Friday, April 23, 2010

Surviving lactic acidosis; lessons from turtles

Lactic acidosis is frequently seen in the hospital setting. Diverse etiologies account for the accumulation of lactic acid as reviewed by Nathan last year. The main impetus for the production of lactate is having a hypoxic state either in the entire organism, the cellular level or an isolated vascular bed. Most cells in the body break down glucose to form water and carbon dioxide. This is a two-step process. First, glucose is broken down to pyruvate through glycolysis. Then, mitochondria oxidize the pyruvate into water and carbon dioxide by means of the Krebs cycle and oxidative phosphorylation. This second step requires oxygen. The net result is ATP, the energy carrier used by cells. If oxygen supply is inadequate (hypoxia), the mitochondria are unable to continue ATP synthesis at a rate sufficient to supply the cell with the required ATP. In this situation, glycolysis is increased to provide additional ATP, and the excess pyruvate produced is converted into lactate and released from the cell into the bloodstream, where it accumulates over time.

I met Nathan at the Origin's of Renal Physiology Course at Mount Desert Island, Maine a few years ago. This is an outstanding course where you get hands on experience exploring renal physiology using marine life just as Homer Smith did. I remember learning that the painted turtle, Chrysemys picta is able to survive extreme lactic acidosis. As a renal fellow we are frequently consulted for this devastating entity. Unfortunately, we are mostly unable to intervene as the answer in a majority of these cases is to correct the underlying problem. Interestingly, many aquatic vertebrates can remain submerged underwater for remarkably long periods of time. A prime example is the painted turtle, Chriysemys picta, a freshwater species found in Canada and the U.S. Its natural winter habit is to continuously submerge itself in ice-covered ponds for months. The turtle is able to sustain vital organ function for long periods of time despite severely hypoxic or even anoxic conditions. Lab studies have shown that these turtles an fully recover for submergences lasting 3 months at 3 C. The plasma concentration of lactate have been measured as high at 200mM. How is this possible?

The turtle has adapted to this environment by using several unique mechanisms. First, the major extracellular buffer, bicarbonate, is particularly high at baseline (40 mM) in the plasma as well as the peritoneal fluid (80 mM) and pericardial fluid (120 mM). This however, does not account for all of the buffering capacity needed to sustained such profound acidosis. The second and most interesting mechanism is its use of is bone-like shell. The shell accounts for 32% of the turtles total body mass. The portion of its skeleton not incorporated into the shell represents an additional 5.5%. Besides the obvious role it plays as a protective armor, the turtle's shell is also the major mineral reservoir for the body. Over 99% of the total body calcium, magnesium and phosphate and 60% of the body's sodium reside in the shell and bone.

Two mechanisms account for the shells buffering of lactate. First, supplemental buffers are released from the shell directly when needed. During periods of extreme anoxia. Plasma levels of calcium and magnesium increase dramatically. Likely, this is a passive process by which the shell is demineralized by acids. Mainly, calcium carbonate is released. So much calcium is sequestered in the shell that little loss is evident even with prolonged periods of acidosis. A similar process occurs during untreated acidosis in CKD. However, the calcium stores are not quite as profound in the human body. The second mechanism involves the uptake on lactate and a proton directly by the shell. The enormous buffering capacity of the shell allows for this.

Chriysemys picta's unique habit of hibernating during the winter months have allowed for this interesting ability to survive profound lactic acidosis by using its shell as a buffer. Unfortunately, lactic acidosis in the hospital setting is typically extremely difficult to control as the buffering capacity of the body cannot tolerate lactate accumulation for an extended period of time. Research performed on marine life, like at Mount Desert Island, allow for the discovery of novel and interesting ways to survive extremes in physiology.

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