, we no longer use it. Kidney transplant, while not perfect remains the best form of renal replacement therapy and gets the win (also my pick).

The picture shows the Sweet 16 and my picks for the Elite 8, with rationale below:

Click to enlarge

Click to enlarge

  • Medicare ESRD Benefit vs KDIGO: No question in my mind; guaranteed coverage for end-stage therapy wins.
  • Epigenetics vs Randomized Clinical Trial: Unproven area of study vs the gold standard? Duh-RCT for the win!
  • HEMO Trial vs ALLHAT Trial: HEMO still guides dialysis therapy today. ALLHAT was important and affects alot of people, but the tip goes to HEMO in my mind.
  • Anti-PLA(2)R vs APOL1: The cause of membranous nephropathy vs the gene that explains the excess burden of kidney failure in African Americans can only mean one answer for me; APOL1 to the elite 8!
  • Captopril vs Tolvaptan: ACE inhibitors are the miracle drugs of nephrology. I cannot believe that Tolvaptan has hung around this long; it's time to retire that glass slipper!
  • UpToDate vs ASN Kidney Week: UpToDate clearly rules the reference rack these days, but for my specialty area I often want to know more, including recent research and the opinions of my colleagues. Kidney Week gives me all of that, as well as an excuse to hobknob with other nephrologists and talk about urine. It will be a battle, but I give Kidney Week the edge.
  • MDRD eGFR Equation vs FeNa: I did not have the eGFR equation advancing to the Sweet 16; nevertheless, I must favor it over FeNa for overall usefullness at this point in the competition.
  • Kidney Biopsy vs Kidney Transplant: Ah, the gold standard of diagnosis vs the gold standard of treatment.  I have to give the win to transplant. Even with biopsy, kidneys fail and require treatment...with transplant.

Head here to learn more about these teams and to vote for the Elite 8. Please allow my opinions to sway your vote; how has Tolvaptan made it this far, anyway???

Now for the state of my bracket:

  • Round 1:  27 out of 32
  • Round 2:  10 out of 16

What are you waiting for? Go vote!

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