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!