Kidney Development and the Recapitulation Theory

The Recapitulation Theory. A debunked postulate first popularized in the middle of the nineteenth century, the recapitulation theory famously states that "ontogeny recapitulates phylogeny." Simply put, during development, the human embryo was thought to fully repeat its evolutionary development. A human embryo would climb out of the primordial ooze, so to speak, and pass through different phases of evolution on its way to becoming a grown fetus. This recapitulation of "lower" forms is commonly demonstrated by comparing embryos at various ages between species, from fish to reptile to mammal, and seeing the similar morphology of the embryos. Granted, this theory has long since been rejected. However, I think it has provides an interesting lens through which to view the development of the kidneys.

Over the course of development, we actually have three different pairs of kidneys, which all have parallels to a different evolutionary form. The most basic of these is the pronephros, which is the most rostral (closest to the head) of the kidneys and is a functioning kidney in immature fish and amphibians. In mammals, however, it doesn't seem to do much but serve as a transitory structure before the mesonephros, the second kidneys, develop during the 4th week. The mesonephros is similar to the functioning kidney in adult amphibians, and is functional in birds and reptiles until they hatch. The mesonephros in mammals is a rudimentary, functional kidney--it has glomeruli, which are the filtering units, and which drain into the mesonephric, or Wolffian, duct, running through the center of the mesonephric tissue. This duct is the great legacy of the mesonephros, because near the distal end it sprouts a little bud, called the ureteric bud, which stimulates the metanephrogenic blastema (the precursor to the kidney) during the 5th week to form the metanephros, the third and final kidney. This metanephros will become the bean shaped organ we have all grown fond of, and then rise upward out of the pelvis and to the costovertebral angle as the fetus grows.

It is easy to see how this process apparently recapitulates lower evolutionary forms, going from amphibian to avian to a final mammalian state, and yet further inquiry has shown that this is not exactly true and that while these are important developmental stages, a human fetus does not undergo all steps of evolution during its time in the womb. What I find fascinating is how two distinct parts of this system, the ureteric bud and the metanephrogenic blastema, interact so precisely to create a connection for the kidneys. The ureteric bud induces the metanephrogenic mesenchyme to form the nephric tubules, the DCT, loop of Henle, PCT, and Bowman's capsule. This mesenchyme reciprocally acts on the ureteric bud causing it to branch and form a tree-like system of collecting ducts. Many growth factors are involved in this nephrogenesis, but of interest is the role of angiotensin II, a vasoconstrictor that interacts with the kidney to help regulate blood pressure. Angiotensin II is often blocked with ACE inhibitor or angiotensin receptor blocker (ARB) medications in people who have hypertension, effectively lowering blood pressure. Recent studies suggest that angiotensin, by interacting with receptors on the ureteric bud, stimulates branching morphogenesis as well as collecting duct elongation and papillogenesis. Therefore, patients are taken off of ACE inhibitors and ARBs when pregnant, because there can be failure of the ureteric bud to stimulate correct nephrogenesis and a wide array of kidney defects may result.

Although the recapitulation theory is defunct, there is something to be said for thinking of the kidneys evolutionarily, since they allow us to concentrate our urine, and regulate body water, so that we can live on land in the first place. An impressive feat, given the extensive multistep process it takes for a single adult kidney to develop.

Fetal Circulation and Baby's First Breath

I am not usually one to brag, but I am pretty good at holding my breath. You may have heard that pearl divers can hold their breaths for minutes at a time; my all-time record makes that seem like a fleeting moment. Yes, at one point I did not take a single breath for over 9 months.

Of course, I am being a little gratuitous here. As you may have guessed, I am talking about the time I spent in the womb, when there was no air to fill my immature lungs anyway. The cardiovascular system is at times remarkable in its simple elegance of function, and one place I think that exemplifies this is in the fetal circulation at the heart and lungs. Normally, all of the blood in our bodies must first be pumped by the heart into the lungs to be oxygenated, and then pumped into the rest of our body to distribute that oxygen. In the fetus, as I alluded to a little bit ago, there is no oxygen in the lungs because you are living in the fluid of the amniotic sac. Oxygenated blood must instead come from the mother by way of the umbilical vein. The fetal body has a unique way of separating oxygenated blood from deoxygenated blood to make sure the most vital organs can grow during crucial stages of development.

There are basically two streams of blood inside the heart: blood from the mother enters through the eustacian valve of the inferior vena cava, and goes across the heart and through a temporary valve between the right and left atria, the foramen ovale. This well-oxygenated blood can then be pumped like in an adult, going from the left heart up into the aorta and primarily heading to the oxygen-hungry developing brain via the carotid arteries. This blood also bypasses the lungs, which would only serve to remove oxygen from the blood. The other stream is oxygen poor, comes from the rest of the body into the superior vena cava, and heads down into the right side of the heart. Normally this would then go to the lungs to become oxygenated, but remember that the lungs are don't function yet. Instead, the blood goes through the ductus arteriosus, a structure that closes after birth, and enters the aorta after the carotids to go to the brain. This steers oxygen-poor blood away from the head and into the unbilical artery, returning it to the mother to be reoxygenated.

A major factor in this shunting has to do with the very high resistance of the arteries of the lungs. In the fetus, the lungs provide a huge barrier to blood flow, which means that most of the blood entering the pulmonary trunk with be diverted through the ductus arteriosus, a good thing for reoxygenation. However, at birth, when taking the that first breath, the pulmonary vascular resistance plummets and all the circulating blood is diverted to the normal pattern of entering the lungs before the systemic circulation. This might seem a little paradoxical, because normally oxygen is a potent vasoconstrictor; vessels that have a high oxygen tension will constrict as if saying "I'm fine here, go oxygenate someone else." In the fetus, the lung vascular expansion is in part due to the mechanical strain of inhalation, but also due to vasodilation mediated by oxygen. It is thought that this is in fact due to oxygen-sensitive potassium channels: fetal pulmonary vasoconstriction may be mediated by inhibiting calcium-sensitive potassium channels. Likewise, the ductus arteriosus is kept open by circulating prostaglandin E2, generated due to the relatively hypoxic, or low oxygen, state. When the newborn begins breathing on its own, this effect will stop (as long as it isn't premature) and the ductus will close.

That shift of blood flow will normally mean the end of the fetal circulation: a large return of blood from the lungs will close the valve to the foramen ovale, and the ductus arteriosus will constrict into a ligament, the end result being that the right side of the heart pumps oxygen poor blood to the lungs and that reoxygenated blood is then returned to and pumped out from the left side of the heart to the body. So, given that I had an impressive bypass tract to leach oxygen from my mom, perhaps I was cheating a little when I held my breath all that time in the womb; nonetheless, with such an elegant fetal circulation, I remain impressed.

One Gene, Curious Outcomes: Lesch-Nyhan Syndrome

Voyeurism is something that one might relate more to art than to medicine. As I learned in my art history course, many artists employ voyeuristic techniques that give the viewer an intimate view of the subject, and thus makes him an observer of distressing, sordid, or scandalous events. In fact, this has many parallels to my entrance into medicine. For instance, during a medical interview, I am privy to information that many would hesitate to otherwise share. Of course, it is medically relevant and important for a proper treatment outcome, but at times of reflection I realize how unique a doctor's role can be. Another aspect of the physician as voyeur, for me, lies in the unique and at times bizzare diseases that we learn about in medical school. In fact, I have a short list of favorite bizzare diseases, which I think are fascinating examples of how the human body is an incredibly intricate machine. One such favorite disease is a congenital enzyme deficiency called Lesch-Nyhan Syndrome. Imagine my surprise, then, when this obscure disorder was the topic of a column by Richard Preston in the New Yorker, titled The Possessed.

Lesch-Nyhan Syndrome is a rare disorder, affecting only one in every 380,000 people worldwide. The disorder is recessive, linked to the X chromosome. Since males only have one X chromosome, it is more likely that they will express the deficiency since they do not have another good copy of the gene, so only rarely has it been reported in females. The gene in question codes an enzyme called hypoxanthine-guanine phosphoribosyl transferase, or HGPRT. It is a lengthy name, but the function of this enzyme is relatively simple. As you may recall, your DNA is made up of little elements called nucleotides; these are divided into two classes, pyrimidines and purines. Normally, purines are recycled in the cell to make new nucleotides for DNA and other functions; this is done by HGPRT. If you lack this enzyme, you have to make new purines from scratch constantly. This means you also need to get rid of the old purines, that you no longer recycle. That process involves breaking them down into uric acid.

Some of the initial symptoms of the disease come form this uric acid accumulation. Babies will often have orange crystals in their diapers, from the crystallization of uric acid in the urine. This is often described as "orange sand." Patients may also present with a variety of neurological disorders. Cognitive function is impaired, with an average IQ of 60 and behavioral disorders. Additionally, there is often spasticity, and these patients display extrapyrimidal dysfunction, which means that the part of the brain which normally coordinates movement (as well as some emotional and impulse control) is not working: it doesn't have enough of the neurotransmitter, dopamine. The part which I find fascinating, however, is that patients with Lesch-Nyhan Syndrome somehow all develop self-mutilating behavior. Little children often present with stubby fingers and chewed up lips, which they have done to themselves in a compulsive manner. What's more, as Preston's description from the above article so vividly describes, the patient seems to be terrified of his hands while at the same time compelled to self-cannibalize them. Those that survive to adulthood (rarely do patients live beyond one or two decades) often have themselves physically restrained, to avoid this bizzare compulsion to "self-sabotage," manifested in these physical as well as strange behavioral acts, such as eating food a patient hates or acting cruelly towards people he loves.

Standard treatment is unfortunately limited to the symptoms of the disease, such as lowering the uric acid content, and most patients succumb to renal failure. However, recently, there has been some very interesting experimental work done with deep brain stimulation, which implants a "pacemaker" for the brain into the dysfunctional basal ganglia. Patients have seen a reduction in their spastic or dystonic movements as well as loss of the self-mutilating behavior. I think this is a fascinating example of how a little enzymatic defect in one gene can manifest as a child who is actually compelled to gnaw at themselves. Perhaps there is a large voyeuristic aspect to the treatment of disease, but this may serve as a reminder of how human physiology is a vast, complicated puzzle.

Hypertension and Heart Failure

I was sitting around the other day, just waiting to bite down into my deep-fried, salt-laden, double bacon cheeseburger sub sandwich, when a little medical school angel appeared on my shoulder and chirped, "wait Andy, what about your blood pressure? It's going to skyrocket!!"

Of course, at this point the little devil on my other shoulder retorted, "blood pressure? So what? Everyone has high blood pressure. What's the worst that this delicious bite of instant gratification could do?"

Luckily, it was cardiology section and the little medical school angel knew just how to answer such a health dilemma. We have all heard of the dangers of high blood pressure, and yet far too many of us carry the diagnosis; in 2003 there were more than 35 million doctor's visits for hypertension. I find that in order for me to want to change a behavior, such as the food that tastes so good but that I vaguely know is bad for me, I have to know why. Why is it so important that I keep my blood pressure normal?

First, let's look at circulation. I think that the circulation is most easily envisioned as a big loop, with a pump, the heart, propelling blood through progressively smaller tubes, arteries and arterioles. These eventually narrow into capillaries to distribute oxygen and nutrients and then expand again as veins to carry away waste and return to the lungs for more air. The tubes have a certain amount of resistance, especially as they get narrower, and hypertension occurs when the relationship between the output from the heart and the total peripheral resistance is altered. High blood pressure can injure many organs when the pressurized blood damages the vessels, including those of the retina (which may result in vision damage), the kidneys, and the brain (which may cause stroke). As we are in cardiology, however, I am worried now about the damage that hypertension inflicts on the heart.

The heart is a fairly simple pump. Blood flows into the right atrium, is contracted into the right ventricle, then sent into the pulmonary, or lung, circulation where it becomes oxygenated. It returns from there and enters the left atrium, is "kicked" into the left ventricle, and this, the strongest chamber of the heart, contracts to send fresh blood to the body. The principle behind this directional flow is that pressure must always decrease from one chamber to the next. Thus, pressure in the atrium is lower than in the veins, and pressure in the ventricle, when it is relaxed, is lower or equal to pressure of the atrium. When the ventricles contract, they increase the blood pressure so that it can perfuse the body, return to the heart, and the cycle begins again. When the heart contracts, this is called systole and the pressure produced is your systolic blood pressure. When it relaxes, this is diastole, and the pressure that remains in the vessels is diastolic blood pressure. This is higher in the vessel than in the heart because there is a valve that closes after the heart contracts. This means that the heart can relax and refill, while the vessels remain pressurized and able to go forward.

For such a simple pump, many things can go wrong. If the left ventricle is trying to pump against high blood pressure, as in hypertension, the ventricle will have to work harder to expel its blood. Recall that blood must go from high pressure to low; the ventricle has to work harder to overcome the high pressure in the aorta. Just like any other muscle, the heart will "get jacked" and you see hypertrophy, or increased size, of the ventricle. This bulking up means that less blood can get into the ventricle chamber, and so you might begin to experience heart failure. The problem is that since the circulation is a big loop, blocking one step results in backing up all the others. So, less blood pumped through the ventricle means blood, and pressure, builds up in the atrium, which then backs up in the lungs. This can result in congestive heart failure, where fluid can actually build up in the small alveoli of the lungs because of the pressure forcing it out of the small, weak capillaries. Pressure can continue back, so that you may get the right side of the heart involved, and even the venous return. So it is that the failure of your left heart to pump past the high blood pressure in your aorta can result in pulmonary edema (swelling with fluid) and right heart failure.

So, when my little medical school angel on my shoulder is confronted with a deep-fried, salt-laden, double bacon cheeseburger sub sandwich, it can fight back, knowing that since the circulation is one big loop, pumping up the pressure in one part will cause the rest of it to try and compensate. Heart failure (and maybe more) just isn't so appetizing.

P.S. Here is a very fun story of hypertension presenting as a medical mystery, from the New York Times.

Big Hearts

Campylobacter Jejuni, Guillain-Barré, and Cooking Chicken

Although I am a second year medical student, that is not the only position I currently hold. I also happen to be a second year chef. Yes, as a newcomer to the world of preparing my own meals thrice a day, I have been experiencing all of the thrills, and potential hazards, of cooking on my own. Perhaps more than most, I have also been acutely aware of the dangers of amateur cooking and my health.

Of these dangers, one that is rather unique to my station in life is a particular bacteria, Campylobacter jejuni. This is a seagull shaped gram negative bacteria with a flagella, or tail, that is one of the leading causes of diarrhea in the world, with 2 million cases a year in the United States. It is not spread person-to-person, but instead is carried in wild and domestic animals, especially birds. While most bacteria that infect the GI tract are only common to the very young and very old, C. jejuni has a large spike among people in their twenties, who you would think have excellent health; this might be because it is very common in undercooked chicken. My naive cooking skills, and the cleanliness of my prep area, are therefore constantly tested by this slender "S"-shaped bacteria.

C. jejuni is microaerophilic, which means that it likes a low oxygen environment, around 5-10%, such as that of your gut. It requires as few as 100 bacteria to be infectious, and the result is a watery or bloody diarrhea that is self-limited, ending in 4-5 days. While unpleasant, and unappetizing, this is nothing remarkable aside from its somewhat unusual target population. More unusual is that roughly 1 in every 1000 infected individuals go on to develop Guillain-Barré Syndrome, an autoimmune disease that affects the myelin coating of your peripheral, motor, and cranial nerves.

Many nerves are wrapped in a fatty cellular coating called myelin. In the periphery, this is composed of specialized cells called Schwann cells, which wrap around the nerve axon as it heads to or from its target tissue. This insulating layer helps the nerve transmission move more quickly, and also keeps it contained to that single axon. If you lose this layer, you can have slowed, abnormal, or even absent nerve signal conduction. Essentially, you may experience symptoms such as fatigue, loss of sensation or strange sensation, and possibly even paralysis, which can be dangerous if it affects your breathing.

In Guillain-Barré Syndrome, it is thought that following an infection, such as C. jejuni, you form an autoimmune response against the myelin coating your nerves. It may also occur after a viral infection, vaccination, or even medication. Any of these may cause your T cells to attack your myelin through molecular mimickry, where the myelin "looks like" the bodily insult. Recovery can take as long as 200 days, and while most people recover from even the most severe cases, there are often lingering effects, such as a degree of weakness. There is no current cure; replacing the serum of your blood or giving intravenous immune globulin (giving an outside antibody will decrease your own antibody production) have been shown to shorten recovery by up to 50%. Interestingly, steroids, which are known to lower your immune response, do not seem to be effective on their own in treating GBS.

What exactly induces Guillain-Barré Syndrome remains a mystery, confounded by the large number of suspected causes. If I were to avoid just one infectious cause, however, my money's on C. jejuni; it is found in the serology of up to 40% of people who present with GBS. Future research may help us solve this puzzle, but for now I might just stick to salad. Bon Appétit!

Vaccines and Autism