eplerenone redux

In response to my snark about the recent EMPHASIS-HF study, I wondered if what I said - that patients with EF less than 35% are already on their way to class III/IV heart failure, therefore lessening the impact of this study - was true.

I guess not, according to the American Journal of Cardiology, almost 30 years ago. In their assessment, resting ejection fraction did not correlate whatsoever with symptoms or exercise capacity. But in that case, if symptomatic heart failure is totally dissociated from resting EF, and clinicians are going to institute therapy based on symptoms, why even include an EF cutoff? Because now, physicians considering eplerenone for their mildly symptomatic patients are going to need to do an echo first. Why not have just done a trial of eplerenone for all mildly symptomatic pts with a diagnosis of HF and then look at how patients did depending on their EF?

preventing GVHD

So I'm working on a big post about lupus (and the the the first approval of a drug specifically for lupus in fifty years), but in the meantime, I've assembled some other random thoughts that won't see the light of day unless I kind of word-vomit them out first. So, here goes.

Leukemia and lymphoma, the "liquid tumors," are so named because they arise from malignant transformation of cells whose precursors originate in the bone marrow. Leukemia occurs from overproliferation of precurors to mature hematopoietic cells which lack the function of fully developed WBCs. Lymphoma occurs from acquisition of malignant properties by differentiated white blood cells which have exited the bone marrow. While chemotherapy has shown success in some limited situations (diffuse large B cell lymphoma, for example), these tumors often recur. The last available option is often to replace the patient's entire hematopoietic lineage, via the so-called "bone marrow transplant." Traditionally, this involved two steps; irradition of the host bone marrow, followed by transplantation with new bone marrow from someone whose cells were least likely to be recognized as foreign by any remaining immune cells in the host (aka, maximal HLA matching).

This procedure was first successfully attempted in mice in 1956, and subsequently attempted in humans with refractory disease in 1957 (Thomas et al. N Engl J Med 257:491-6). The same group first successfully achieved temporary remission with BMT in 1959, in a study published in the Journal of Clinical Investigation.

Unfortunately, almost as soon as successful remissions with transplants were describe, so too were significant adverse effects, in which transplanted white blood cells would see the host as foreign and attack it. This destruction, first described in 1957 was largely focused in the skin (causing a sclerosing skin rash), and in the intestine (causing inflammatory diarrhea), known collectively as graft versus host disease. It was demonstrated in 1978 that T cells were critical for the graft versus host response. In order to try and minimize this devastating, and potentially lethal, side effect, early emphasis in BMT development was placed on achieving maximal HLA matching.

Interestingly, in 1979, a paper in the New England Journal of Medicine demonstrated an unexpected finding; patients receiving a mismatched SCT were actually less likely to relapse if they developed GVHD. Based on this, the theory was put forward that donor T cells could have both positive and negative effects; that is, they would seek out and reject tumor cells, but would inflict life-threatening collateral damage on host tissue at the same time. It has since been demonstrated that selective transfer of donor lymphocytes in patients with relapsed disease following non-selective BMT can achieve complete and permanent remission in some cases. Given this, the call for optimizing allogeneic (aka, non-HLA matched) stem cell transplants for graft-mediated tumor rejection while controlling graft versus host disease continues to grow.

One method of minimizing graft versus host disease while permitting anti-tumor immunity seems to be via increasing the presence of regulatory T cells. As shown on the left, in mice, co-transfer of regulatory T cells appears to suppress GVHD while still permitting tumor rejection and significantly improving survival. A role for Tregs is further evidenced by the relatively low rate of GVHD in patients receiving transplants of umbilical cord blood, which appears to be enriched in Tregs. Therefore, the search continues for treatments that might continue to shift this balance in favor of anti-tumor immunity and away from off-target anti-host tissue effects.

A new study in the Journal of Experimental Medicine shows some promise in doing just that. This study focuses on targeting BTLA, an inhibitory, immunoglobulin-family receptor that is expressed on Th1, but not Th2 cells. BTLA interacts with both B7 family members (similar to other co-stimulatory molecules such as CD28) but also with TNF family receptors. Ligation of BTLA induces activation of SHP family phosphatases that limit T cell activation and IL-2 production. It is required for the generation of antigen-specific Tregs in response to antigen without co-stimulation. Interestingly, BTLA expression appears to be downregulated by the presence of bacterial CpG nucleotides. It is further notable that studies have shown persistent BTLA4 expression on anti-tumor, but not anti-viral cytotoxic lymphocytes, suggesting that BTLA may have a critical role in supressing anti-tumor immunity.

In this paper, the authors treated donor bone marrow with an an agonist anti-BTLA antibody prior to transfer and found that it virtually eliminated development of GVHD as measured by clinical scoring, loss of body weight, and development of intestinal mucosal inflammation and ulceration. Further investigation showed that BTLA stimulation decreased effector T cell development while maintaining Treg development, which is in line with evidence of BTLA in inducing tolerance. Of note, treatment with agonist anti-BTLA did not successfully treat GVHD when given 14 days after transfer, suggesting that BTLA's tolerance inducing effects are restricted to initial development and do not diminish effector function of differentiated Teff cells.

Finally, the authors showed in a minimal residual disease model that agonist anti-BTLA treatment did not significantly inhibit graft versus tumor responses, which still required T cell function as evidenced by the poor response of animals receiving T cell depleted transplants. The search for highly efficacious, broadly applicable cell therapy remains elusive, but providing the proper mileu to support development of an optimal balance of anti-tumor immunity and host tolerance will rely on a combination of careful cell selection and subtle skewing of cell differentiation.

I know, that's kind of a weak ending, but I'm just not ready to jump into heart failure, stroke, or asthma tonight. (Yeah and definitely not lupus either)

spring cleaning

I know, I said a big post on lupus was coming, imaginary blog readers. But I haven't been able to read the reviews yet. So let me leave you with the few other interesting pieces I've read in the past few weeks before I vanish until December.

Eplerenone in CHF (the EMPHASIS-HF study)

Yeah, there's nothing that's going to rock your world in this recent NEJM study; following the RALES study which showed an indication for spironolactone treatment in patients with class III/IV CHF, this study looked at almost 3,000 patients with class II CHF (mild symptoms only) and an EF of no greater than 35% and found a significant morbidity and mortality benefit. Yeah. If you really want to see if mineralocorticoid antagonism works as preventive therapy, look in patients who already don't have frank evidence of pathological remodeling. Aren't these patients on the doorstep of class III heart failure already? Boo.

Tonic inhibition and recovery after stroke

Ischemic strokes are a leading cause of morbidity and mortality, especially in the elderly, whose risk factors for stroke (hypertension, diabetes, hyperlipidemia) tend to be more prevalent. Aggressive risk factor control clearly reduces the risk of developing a stroke, or a future stroke after one happens. But almost nothing has been shown to reduce functional impairment caused by a stroke after it happens. Really, the only effective intervention is early rehabilitation, which has been shown in multiple randomized control studies to improve functionality by inducing cortical remodeling following a stroke. Subsequent studies have shown that the cortical remodeling that drives partial recovery of function following a stroke is not the infarcted tissue but rather the peri-infarct tissue. Excitation of peri-infarct tissue following stroke drives long-term potentiation, resulting in effective remodeling. However, long-term potentiation requires sustained synaptic neurotransmission, which is limited in peri-infarct cortex. Why exactly is this?

Count on Nature to give us the answers. A letter published a few weeks ago describes a breakthrough in understanding the physiologic brakes on peri-infarct cortical remodeling. The study focuses on GABA, an inhibitor neurotransmitter with both activity that is both synaptic (released in response to stimulus) and tonic (released at a constant rate to set a post-synaptic excitability threshold). Tonic GABA release has been shown to oppose long term potentiation and memory. The authors of the above study wondered if similar GABA-mediated tonic inhibition repressed cortical remodeling following a stroke.

Indeed, tonic GABA-mediated inhibition was found to be markedly increased in peri-infarct cortex following photothrombotic stroke in mice. This increased GABA tone increased the excitability threshold and was completely reversed by the GABA inhibitor gabazine.

Having established the role for GABA in post-infarct tonic inhibition, the authors then addressed whether GABA inhibition following stroke could restore functional capacity. Indeed, GABA blockade improved foot paw symmetry during locomotion and decreased foot faults during measured tasks.

But is there actual utility to GABA blockade in pts who undergo a stroke? Well, its complicated. The main problem is that GABA mediated inhibition immediately following a stroke limits infarct size; accordingly, GABA blockade improved murine mortality when given 3 days after a stroke but not when given immediately afterwards. Furthermore, prolonged GABA inhibition eventually led to worsening of functional performance. While this calls for careful modulation of GABA inhibition, it actually provides a potentially clincially applicable regimen: initiation of therapy a few days after a stroke, when symptoms are sure to be present, and stopping therapy after a limited amount of time (although improvements in functional status are not completely sustained after treatment is withdrawn.

Uh, CX3CR1 will have to wait for a time when I'm not actively going into a coma.

the white tiger

"In the old days there were one thousand castes and destinies in India. These days, there are just two castes: Men with big bellies, and men with small bellies. And only two destinies: eat or get eaten up."

"The darkness will not be silent. There is no water in our taps, and what do you people in Delhi give us? you give us cell phones. Can a man drink a phone when he is thirsty?"

"Go to Old Delhi,and look at the way they keep chickens there in the market. Hundred of pale hens and brightly colored roosters, stuffed tightly into wire-mesh cages. They see the organs of their brothers lying around them.They know they are next, yet they cannot rebel. They do not try to get out of the coop. The very same thing is done with humans in this country."

If you ask Aravind Adiga, he wouldn't go so far as to say that democracy is a dirty word, but its clear from his searing first novel that its quite far from a panacea. The book speaks from the point of view of Balram Halwai, a member of India's poor, who serve largely as a servant class for the few, but highly powerful elite. Through Balram's eyes we see how the rapid concentration of wealth into India's upper crust allows them to enter into a corrupt bargain with the politicians in India; the wealthy use their resources to keep politicians on power; the politicians permit the continued inequality of wealth distribution. The net effect of this is that the resources that are generated from India's economic growth (aka, cell phones, laptops, etc.) are useless in uplifting the majority of India that lacks basic irrigation or sanitation. Adiga doesn't spare his wrath or disdain for the majority of Indians in "the darkness" who accept their fate (see his comparison of the citizenry to chickens in the coop watching their brothers be slaughtered), which is reflected in the persona of Halwai, a boy driven so crazy by his station in life that he commits murder in order to obtain true freedom. It is surprising in a country in the majority of the citizenry are held captive by the concentrated power of the few and wealthy that generally nonviolent farmers have been captivated by the promise of freedom and equality from fringe groups such as the Naxalites?

I like standing next to you, Sean...it makes me feel tough.

I know I said I'd blog about asthma and chemokines and neurotransmitters and strokes, but...I'm all amped up over The Social Network (two weeks after everyone else) so, here's a "stuff I've been watching and/or listening to" post!

1. The Social Network

There are so many things that made this movie brilliant, and no one who acted in this movie is undeserving of praise, to be sure, but ultimately, this movie is about a central iconoclastic figure, and its what Jesse Eisenberg, Aaron Sorkin, and David Fincher bring to his character that defines the movie. After all, this is a movie that takes place largely in front of a computer, yet the tension (brought brilliantly to life by Trent Reznor and Atticus Ross, hoorah!) remains palpable for the entirety of the movie. And I think its because we can't make up our mind about Zuckerberg. While it's clear that he is ruthless, whatever emotions we suspect lie under the surface range from haughty to childish to spurned to vindictive to needy to regretful without so much as an eyebrow furrow. Unsurprisingly, I think the New Yorker is right when they say that that tension is upheld by the the essential conflict between Fincher and Sorkin's worldview:

The portrait of Zuckerberg, I would guess, was produced by a happy tension, even an opposition, between the two men—a tug-of-war between Fincher’s gleeful appreciation of an outsider who overturns the social order and Sorkin’s old-fashioned, humanist distaste for electronic friend-making and a world of virtual emotion.

I think different people will likely come down on different sides of the fence on the issue of Zuckerberg's ethics. On one hand, one could easily make an argument that his was the only moral code that was transparent (aka he respected only productivity) and that his all-consuming commitment to Facebook validates his desire to control the involvement of all other partners (notice how he was programming in virtually every scene in the movie and how he was content to let his associates take some marginal credit until the second that they compromised the integrity of the product). On the other hand...the job he pulled on Eduardo was cold, man. And that makes me wonder - does so-called social media like Facebook actually promote dehumanization by allowing people to only present to the world what they choose and not reform the parts of themselves that are petty, angry, vindictive, or otherwise damaging?

2. Cee-Lo

Let's switch gears from the razor-sharp, coldly perfect Social Network soundtrack (as mentioned before, by the incomparable Trent Reznor) to 70s soul-loving fun-fest that is Cee-Lo's newest album, The Lady Killer. It's almost unnecessary to review this album; just listen to and/or watch the video of his first single, "Fuck You." I mean, how can you get better than "I guess she's an X-Box, and I'm more Atari?" You can't. But for the record, almost equal to this song in quality is his transformative cover of Band of Horses' "No One's Gonna Love You." Video for "Fuck You" below.

3. The Arcade Fire

It's flown under the radar alot more than their previous albums, I really think that The Suburbs is equal in quality to Arcade Fire's past two albums. In terms of of range, they continue to feature uplifting, somewhat bombastic pieces like "Sprawl II (Mountains Beyond Mountains)" and "Rococo," uptempo NYC-rock pieces like "Ready to Start" and "Month of May" and more pensive pieces like "City With No Children" or Modern Man."

Where the band has really taken a step forward is lyrically. After an ill-advised turn for the faux-political (no doubt Obama 'Yes We Can' inspired), they turn inward and deliver an album that is about getting old, giving up the dreams of your youth, and accepting a life that feels unfulfilled. Now, as a former suburbanite, and someone who has little tolerance for people who sneer at people from the suburbs, I would ordinarily hate on this hipsteresque superiority complex, but the album finds the hipster obsession with what is transiently 'cool' to be equally stupid (see their song "Rococo"). Ultimately, the album seems to be about themselves, as artists at an intermediate point, caught between two disappointing choices. Just some snippets from some of my favorite songs from the album:

"So can you understand/why I want a daughter while I'm still young?/I want to hold her hand/and show her some beauty/before this damage is done." - The Suburbs

"They heard me singing and they told me to stop/quit these pretentious things and just punch the clock." - Sprawl II (Mountains Beyond Mountains)

"I feel like I've been living in/a city with no children in it/A garden left for ruin by/a billionaire inside of a private prison." - City with No Children

"Let's go downtown and talk to the modern kids./They will eat right out of your hand/using great big words that they don't understand" - Rococo

4. Kanye West's Beautiful Dark Twisted Fantasy

Kanye West also seems to be having a struggle with his identity, although it might just be between whether he has Narcissistic Personality Disorder or is full-on bipolar. I acutally think that Kanye is incredibly savvy, and realizes that acting out as he does is a way more effective marketing tactic than a music video is nowadays (and we all know how frustrated he is about his lack of music video recognition.) I happen to actually agree with him when it comes to his treatment on the Today show - as if people are going to listen to his explanation when they get to watch him yell at Taylor Swift again. Shut up, Matt Lauer. Meanwhile, his music continues be the absolute gold standard for hip-hop. The guy comes out with a sneering challenge to all of his critics with his first single, "Power," then issues a free remix in which he completely rewrites the song, and its even better than the original. His collabo with Jay-Z and Nicki Minaj, "Monster," is probably the strangest, coolest single since the era of Missy Elliot and Busta Rhymes. For me, personally, it will be difficult to match Graduation in quality, but i certainly agree with Rolling Stone's opinion that he is one of the few artists in music with any interest in challenging us:

There’s a famous story about Queen making "Bohemian Rhapsody": Whenever the band thought the song was finished, Freddie Mercury would say, "I’ve added a few more ‘Galileos’ here, dear." But nobody can out-Galileo Kanye. With Fantasy, he makes everybody else on the radio sound laughably meek, but he’s also throwing down a challenge to the audience. Kanye West thinks you’re a moron if you settle for artists who don’t push as hard as he does. And that means pretty much everybody.

5. The Young Money Crew: Lil' Wayne, Drake, and Nicki Minaj

My love for Lil' Wayne is well-established in this blog, so I'll just say that his assembly of the Young Money crew is yet another feather in his cap. Unlike other successful hip-hop artists who ascend to the level entrepreneurs (Jay-Z, P. Diddy, Master P, etc.) Wayne's hires reflect an eye for talented, unique young artists. Like Drake, a half-Jewish (and bar mitzvah-ed!) former teen soap actor who had released a mixtape in which he rapped over unconventional artists like Peter Bjorn & John. Or Nicki Minaj, a young, african/indonesian/trinidadian rapper who raps under multiple pseudonyms, sports a strange Barbie obsession, and a rapping style that morphs from British accents to reggaeton. Now, Drake is probably the most popular hip-hop artist on the charts, and Nicki Minaj's performance on Kanye's "Monster" is probably the best verse delivered all year. Also, they were both in the New York Times. Also, Nicki Minaj's single, "Check it Out," which samples "Video Killed the Radio Star" is one of the most clever things I've ever heard. And Wayne? Well, he just got out of prison, released a new album (which is apparently only a predecessor to the forthcoming Tha Carter IV), and will drop in on fellow Young Money albums to occasionally drop a few blistering verses (like his performance in Drake's "Miss Me" where he reminds us "I got so many styles - I am a group.")

I'll leave you with Nicki Minaj's video for "Check it Out." Haters, you can kill yourself.

regulation, part 2: health care

Peter Orszag had some very interesting thoughts on health care reform in recent issues of the New York Times. In his most recent piece, "To save money, save the health care act" published last week, Orszag freely admits that the plan has flaws, but also makes the legitimate point that fundamental reform of a health care system devoid of any form cost control (or for lack of better terminology, health care rationing) is going to be messy. I think the piece has some flaws, but I think this statement is an important one to note:

There are four ways to contain health care costs: by reducing payments to providers and suppliers; by rationing services; by having consumers pay a greater share; and by giving providers incentives to be more efficient.

So, lets consider each of those methods individually.
1) Reducing payments: Despite the shooting myself in the footishness of this, its certainly necessary. Part of the equation is that we are spending too much money on health care, but reducing costs means reducing compensation. So what should we paying for and what shouldn't we be paying for? Well, the fact of the matter is that we should be decreasing compensations for interventions that are not proven to improve overall prognosis (like: vertebroplasties, knee arthrocenteses, 4th line chemotherpeutic agents, renal replacement therapy in patients with hepatorenal syndrome). Conversely, we should be creating and/or increasing compensations for primary care interventions that reduce cost-ineffective, but necessary procedures (aka, effective smoking cessation counseling, vaccinations, obesity management).

2) Rationing services: Now, part and parcel of reducing payments is going to include reducing the number of health care services that should be provided. How do we decide what to ration? With QALYs, of course. See Peter Singer's NYT article "Why we must ration health care" for elaboration.

3) Having consumers pay: Certainly, increasing consumer contributions to the health care pot will help reduce the incurrence of health care debt. But high premiums seems to be at the core of people's discontent with the health care system. And while health care rationing will improve premiums, I don't think that people will be willing to offset those savings with increased payments. Rather, the answer probably involves insuring some of the 47 million Americans who are currently uninsured, perhaps with catastrophic and preventative insurance coverage that will reduce the significant amounts of debt they incur. This would be the same population in which reduction of health care interventions not shown to improve mortality would first be implemented.

4) Improve provider incentives: Finally, the issue of how providers are motivated. This issue has been broached by Atul Gawande, and is addressed by both Orszag and the health care bill, by tracking and ultimately attempting to reward and penalize providers based on the health of their patients rather than a fee-for-service model that rewards procedures rather than outcomes. There is a clear precedent for this: the No Child Left Behind Act, which provides a negative incentive for poor student performance. This seems alright, except for the fact that it may discriminate against school districts where students are more difficult to motivate. Similarly, infusing accountability into a compensation system for providers might penalize the providers who face the most daunting sets of patients (many comorbidities, poor compliance).

Certainly, one clear negative incentive that can be removed is the practice of "defensive medicine" in which doctors prescribe additional tests and/or interventions simply to avoid being sued for for being insufficiently aggressive. This practice, as delineated by JAMA, is widely pervasive, and seems to primarily take the form of unnecessary imaging to rule out highly unlikely pathology. Tort reform will doubtlessly reduce the practice of defensive medicine, though the extent of cost savings is difficult to estimate. And for those of you fuming over Obama and Orszag's socialist tendencies, let there be no mistake that both of them agree with tort reform.

Other (or even undiscovered) methods of cost reduction

One of the final aspects of the health care plan, one of the least mentioned, and probably my favorite, is the pool of money (the so-called Innovation Center) dedicated to supporting cost-effective initiatives. It's essentially a fund to say "If you have an idea to save money, we'll give you a little money to try it, and if it works, we'll give you more money. So go to town." Sounds like typical government waste? Well, as Atul Gawande noted, this was pretty much the model that led to agricultural reform. As he states, the answer involves engaging local providers to institute reform from the ground up:

At this point, we can’t afford any illusions: the system won’t fix itself, and there’s no piece of legislation that will have all the answers, either. The task will require dedicated and talented people in government agencies and in communities who recognize that the country’s future depends on their sidestepping the ideological battles, encouraging local change, and following the results. But if we’re willing to accept an arduous, messy, and continuous process we can come to grips with a problem even of this immensity. We’ve done it before.

Was it worth it?

I'll close with an extreeeemely interesting piece by William Saletan at Slate. In it, he vociferously defends the Pelosi-led congress, and refutes the idea that the resetting of congressional balance reflects a failure of governance by Pelosi. Rather, he states, she did what she ought to have done: used her Democratic majority to institute legislation that she felt supported the common good.

Politicians have tried and failed for decades to enact universal health care. This time, they succeeded. In 2008, Democrats won the presidency and both houses of Congress, and by the thinnest of margins, they rammed a bill through. They weren't going to get another opportunity for a very long time. It cost them their majority, and it was worth it. And that's not counting financial regulation, economic stimulus, college lending reform, and all the other bills that became law under Pelosi. So spare me the tears and gloating about her so-called failure. If John Boehner is speaker of the House for the next 20 years, he'll be lucky to match her achievements.

Awesome. Coming soon: GABA in stroke, chemokines in asthma!

The Purple Rose of Cairo

I've seen almost every movie Woody Allen's made but, for some reason, I always held out on seeing this one. I think something about the name reminded me of "The Curse of the Jade Scorpion" which is almost definitely his WORST movie.

Anyway, I just finished watching it for the first time and I am absolutely stunned. He beautifully weaves silly romanticism with devastating realism in a way that is in keeping with his style but he was never so on the mark. I think he gets closest with "Hannah and Her Sisters" but this movie has more of a resemblance to Fellini's "Nights of Cabiria." I'm glad I waited to see this one.



It's nice to discover new things.

regulation, part 1

Well, that's the best way I can make four things that I'm going to write about seem related, when they're not related.

1. Autoregulation of salt-water balance by the kidney. This has been a topic of interest for me recently, because I'm rotating on the Nephrology service at Bellevue. As a result of this, I've been trying my best to understand the kidney.

So, there are two major functions of the kidney. The first is to filter and excrete toxins and toxic metabolites (important, but not that interesting). The second is to sense, and carefully regulate, total body fluid and electrolyte balance. This is a difficult, and essential job: too little fluid and the body can't deliver oxygen to vital tissues; too much fluid and it starts to accumulate in the lungs, abdomen, and extremities. In healthy patients, the kidney responds quite acutely to changes in volume (changes so small that they may be beyond the limit of our measurable detection). This appears to be via a set of cells known in aggregate as the juxtaglomerular apparatus, or JGA. The JGA is composed of 2 groups of cells. First, the granular cells, which line the afferent and efferent arterioles supplying and draining each glomerulus, are thought to act as 'pressure sensors' that react to miniscule changes in arteriolar pressure and respond with appropriate vasodilation or vasoconstriction. This transmits small increases or decreases in blood volume to small changes in glomerular filtration in the kidney. Second, the 'macula densa' cells within the distal tubule sense changes in delivery of tubular fluid to the distal convoluted tuble and adjust GFR and proximal reabsorption (via renin-angiotensin-aldosterone system activation).

Of course, there are well known situations in which renal autoregulation goes wrong. The most common of these diseases is CHF, in which decreased cardiac output results in reduced renal artery perfusion; this is pathologically interpreted as a sign of low volume by the renal JGA, resulting in sodium retention, pulmonary vascular congestion, and peripheral edema.

Another common syndrome of renal dysregulation is advanced liver cirrhosis. Fluid balance is markedly altered in cirrhosis, as demonstrated by significant accumulation of fluid in the peritoneal cavity (cirrhosis) - this is thought to be due to both hypoalbuminemia that results from decreased hepatic synthetic function and pathologic sodium and water retention by the kidney. This is evidenced by chronic high renin, aldosterone, and vasopressin levels seen in cirrhotic patients, and low urinary sodium characteristic of increased proximal tubular reabsorption. However, the stimulus for sodium retention by the kidney in cirrhosis is unknown. A number of hypotheses have been put forward to explain this phenomenon:

the low plasma volume hypothesis: cirrhosis-induced portal hypertension (increased hydrostatic pressure) + hypoalbuminemia (low oncotic pressure) leads to fluid transudation, low plasma volume, and RAAS activation. Sounds good, but doesn't work, as direct measurements of plasma volume in 1967 found that patients with advance cirrhosis have high, not low plasma volume. Furthermore, an elegant temporal analysis of fluid overload in a dog with cirrhosis in the American Journal of Physiology in 1977 demonstrated that high plasma volume in the splanchnic circulation as well as sodium retention preceded portal hypertension.

the underfilling hypothesis: popularized by Robert Schrier at the University of Colorado, this suggests that systemic vasodilation leads to decreased ‘effective’ arteriolar blood volume and leads to volume expansion. This is supported by the use of various therapies to improve arteriolar filling, including vasoconstrictors and head-up water immersion (to be discussed).

The key regulator in the underfilling hypothesis is thought to be nitric oxide, which induces profound systemic vasodilation and would lead to renal underperfusion and hepatorenal syndrome; however, evidence for this is lacking, as is evidence for the utility of nitric oxide synthase inhibitors in preventing or treating HRS. However, there are physiological reasons to suspect that nitric oxide production by the liver in response to portal hypertension is possible given the fairly strong evidence that the liver, and in particular, the hepatic artery, serves as pressure sensors;

1) electrical stimulation of portal nerves has potent effects on renal blood flow and urine output
2) other acute causes of portal hypertension, such as thrombotic disease (Budd-Chiari syndrome) induce potent hepatic artery vasodilation and hepatorenal syndrome, while elimination of portal pressures with intrahepatic portocaval shunts improves HRS in patients with portal hypertension.

Treatment options for hepatorenal syndrome continue to be quite limited, but are based ultimately on the idea that systemic vasodilation secondary to portal hypertension leads to renal arteriolar underfilling and prerenal failure. The only current therapy with any basis for efficacy is a study published in the Journal of Clinical Gastroenterology in 2009, in which a combination of midodrine/octreotide (splanchnic vasoconstrictors which theoretically counteract systemic vasodilation) along with albumin (which exerts positive oncotic pressure to hold fluid within blood vessels). This combination was the first to demonstrate a mortality benefit in patients with hepatorenal syndrome, although it has been difficult to reproduce in follow-up studies.

In my quest to find weird, alternate, cost-effective therapies, however, I came across a somewhat old practice that has fallen out of favor for reasons that are not entirely clear to me. It has been proposed for centuries that water immersion leads to increased urination; this concept of so-called “immersion diuresis” is thought to be secondary to two properties: thermal heat loss and hydrostatic water pressure, both leading to systemic vasoconstriction, improved renal perfusion, suppression of ADH, and natriuresis. In case you’re wondering, this idea is what led ultimately to the clever prank in which you put a sleeping friend’s hand in water causing him or her (who are we kidding – its always him) to pee himself.

That wouldn’t much thrill Dr. HC Bazett, the physiologist from the University of Pennsylvania who first published the effect of water immersion on diuresis in humans. Dr. Bazett’s subsequent studies found that the pressure component was far more important than the temperature component; aka, total body immersion is required to achieve significant diuresis (take that, pranksters).

Subsequently, head-out water immersion (pictured above, looking like a torture machine, and so named, according to the illustrious Dr. David Golfarb, because “some idiot medical student probably drowned some poor cirrhotic, so they had to put ‘head-out’ in the title”), was shown to improve venous return, increase right atrial pressure, increase stroke volume, and improve cardiac output.

A number of nephrologists, including Dr. Schrier, applied this data to their particular field and organ of interest, demonstrating that head-out water immersion could indeed improve renal function by decreasing renin-angiotensin mediated vasoconstriction and improving renal perfusion and urine output (right, from a letter to the editor published in N Engl J Med in 1983). And while studies on the true efficacy of this practice are somewhat conflicting, one could easily say the same about the far more expensive therapy of octreotide, midodrine, and albumin. So why don’t people ever try this? Beats me.

Yikes, this post was long. Stay tuned for regulation part 2, featuring: asthma, strokes, and health care policy!

mr. arkadin

"I knew what I wanted. That's the difference between us. In this world there are those who give and those who ask. Those who do not care to give... those who do not dare to ask. You dared."

God, this movie sucked.

since nobody will post about lung cancer screening

I'm working on something about homeostatic control of volume status.