Overview of the Cardiovascular and Renal Systems

The Heart

The heart is located in the chest, behind the sternum (breastbone), slightly to the left of the center of the body. Surrounding and protecting the heart is a membrane called the pericardium (literally meaning “around the heart”). Though the heart muscle tirelessly pumps blood around the body for a lifetime, the size of the organ is relatively small. A normal heart is approximately the size of a closed fist. A cross-section reveals four chambers, two upper chambers known as atria, and two lower chambers called ventricles.

The right atrium is attached to the vena cava, a vein that returns deoxygenated blood to the heart and is the largest vein in the body. The right atrium is a relatively small chamber with limited muscle mass that serves largely as a holding chamber for blood returning to the heart. Separating it from the right ventricle is the tricuspid valve. This three-leafed valve, like the other valves of the heart, is made of strong connective tissue to hold up against the heart’s powerful beats. When the right ventricle is contracting, the tricuspid valve is tightly closed. After the contraction is complete, the pressure in the right ventricle decreases, allowing the tricuspid valve to open and the blood in the atrium to flow to the ventricle. Just before the tricuspid valve closes once more, the atrium contracts to force extra blood into the right ventricle.

The right ventricle, located below the right atrium, is responsible for pumping blood out of the heart and into the lungs, where it can become oxygenated. It is the second-largest chamber of the heart but is considerably smaller than the left ventricle because it only pumps blood a relatively short distance. Separating the left and right ventricles is the septum, a thick wall of cardiac muscle. When the right ventricle contracts, the rising pressures force open the pulmonary valve and drive the blood into the pulmonary artery system, toward the lungs. Oxygenated blood returning to the heart via the pulmonary veins enters the left atrium. Like the right atrium, blood flows freely into the ventricle while the valve between the two is open. The mitral valve, also known as the bicuspid valve for its two leaflets, allows blood to enter the left ventricle. Just before its closure, the left atrium contracts to ensure the left ventricle is at capacity.

The true powerhouse of the heart is the left ventricle. This is the largest of the heart’s chambers and makes up the pointed end of the heart known as the apex. The muscles around the chamber need to be bulky and powerful enough to pump blood around the entire body. When a contraction begins, the mitral valve is slammed closed and the blood is pushed through the aortic valve.

These four chambers of the heart work in harmony to pump blood to the body; however, without a functioning pacemaker to keep each chamber in sync, the pump would quickly fail. Beneath the mighty cardiac muscles is a complex electrical system that ensures each chamber contracts on time (Figure 14-1). The origin of each beat is in the sinoatrial (SA) node. This is a collection of specialized cells in the right atrium that are autorhythmic, which are able to initiate electrical impulses themselves (without external input) and stimulate heart muscle contraction. Once the cells of the SA node start the contraction, a wave is set off in neighboring cells, allowing them to contract, as well. The wave of contraction first moves across the right atrium and, next, enters the left atrium, causing it to contract soon after the right.

Anatomy of the heart.

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Anatomy of the heart.

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Anatomy of the heart.

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When the wave reaches the bottom of the atria, it encounters a second area of autorhythmic cells called the atrioventricular (AV) node. This is the gateway to the electrical system of the ventricles. If the wave of depolarization that started in the SA node were simply allowed to spread across the entire heart, the beats would be slow, out of sync, and ineffective. Instead, the heart contains a system of nerves that quickly move the wave from the AV node down to the bottom of the ventricles. The electrical charge passes through the AV node to the Bundle of His (HISS), a group of nerve fibers in the septum that distributes it between the left and right bundle branches in the septum and down to another nerve group, the Purkinje fibers, that quickly spreads the depolarization from the bottom of the ventricular muscles upward. The resulting ventricular contraction can be compared to squeezing toothpaste from the bottom of the tube rather than from the top.

Without any outside input, the regular depolarization of the SA node can keep a steady heartbeat around 100 beats per minute. There are, however, certain events that can alter the rate of the heart’s natural pacemaker. The sympathetic nervous system (SANS), responsible for the so-called “fight or flight response,” can raise the heart rate in order to increase the amount of oxygen-rich blood circulating the body, while the parasympathetic nervous system (PANS) can slow the heart rate down. A number of hormones, such as epinephrine, can also influence the rate at which the SA node depolarizes.

The Vasculature

The contraction of the left ventricle ejects approximately 70 mL (just over 2 ounces) of blood through the aortic valve into the aorta, the largest artery in the vasculature (Figure 14-2). Most of the blood ejected from the heart follows this large artery out to the rest of the body, but a small amount enters the coronary arteries that surround the heart and supply the oxygen needed to keep the heart pumping. Arteries are large vessels surrounded by layers of elastic fibers, smooth muscle, and endothelial cells. The arteries closest to the heart play an important role in helping the heart push blood around the body and are often called elastic arteries. The beat of the left ventricle causes a sharp increase in pressure in the arteries, resulting in a stretching of the vessel walls. As the heart relaxes, the artery constricts to its normal size and advances blood further along. These larger arteries branch off into smaller arteries that tend to have less-elastic fibers and thicker muscular layers. Often called muscular arteries, they play a role in regulating blood pressure. Signals from the ANS, hormones, or other substances can interact with the smooth muscle to cause vasoconstriction or vasodilation.

Vasculature.

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Vasculature.

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Vasculature.

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As the blood moves throughout the body, it next encounters arterioles, which are nearly microscopic blood vessels that eventually connect to the capillaries. Like the muscular arteries, arterioles play an important role in regulating blood pressure. As blood vessels become smaller, the friction of the blood against the vessel wall increases and contributes to systemic vascular resistance (SVR), an important factor in determining blood pressure. Arterioles also contain precapillary sphincters, small rings of smooth muscle that control the flow of blood into the capillary beds. Signals from surrounding tissues help to regulate the opening and closing of the sphincters and which capillary beds receive blood flow.

The smallest of all blood vessels are the capillaries, bridging the gap between the arterial and venous sides of the circulatory system. These microscopic blood vessels fan outward from arterioles and come into contact with nearly every cell in the body. Some capillaries are so small that red blood cells must move in single file at their narrowest point. It is at the level of the capillary that cellular exchange can occur, trading oxygen, nutrients, and hormones from the blood for cellular debris, carbon dioxide, and other waste products from the cells. The capillaries next begin to converge, each smaller vessel joining with another, to form the beginnings of the venous system. As capillaries come together, they create venules, small vessels that eventually flow into full-sized veins. While veins, like arteries, contain layers of elastic fibers, smooth muscle, and endothelial cells, there are a number of important differences. Due to their distance from the heart, veins are not designed to withstand high pressures; therefore, all the layers are thinner on the venous side of the vasculature. The veins of the extremities (hands, feet) contain one-way valves to help encourage the flow of blood, even against the force of gravity. Without these valves, blood could flow backward or pool in the feet, delaying its return to the heart. Since the beating of the heart only minimally affects venous blood flow, veins rely on the help of surrounding skeletal muscle to keep blood moving. As we move about, muscles contract, putting pressure on nearby veins. Blood is then forced upward through sets of valves, one step closer to returning to the heart. As the veins approach the heart, many of them converge to form the vena cava, the largest vein in the vasculature, which returns the deoxygenated blood to the right atrium where the cycle can begin once more (Figure 14-3).

Arteries versus veins.

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Arteries versus veins.

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Arteries versus veins.

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The Kidneys

The kidneys are the pair of bean-shaped organs responsible for filtering blood and regulating a number of important processes. Located near the lower back, the kidneys are often described as retroperitoneal organs because they can be found behind (retro to) the peritoneal cavity (Figure 14-4). A number of important features can be identified in a cross-section view of a kidney. First, blood is delivered via the renal artery. The renal artery enters the kidney through the renal hilus, the concave area in the middle of the organ. The blood vessels spread outward, reaching the outermost area of the kidney, called the renal cortex. Just beneath the renal cortex lies the renal medulla. Embedded between these two areas are roughly 1 million nephrons, specialized units that filter the blood, working together to regulate blood pressure and create urine, among other important tasks. Once filtered, the blood and urine leave the kidney through the renal hilus in renal veins and the ureter, respectively.

Anatomy of the kidney.

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Anatomy of the kidney.

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Anatomy of the kidney.

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The Nephron

To understand the kidney’s vital role in homeostasis and the creation of urine, we must understand its functional unit, the nephron. Each nephron contains two main components: the renal corpuscle and the renal tubule (Figure 14-5). Blood entering the kidney travels along arterioles until it reaches a glomerulus, a tightly tangled mass of capillary vessels. A membrane known as Bowman’s capsule surrounds each glomerulus. Here, nearly all of the blood’s water and solutes pass out of the bloodstream and into the renal tubule. The rate at which these substances are filtered into the renal tubule is called the glomerular filtration rate (GFR), an important estimate of overall renal function. This value is used to classify patients into various stages of kidney disease. See Table 14-1 for more details. The remaining blood flows out of the glomerulus and enters the peritubular capillaries. These small vessels closely follow along the route of the renal tubule so that additional solutes and water can be exchanged between the bloodstream and the nephron in processes called tubular reabsorption and tubular secretion.

Structure of the nephron.

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Structure of the nephron.

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Structure of the nephron.

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The first segment of the tubule, known as the proximal convoluted tubule, performs the bulk of the reabsorption. Most of the usable solutes, such as glucose, amino acids, and nutrients, are transported back into the blood from the renal tubule. In the reverse direction, tubular secretion causes unfiltered waste products in the blood to move into the renal tubule for excretion.

Thus far, the filtered materials in the renal corpuscle and proximal tubule have been located in the renal cortex, the outermost layer of the kidney. The next segment of the renal tubule, called the loop of Henle, takes the filtrate deep into the medulla of the kidney before making a sharp turn and returning to the renal cortex. Here, the body can perform important adjustments to both the concentration and the composition of the urine being formed. In the descending loop, additional water can be reabsorbed into the blood, while, in the ascending loop, electrolytes can be independently reabsorbed. Depending on signals from the body, the loop of Henle can help to create either dilute or concentrated urine by reabsorbing more or less water.

Next, the filtrate enters the distal convoluted tubule. Since a great deal of the filtered water has already been absorbed in previous areas of the tubule, very little reabsorption takes place here. The urine in a number of distal tubules drains into a single shared collecting duct. Like the loop of Henle, the collecting ducts play a major role in regulating urine concentration. Usually, the collecting ducts are impermeable to water, meaning nearly all of the water delivered to them is excreted in the urine. An important hormone, called vasopressin or antidiuretic hormone (ADH), can drastically alter the way a collecting duct works. As its name implies, the body releases ADH when it needs to hold onto extra fluid. ADH, discussed in detail later in this chapter, acts at the level of the collecting duct, causing the opening of aquaporins. These small channels allow the body to reabsorb large amounts of water that typically would be excreted, to create very concentrated urine.

The composition of the urine draining through the numerous collecting ducts will remain largely unchanged throughout the rest of its journey. A number of collecting ducts converge to drain into minor and major calyces, which are cup-like containers that eventually lead to the ureter and bladder before being excreted as urine.

Electrolyte Balance and Diuretics

The term electrolyte refers to a substance that has an electrical charge when dissolved in water. Also known as ions, these substances are further divided into two groups, cations and anions, depending on the type of charge they have. When a cation comes into contact with an anion, the opposite charges lead to a strong attraction. Once dissolved in water, however, the two halves are separated and surrounded by water molecules. In their dissolved form, the body can use electrolytes in a number of ways to perform the various functions needed to maintain homeostasis. It is important that the body have a sufficient amount of each of these electrolytes stored but having excessive amounts can also lead to serious dysfunctions. The kidneys are responsible for maintaining the proper electrolyte balance, holding on to the electrolytes the body needs while excreting those it has in excess.

The cations are positively charged ions and include substances like sodium (Na⁺), potassium (K⁺), calcium (Ca²⁺), and magnesium (Mg²⁺). Sodium is the most abundant cation in the body and is found primarily outside of the cells. Levels of this electrolyte can be reduced if a patient has vomiting, diarrhea, or does not take in enough sodium in the diet. The resulting condition is known as hyponatremia and can be remedied with intravenous (IV) administration of normal saline.

Hypernatremia, or elevated sodium levels, is typically caused by dehydration. The body’s natural thirst mechanism is usually sufficient to replace lost fluids and bring the sodium concentration into the normal range, though some patients may require IV rehydration. When sodium levels are outside of the normal range, the central nervous system is the primary organ system affected, causing symptoms such as dizziness, confusion, or seizures.

Potassium is primarily found inside of the cells, with only small amounts measurable in the blood. When potassium levels are either elevated or depleted, patients are at risk for developing life-threatening arrhythmias or muscle paralysis. Potassium levels are often decreased, a condition known as hypokalemia, when a patient is taking diuretics, a group of medications that will be discussed below. Potassium supplements can be prescribed to help patients maintain appropriate levels in the body. Potassium supplements are available in a variety of salts (potassium chloride, potassium gluconate, etc.) and oral dosage forms (liquids, long-acting tablets, effervescent tablets) that are listed in Medication Table 14-1 (Medication Tables are located at the end of the chapter). Potassium may also be administered intravenously for patients who are unable to take oral doses or who need a fast-acting dose.

Hyperkalemia, on the other hand, is an increased level of potassium usually caused by decreased kidney function. If the kidneys cannot filter properly, potassium can accumulate in the blood stream, and patients may require medications or dialysis to bring these levels down. Some medications also predispose patients to hyperkalemia, including the potassium-sparing diuretics (discussed later in the chapter) and the ACE inhibitors (covered in Chapter 15). Potassium supplements and salt substitutes may also increase potassium levels.

The most common pharmacological treatment for hyperkalemia is sodium polystyrene sulfonate (SPS or Kayexalate). This medication, available as a suspension or powder, is a resin that contains sodium ions. When administered orally or rectally, the sodium is exchanged for potassium ions in the large intestine before being excreted in the feces. Doses of 15 g can be given by mouth as compared to 30–50 g given rectally up to four times per day. If not monitored carefully, patients may experience hypokalemia or hypernatremia, though the most common side effects are nausea, vomiting, diarrhea, and constipation.

Anions have a negative charge and include chloride (Cl^–), phosphate (PO₄^3–), and bicarbonate (HCO₃^–). The most common anion, chloride, works to balance the positively charged sodium in the body. Like its counterpart, chloride is primarily found outside of cells and helps regulate the balance of water. Phosphate is important in many of the body’s metabolic processes.

Bicarbonate is an important component of the body’s acid–base balancing system. The kidney and respiratory system regulate acid–base balance, measured as pH. Reported on a scale of 0 to 14, with 0 being the most acidic and 14 the most alkaline (basic), pH 7 is neutral and body fluid pH is about 7.4 (slightly alkaline). Often called a buffer, bicarbonate helps to neutralize acid and keep pH at appropriate levels.

Clinicians frequently order laboratory tests to check the precise amount of each electrolyte in the serum. For a detailed list of normal serum electrolyte concentrations, see Table 14-2.

Diuretics are medications that increase the excretion of water in the urine by various actions on the kidney. For many patients who have hypertension or retain water, diuretics are an important treatment. By creating more dilute urine, diuretics cause a decrease in the blood volume and pressure but can also have a significant impact on the concentration of electrolytes in the body. There are many different classes of diuretics and each tends to affect a different segment of the nephron.

Some of the most potent diuretics available work at the loop of Henle. These so-called loop diuretics, such as bumetanide, furosemide, and torsemide, stop the reabsorption of sodium and water into the bloodstream, leaving them in the urine. Compared to other diuretics, the loop diuretics cause a profound diuresis that is often dose-related, meaning the effect can be intensified as the dose is increased. The effect is so strong that care must be taken not to cause an over-diuresis and dehydration. As is the case with nearly all diuretics, the effect on electrolyte balance must be closely monitored to avoid deficiencies in sodium, potassium, magnesium, and calcium.

The thiazide diuretics work at the distal convoluted tubule. This commonly used class of diuretics includes hydrochlorothiazide, chlorthalidone, and metolazone. As their mechanism is very similar to the loop diuretics, thiazides cause many of the same electrolyte-related side effects when used at higher doses. Fortunately, when they are used to treat hypertension, low doses are typically sufficient and the electrolyte depletion is often avoided. One of the unique side effects of the thiazides is hyperglycemia, necessitating cautious use in patients with type 2 diabetes (Medication Table 14-2).

While diuretics act on the renal tubules and loop of Henle, other agents cause diuresis by interfering with the action of ADH. One of the most common substances hindering the ADH effect is alcohol. When consumed, it decreases the production of ADH and, consequently, causes a decrease in the number of aquaporins in the collecting duct. Spironolactone and eplerenone, the potassium-sparing diuretics, are examples of medications that interfere with aldosterone to cause diuresis. They are called potassium-sparing because, unlike the other diuretics described above, these cause a loss of sodium and water in exchange for potassium. By blocking the receptors that aldosterone normally acts upon, aquaporin insertion is limited. Without these important channels, water cannot be reabsorbed into the blood and is excreted in the urine. Other potassium-sparing diuretics are available, including amiloride and triamterene, but their mechanism of action is poorly understood. It is thought that they block the reabsorption of sodium in the distal tubule and collecting duct.

Kidney Stones

In a functioning nephron, numerous minerals are successfully filtered out of the bloodstream and into the renal tubule. If conditions are optimal, these dissolved substances can be effectively transported without causing harm, either being reabsorbed or excreted in the urine. Under certain circumstances, however, kidney stones, or renal calculi, can form when dissolved substances bind together to create a solid precipitate. Though the composition of a stone can vary, the most common is a combination of calcium and oxalate. About 80% of all kidney stones are made of this combination. Since the renal tubules and the ureters are not designed to transport solid masses, patients experience intense, sharp flank pain as the stones travel down the urinary system. Left untreated, most small stones can be passed without significant damage to the body. If the stones exceed 1–2 mm in size, however, an obstruction may occur. Without an open passage to the bladder, urine backs up into the kidney, potentially causing permanent damage and renal failure.

A number of strategies can be used to treat kidney stones, though the most effective treatment is to prevent the formation of the stone in the first place. Patients experiencing dehydration are at an increased risk of stone formation, and adequate hydration can ensure that enough fluid is filtered into the tubule to keep stone-forming substances dissolved. Another approach to preventing kidney stones is to decrease the concentration of the ingredients necessary to create a stone. Dietary sources of oxalate, such as chocolate, rhubarb, and spinach, should be avoided and medications, such as hydrochlorothiazide, can be used to increase the reabsorption of calcium out of the kidney.

Once a kidney stone has formed, medications can, once again, play a large role in treatment. To treat the intense pain associated with stone formation, nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are commonly used to improve a patient’s quality of life. In the most severe cases, however, medications may not be sufficient to treat large stones. In a noninvasive procedure known as lithotripsy, physicians can attempt to break apart a stone using sound waves. For the rare case where noninvasive methods fail, surgical removal of a calculus is also an option.³

Diabetes Insipidus

Diabetes insipidus is a disorder involving ADH. As described earlier, ADH is responsible for the insertion of aquaporins into the collecting ducts of the kidneys. Released in response to dehydration, ADH allows the body to reabsorb extra water that would otherwise be excreted in the urine. Diabetes insipidus disrupts the body’s ability to produce or use this important hormone.

ADH is typically produced in the hypothalamus and stored in the pituitary gland of the brain. In cases of central diabetes insipidus, this function is lost, due to trauma, infection, cancer, or other reasons. For some patients, the dysfunction lies not with the ability of the brain to produce the hormone, but with the kidney’s ability to respond to it. Nephrogenic (originating in the kidneys) diabetes insipidus, which may be caused by certain medicines or genetics, does not affect the ability to produce ADH, but disrupts the body’s ability to use it.

The symptoms of diabetes insipidus are uniform, regardless of the cause of the disease. Because these patients cannot concentrate their urine, excessive amounts of water are lost. In severe cases, patients can have increased urine output, up to 10 times that of a healthy individual. The brain responds to this dehydration with extreme thirst in an attempt to replace fluid losses.

The treatment of central diabetes insipidus relies on the replacement of ADH. Desmopressin (DDAVP), a synthetic version of the hormone that can be administered orally or as a nasal spray, can restore the body’s ability to concentrate urine and relieve the symptoms of extreme thirst. Orally, desmopressin is initially dosed as 0.05 mg twice daily or one spray (10 mcg) 1–3 times per day intranasally and is titrated to the desired effect. Typically, the medication is well tolerated but may cause low sodium levels or water retention if patients do not follow strict fluid restrictions.⁴

As nephrogenic diabetes insipidus decreases the kidney’s ability to respond to ADH, a different approach must be used in its treatment. If caused by a medication, the symptoms may resolve after the offending agent is discontinued. For those patients with genetic defects, treatment focuses on maintaining adequate hydration and limiting sodium intake.

Nephropathy

Renal disease, also known as nephropathy, is a process in which damage occurs to the kidney, resulting in a decreased functionality of the organ. Many conditions can lead to a nephropathy, and the most common include hypertension, diabetes, and analgesic use. If left unchecked, the damage done to the kidney can become extensive, leaving the patient without a way to filter the blood of waste products and maintain electrolyte balance. In such cases, patients must rely on dialysis.

Hypertensive nephropathy takes place in patients who have longstanding hypertension. While high blood pressure can negatively affect a number of body systems, the kidneys are especially at risk. The tiny capillaries of the glomerulus and the larger arterioles become thickened under the increased pressure, leading to a condition known as glomerulosclerosis, or scarring of the glomerulus. As the vessel walls become thicker, it becomes more difficult for blood to flow freely to the kidney and oxygen supply dwindles. Without oxygen, the cells of the nephron begin to die off and cannot continue to filter the blood. If left untreated, the glomerulosclerosis can become so widespread that the kidney may cease to function all together, ending in complete renal failure and dialysis. To avoid these dire results, it is important to treat the underlying cause: uncontrolled hypertension. Refer to Chapter 15 for a detailed explanation of the treatment of hypertension.

Diabetic nephropathy refers to a progressive decline in renal function that can be attributed to uncontrolled diabetes mellitus. Though the root cause of this kidney dysfunction differs from hypertensive nephropathy, the type of damage seen at the level of the nephron is very similar. Chronically elevated blood sugar leads to a glomerulosclerosis and decreased functioning of the nephron. If blood sugars remain elevated, the disease can progress to complete renal failure and a dependence on dialysis. In the United States, diabetic nephropathy is the leading cause of dialysis dependence. As seen in hypertensive nephropathy, the best treatment for diabetic nephropathy is to control its underlying cause. By keeping blood sugars at acceptable levels, the risk of glomerulosclerosis is greatly reduced and progression of kidney disease becomes less likely. In addition to preventative measures, many patients diagnosed with diabetes are prescribed medications from the class known as ACE inhibitors, such as lisinopril, enalapril, or ramipril, or angiotensin receptor blockers (ARBs), such as candesartan, irbesartan, or valsartan. These agents help to protect the kidneys from damage by increasing the blood flow in renal arteries. For more information regarding the treatment of diabetes mellitus, see Chapter 10.

In some cases, medications may be the primary cause of nephropathy. The most commonly used class of medications that cause kidney damage is NSAIDs, such as ibuprofen, naproxen, or indomethacin. Though generally safe if taken for short periods of time, chronic use of these medications can cause serious damage to the kidneys. In a normally functioning glomerulus, many different substances help regulate blood pressure. One such compound is prostaglandin E2 (PGE2), which acts as a vasodilator on renal arterioles and helps maintain adequate blood supply. In the presence of NSAIDs, the production of PGE2 is inhibited and the blood pressure balance is tipped in favor of vasoconstriction. With blood supply decreased, glomerulosclerosis can set in and lead to decreased GFR and, eventually, all-out renal failure. To avoid the consequences of analgesic nephropathy, the use of NSAIDs should be limited to the lowest dose and shortest duration possible.