What is nephrology?

Science and Profession

Nephrology is the branch of medicine that deals with the function of the kidneys. As a consequence, a nephrologist frequently deals with problems related to homeostasis, that is, the maintenance of the internal environment of the body. The most obvious function of the kidneys is their ability to regulate the excretion of water and minerals from the body, at the same time serving to eliminate nitrogenous wastes in the form of urea. While such waste material, produced as by-products of cell metabolism, is removed from the circulation, essential nutrients from body fluids are retained within the renal apparatus. These nutrients include proteins, carbohydrates, and electrolytes, some of which help maintain the proper acid-base balance within the blood. In addition, cells in the kidneys regulate red blood cell production through the release of the hormone erythropoietin.

The human excretory system includes two kidneys, which lie in the rear of the abdominal cavity on opposite sides of the spinal column. Urine is produced by the kidneys through a filtration network composed of 2 million nephrons, the actual functional units within each kidney. Two ureters, one for each kidney, serve to remove the collected urine and transport this liquid to the urinary bladder. The urethra drains urine from the bladder, voiding the liquid from the body.

Each adult human kidney is approximately 11 centimeters in length, with a shape resembling a bean. When the kidney is sectioned, three anatomical regions are visible: a light-colored outer cortex; a darker inner region, called the medulla; and the renal pelvis, the lowest portion of the kidney. The cortex consists primarily of a network of nephrons and associated blood capillaries. Tubules extending from each nephron pass into the medulla. The medulla, in turn, is visibly divided into about a dozen conical masses, or pyramids, with the base of the pyramid at the junction between the cortex and medulla and the apex of the pyramid extending into the renal pelvis. The loops (such as the loop of Henle) and tubules within the medulla carry out the reabsorption of nutrients and fluids that have passed through the capsular network of the nephron. The tubules extend through the medulla and return to the cortical region.

There are approximately 1 million nephrons in each kidney. Within each nephron, the actual filtration of blood is carried out within a bulb-shaped region, Bowman’s capsule, which surrounds a capillary network, the glomerulus. In most individuals, a single renal artery brings the blood supply to the kidney. Since the renal artery originates from a branch of the aorta, the body’s largest artery, the blood pressure within this region of the kidney is high. Consequently, hypotension, a significant lowering of blood pressure, may also result in kidney failure.

The renal artery enters the kidney through the renal pelvis, branching into progressively smaller arterioles and capillaries. The capillary network serves both to supply nutrition to the cells that make up the kidney and to collect nutrients or fluids reabsorbed from the loops and tubules of the nephrons. Renal capillaries also enter the Bowman’s capsules in the form of balls or coils, the glomeruli. Since blood pressure remains high, the force filtration in a nephron pushes about 20 percent of the fluid volume of the glomerulus into the cavity portion of the capsule. Most small materials dissolved in the blood, including proteins, sugars, electrolytes, and the nitrogenous waste product urea, pass along within the fluid into the capsule. As the filtrate passes through the series of convoluted tubules extending from the Bowman’s capsule, most nutrients and salts are reabsorbed and reenter the capillary network. Approximately 99 percent of the water that has passed through the capsule is also reabsorbed. The material which remains, much of it waste such as urea, is excreted from the body.

Nephrology is the branch of medicine that deals with these functions of the kidney. Loss of kidney function can quickly result in a buildup of waste material in the blood; hence kidney failure, if untreated, can result in serious illness or death. Within the purview of nephrology, however, is more than the function of the kidneys as filters for the excretion of wastes. The kidneys are also endocrine organs, structures that secrete hormones into the bloodstream to act on other, distal organs. The major endocrine functions of the kidneys involve the secretion of the hormones renin and erythropoietin.

Renin functions within the renin-angiotensin system in the regulation of blood pressure. It is produced within the juxtaglomerular complex, the region around Bowman’s capsule in which the arteriole enters the structure. Cells within the tubules of the nephron closely monitor the blood pressure within the incoming arterioles. When blood pressure drops, these cells stimulate the release of renin directly into the blood circulation.

Renin does not act directly on the nephrons. Rather, it serves as a proteolytic enzyme that activates another protein, angiotensin, the precursor of which is found in the blood. The activated angiotensin, called angiotensin II, has several effects on kidney function that involve the regulation of blood pressure. First, by decreasing the glomerular filtration rate, it allows more water to be retained. Second, angiotensin II stimulates the release of the steroid hormone aldosterone from the adrenal glands, located in close association with the kidneys. Aldosterone acts to increase sodium retention and transport by cells within the tubules of the nephron, resulting in increased water reabsorption. The result of this complex series of hormone interactions within the kidney is a close monitoring of both salt retention and blood pressure and volume. In this manner, nephrology also relates to the pathophysiology of hypertension—high blood pressure.

The kidneys also regulate the production of erythrocytes, red blood cells, through the production of the hormone erythropoietin. Erythropoietin is secreted by the peritubular cells associated with regions outside the nephrons in response to lowered oxygen levels in the blood, also monitored by cells within the kidney. The hormone serves to stimulate red cell production within the bone marrow. Approximately 85 percent of the erythropoietin in blood fluids is synthesized within the kidneys, the remainder by the liver.

Since proper kidney function is related to a wide variety of body processes, from the regulation of nitrogenous waste disposal to the monitoring and control of blood pressure, nephrology may deal with a number of disparate syndromes. The kidney may represent the primary site of a disease or pathology, an example being the autoimmune phenomenon of glomerulonephritis. Renal failure may also result from the indirect action of a more general systemic syndrome, as is the case with diabetes mellitus. In many cases, the decrease in kidney function may result from any number of disorders, which poses many problems for the nephrologist.

Proper function of the kidney is central to numerous homeostatic processes within the body. Thus nephrology by necessity deals with a variety of pathophysiological disorders. Renal dysfunction may involve disorders of the organ itself or pathology associated with individual structures within the kidneys, the glomeruli or tubules. Likewise, the disorder within the body may be of a more general type, with the kidney being a secondary site of damage. This is particularly true of immune disorders such as lupus (systemic lupus erythematosus) or diabetes. Conditions that affect proper kidney function may result from infection or inflammation, the obstruction of tubules or the vascular system, or neoplastic disorders (cancers).

Immune disorders are among the more common processes that result in kidney disease. They may be of two types: glomerulonephritis or the more general nephrotic syndrome. Glomerulonephritis can result either from a direct attack on basement membrane tissue by host antibodies, such as with Goodpasture’s syndrome, or indirectly through deposits of immune (antigen-antibody) complexes, such as with lupus. Nephritis may also be secondary to high blood pressure. In any of these situations, inflammation resulting from the infiltration of immune complexes and/or from the activation of the complement system may result in a decreased ability of the glomeruli to function. Treatment of such disorders often involves the use of corticosteroids or other immunosuppressive drugs to dampen the immune response. Continued recurrence of the disease may result in renal failure, requiring dialysis treatment or even kidney transplantation.

Activation of the complement system as a result of immune complex deposition along the glomeruli is a frequent source of inflammation. Complement consists of a series of some dozen serum proteins, many of which are pharmacologically active. Intermediates in the complement pathway include enzymes that activate subsequent components in a cascade fashion. The terminal proteins in the pathway form a “membrane attack complex,” capable of significantly damaging a target (such as the basement membrane of a Bowman’s capsule). Activation of the initial steps in the pathway begins with either the deposition of immune complexes along basement membranes or the direct binding of antibodies on glomerular surfaces. The end result can be extensive nephrotic destruction.

Nephrotic syndrome, which can also result in extensive damage to the glomeruli, is often secondary to other disease. Diabetes is a frequent primary disorder in its development; approximately one-third of insulin-dependent diabetics are at risk for significant renal failure. Other causes of nephrotic syndrome may include cancer or infectious agents and toxins.

Diagnostic and Treatment Techniques

Nephrologists can measure glomerular function using a variety of tests. These tests are based on the ability of the basement membranes associated with the glomeruli to act as filters. Blood cells and large materials such as proteins dissolved in the blood are unable to pass through these filters. Plasma, the liquid portion of the blood containing dissolved factors involved in blood-clotting mechanisms, is able to pass through the basement membrane, the driving force for filtration being the hydrostatic pressure of the blood (blood pressure).

The glomerular filtration rate (GFR) is defined as the rate by which the glomeruli filter the plasma during a fixed period of time. Generally, the rate is determined by measuring either the time of clearance of the carbohydrate inulin from the blood or the rate of clearance of creatinine, a nitrogenous by-product of metabolism. Though the rate may vary with age, it generally is about 125 to 130 milliliters of plasma filtered per minute.

Any significant decrease in the GFR is indicative of renal failure and can result in significant disruptions of acid-base or electrolyte balance in the blood. A decrease in the GFR can sometimes be observed through measurements of urine output. Healthy individuals usually excrete from 1 to 2 liters of urine per day. If the urine output drops to less than 500 milliliters (0.5 liter) per day, a condition known as oliguria, the body suffers a diminished capacity to remove metabolic waste products (urea, creatinine, or acids). Taken to an extreme, in which the filtering capacity is completely shut down and urine formation drops below 100 milliliters per day (anuria), the resulting uremia may cause death in a matter of days.

Anuria may have a variety of causes: kidney failure; hypotension, in which blood pressure is insufficient to maintain glomerular filtration; or a blockage in the urinary tract. As waste products, fluids, and electrolytes (especially sodium and potassium) build up, the person may appear puffy, be feverish, and exhibit muscle weakness. Heart arrhythmia or failure may also occur. Mediation of the problem, in addition to attempts to alleviate the reasons for kidney dysfunction, include regulation of fluid, protein, and electrolyte uptake. Medications are also used to increase the excretion of potassium and tissue fluids, assuming that the cause is not a urinary blockage.

The nephrologist or other physician may also monitor kidney function through measurements of serum analytes or through observation of certain chemicals within the urine. The levels of blood, urea, and nitrogen (BUN), nitrogenous substances in the blood, present a rough measure of kidney function. Generally, BUN levels change significantly only after glomerular filtration has been significantly disrupted. The levels are also dependent on the amount of protein intake in the diet. When changes occur as a result of renal dysfunction, BUN levels can be a useful marker for the progression of the disease. A more specific indicator of renal function can be the creatinine concentration within the blood. Serum creatinine, unlike BUN levels, is not related to the diet. In the event of renal failure, however, changes in BUN levels usually can be detected earlier than those of creatinine.

As the glomeruli lose their ability to distinguish large from small molecules during filtration, protein can begin to appear in the urine, the condition known as proteinuria. Usually, the level of protein in the urine is negligible (less than 250 milligrams per day). A transient proteinuria can result from heavy exercise or minor illness, but persistent levels of more than 1 gram per day may be indicative of renal dysfunction or even complications of hypertension. Generally, if the problem resides in the loss of tubular reabsorption, levels of protein generally are below 1 to 2 grams per day, with that amount usually consisting of small proteins. If the problem is a result of increased glomerular permeability caused by inflammation, levels may reach greater than 2 grams per day. In cases of nephrotic syndrome, excretion of protein in the urine may exceed 5 grams per day.

Measurement of urine protein is a relatively easy process. A urine sample is placed on a plastic stick with an indicator pad capable of turning colors, depending on the protein concentration. Analogous strips may be used for detection of other materials in urine, including acid, blood, or sugars. The presence of either red or white blood cells in urine can be indicative of infection or glomerulonephritis.

In addition to the filtration of blood fluids through the nephrons, the reabsorption of materials within the tubules results in increased urine concentration. A normal GFR within a healthy kidney produces a urine concentration three or four times as great as that found within serum. As kidney failure progresses, the concentration of urine begins to decrease, with the urine becoming more dilute. The kidneys compensate for the decreased concentration by increasing the amount of urine output: The frequency of urination may increase, as well as the volume excreted (polyuria). In time, if renal failure continues, the GFR will decrease, resulting in the retention of both analytes and water.

Determination of urine concentration is carried out following a brief period of dehydration: deprivation of fluids for about fifteen hours prior to the test. This dehydration will result in increased production by the hypothalamus of antidiuretic hormone (ADH), or vasopressin, a chemical that decreases the production of urine through increased renal tubule reabsorption of water. The result is a more concentrated urine. Following the dehydration period, the patient’s urine is collected over a period of three hours and assessed for concentration. Significantly low values may be indicative of kidney disease.

A battery of tests in addition to those already described may be utilized in the diagnosis of kidney disease. These may include intravenous pyelography (in which a contrast medium is injected into the blood and followed as it passes through the kidneys), kidney biopsy, and ultrasound examinations. Diagnosis and course of treatment depend on an evaluation of these tests.

Perspective and Prospects

The roots of modern nephrology date from the seventeenth century. In the early decades of that century, the English physician William Harvey demonstrated the principles of blood circulation and the role of the heart in that process. Harvey’s theories opened the door for more extensive analysis of organ systems, both in humans and in other animals. As a result, in 1666, Italian anatomist Marcello Malpighi, while exploring organ structure with the newly developed microscope, discovered the presence of glomeruli (what he called Malpighian corpuscles) within the kidneys. Malpighi thought that these structures were in some way connected with collecting ducts in the kidneys that had recently been found by Lorenzo Bellini. Malpighi also suspected that these structures played a role in urine formation.

Sir William Bowman, in 1832, was the first to describe the true relationship of the corpuscles discovered by Malpighi to urine secretion through the tubules. Bowman’s capsule, as it is now called, is a filter that allows only the liquid of the blood, as well as dissolved salts and urea within the blood, into the tubules, from which the urine is secreted. It remained for Carl Ludwig, in 1842, to complete the story. Ludwig suggested that the corpuscles function in a passive manner, in that the filtrate is filtered by means of hydrostatic pressure through the capsule into the tubules and from there concentrated as water and solutes that are reabsorbed.

The first definitive work on urine formation, The Secretion of the Urine, was published by Arthur Robertson Cushny in 1917. In the monograph, Cushny offered a thorough analysis of the data published on kidney function. Though Cushny was incorrect in some of his conclusions, the work catalyzed intensive research activity on the functions of the kidney. A colleague of Cushny, E. Brice Mayrs, made the first attempt to determine the glomerular filtration rate, measuring the clearance of sulfate in rabbits. In 1926, the Danish physiologist Poul Brandt Rehberg demonstrated the superiority of creatinine as a marker for glomerular filtration; the “guinea pig” for the experiment was Rehberg himself.

A pioneer in renal physiology, Homer William Smith, began his research while serving in the United States Army during World War I. Until he retired in 1961, Smith was involved in much of the research related to renal excretion. It was Smith who developed inulin clearance as a measure of the GFR; his later years dealt with studies on mechanisms of solute excretion.

With the newer technology of the late twentieth century, more accurate methods for analysis became available. These have included ultrasound scanning, intravenous pyelography, and angiography. In addition, better understanding of immediate causes of many kidney problems has served to control or prevent some forms of renal failure.

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