The Kidney

The kidneys are very important organs within the human body. They guard blood volume, filter the blood and form urine, regulate water, electrolyte and acid base balance, produce some small hormones and participate in the metabolism of others. At rest, an estimated 20% of cardiac output (~1000ml/minute) flows through the kidneys where it is filtered and reconditioned.
The kidneys have a major role in maintaining an internal environment that is compatible with life. These small organs must keep fluids, minerals (such as calcium and magnesium), and electrolytes (such as sodium and potassium) in balance while excreting waste products in the urine. One of the main tasks is to keep an appropriate amount of water in the body. Approximately 50-70% of body weight is attributed to water. The water is distributed between two compartments, that which is inside the cells (~2/3rds) and that which is outside the cells (~1/3rd). The water outside of the cells is further divided between the blood and tissues . Tissue fluid and blood plasma contain about the same electrolyte composition but plasma contains a large amount of protein. All of these compartments are in balance with each other, so that changes in one eventually causes changes in the others. Abnormalities in fluid distribution (such as edema) are associated with some common diseases and diuretics are used to help correct these imbalances.

Anatomy
The kidneys are located at the back of the abdominal cavity, one on each side of the spinal column with the top of each being at about the 12th thoracic vertebral level. The right kidney is slightly lower than the left. Each kidney weighs about 113 to 170 gm and is about 11.4 cm long, about 6 cm wide, and 2.5 cm thick.
Each kidney is shaped like a kidney bean with the concave border facing the midline. The center of concave border is called the hillus. The ureter, blood vessels and nerves enter the kidney via the hillus. This expanded region of the ureter is called the renal pelvis. The interior portion of the kidney structure is called the renal medulla which is surrounded by a layer called the renal cortex. The regions are anatomically and functionally differentiated.
The renal cortex contains blood vessels, connective tissue, convoluted tubules, and glomerular capsules. The latter two structures are portions of the functional units of the urine formation, the nephrons. The medullary region contains collecting ducts, lymphatic ducts, and blood vessels that are organized into 8 to 18 conical structures called renal pyramids which project into extensions of the renal pelvis called calyces.
The nephron is the structural and functional unit in kidney function. A nephron consists of a glomerular capsule, proximal convoluted tubule, loop of Henle, and distal convoluted tubule which leads to a collecting duct. The capsule consist of a thin endothelial (simple squamous) layer surrounding a tuft of capillaries (glomerulus) and a contiguous layer of endothelial cells that form the remainder of the capsule and lead into the proximal convoluted segment.
The proximal convoluted segment is made of simple cuboidal cells with microvilli on their luminal surface. The proximal convoluted segment connects to the loop of Henle which consists of a descending segment, a thin segment of varying length, and an ascending segment. The loop descends into the medulla and then does a hairpin turn to return to the cortex where the nephron continues as a distal convoluted segment. This segment is composed of simple cuboidal cells with fewer microvilli than those in the proximal convoluted segment.
In the cortex, the distal convoluted segment comes in contact with the glomerular blood supply in an adaptation called the macula densa, part of the juxtaglomerular apparatus. The endothelium of the tubule becomes more dense and columnar and is in close apposition to specialized cells of the afferent arteriole. The juxtaglomerlular apparatus is involved in regulating glomerlular filtration rate, systemic blood pressure and thirst via the renin-angiotensin system and the formation of red blood cells via the production of the hormone erythropoietin.
Two or more distal convoluted segments empty into a collecting duct, lined with simple cuboidal cells, that descends into a medullary pyramid and empties into a calyx of the renal pelvis. From there urine travels into the renal pelvis to the ureter to the bladder and then out through the urethra.
Blood enters the kidney via the renal artery at the hillus. The renal artery branches to feed segments of the kidney then branches again to form interlobar arteries. At the interface of the cortex and medulla interlobar arteries become arcurate arteries that further branch to form interlobular arteries. The afferent arteriolar supply to the glomeruli arise from these interlobular arteries. After blood passes through the glomerulus it leaves via the efferent arteriole and then enters a capillary network (peritubular capillaries) that surrounds the proximal and convoluted tubules of the nephron. In the medulla, the peritubular network is extended to include capillaries (vasa recta) in close contact with the loop of Henle. Blood leaves the kidney by following the interlobular veins to the arcuate veins to the interlobular veins that join to form the renal vein which empties into the vena cava.
Nervous supply to the kidney is largely from the sympathetic portion of the autonomic system. When stimulated, the sympathetic input causes vasoconstriction at the afferent arterioles.

Formation of Urine
Blood entering the glomerulus is filtered through the capillary cell membranes, a thin basal lamina and the thin membrane of the visceral layer of Bowman's capsule. Blood pressure drives filtration with some local control given by constriction of the afferent or efferent arterioles. The basal lamina between the endothelial layers acts as a filter paper and has a negative charge that helps to repel the plasma proteins. Water, small molecules (glucose, amino acids, urea), electrolytes (sodium, chloride, potassium) some small proteins are freely filtered at the glomerulus while blood cells and large plasma proteins (larger than ~70,000 MW) are retained in the blood stream. The resultant ultrafiltrate in the nephron is altered by the processes of secretion and reabsorption before exiting the kidney.
In the proximal convoluted tubule all the glucose and amino acids are recovered by active transport across the tubular epithelium. Sodium and potassium are also actively reabsorbed. In fact, about 2/3 of that filtered is reabsorbed in the proximal convoluted tubule and water follows along. Negative ions, such as bicarbonate, are passively reabsorbed. Chloride is actively transported out of the filtrate in the loop of Henle (thick segment). Large molecules are reclaimed by pinocytosis and some toxic or foreign chemicals are secreted either actively or passively. For instance, antibiotics, such as penicillin, are secreted into the ultrafiltrate across the tubular membrane.
In the distal convoluted tubule the movement of sodium, potassium and hydrogen ions are actively transported by a carrier mediated mechanism under the control of aldosterone. To maintain electrical neutrality, potassium or hydrogen are secreted into the tubule in exchange for sodium. Aldosterone stimulates sodium reabsorption in the distal convoluted tubule and collecting ducts, intestine and salivary glands, but is really more important in the long term control of blood potassium levels. If potassium is excreted in excess, then hypokalemia, manifested by muscle weakness and possibly heart fibrillation, may result. The ions themselves (in addition to ACTH) regulate aldosterone secretion; increased blood potassium or decreased blood sodium levels stimulate the secretion of aldosterone from the adrenal cortex.
As the filtrate leaves the distal convoluted tubule it is reduced in volume but isotonic to hypotonic. In the presence of antidiuretic hormone (ADH), the distal convoluted tubule and collecting duct are permeable to water and the urine becomes hypertonic as it passes through the medulla. Eighty percent of the water filtered at the glomerulus must be reabsorbed (obligatory water) during passage through the nephron. The remaining 20% (facultative water) may or may not be resorbed dependent on the hydration state of the animal. In dehydration, low blood volume (volume receptors) and hypertonicity of the blood (sensed via brain osmoreceptors) work together to return things to normal.
Diuresis is the production and passage of large amounts of urine. Osmolar diuresis is caused by a resorbable or nonresorbable solute in the tubular fluid. For instance, in diabetes mellitus the tubular active transport mechanism for glucose may be exceeded such that glucose remains in the tubular lumen drawing water with it. This accounts for the increased urine volume seen in untreated diabetes mellitus. Diabetes insipidis occurs when ADH is lacking and facultative water is lost.
Urine is normally amber or straw colored, can have a pH of 4.6 to 8 (although it is normally acidic), contains less than 0.1 gm or protein, and contains less than 0.3 gm of glucose. In 24 hours, 600 to 2500 ml may be voided.

Urination or Micturation
Urine collects in the renal pelvis and then flows with the assistance of peristaltic contractions of the ureter to the bladder. When there is 150-300 ml of urine in the bladder, stretch receptors become active and a spinal reflex to void the bladder is initiated. Increased filling causes increased pressure and a further increase in the frequency of the reflex. Higher brain centers can override the urgency to urinate for a time or actually facilitate it. Eventually the micturation reflex is initiated and the internal bladder sphincter relaxes and the detrusor muscle of the bladder contracts to expel the urine via the urethra. The female urethra is about 9.5 cm long and the male urethra is some 20 cm long.

Abnormal Renal Function
Disease of the kidney is manifest by various symptoms such as edema, lumbar pain, fever, alterations in urination, urinary blood or pus, change in size of the kidney or tenderness and swelling in the region. Kidneys are examined by palpation, cystoscopy or endoscopy. Kidney function is evaluated by clearance tests and urinalysis.

Glomerular Disease
Chronic renal failure is most commonly caused by damage to the glomerulus, usually by immunologic attack. Immunoglobulins may attack the basement membrane between the glomerulus and Bowman's capsule or damage may be caused by the precipitation of immune complexes in the glomeruli. However, chemicals, radiation or lack of oxygen may also cause glomerular damage. Some types of glomerular nephritis occur following a bacterial, viral or parasitic infection. Blood and mild proteinuria (protein in the urine) are seen in the urine and some degree of peripheral edema and hypertension are frequently first signs. In children, acute forms result in mortality only in 1% of cases and rarely is there any permanent damage to the kidneys. In adults, the incidence is lower and some 25-50% of patients develop chronic renal disease.

Interstitial Disease
Renal tubular disorders may arise from infections, toxins, metabolic imbalances or immunologic attack. Metabolic acidosis, loss of sodium, potassium, chloride and water occur as the kidney looses its concentrating ability. Drugs such as certain antibiotics, aspirin and diuretics are the most common offenders. If the drugs are discontinued renal function will usually return to normal. Excesses of uric acid, as seen in gout, can accumulate in the renal tubules as crystals causing obstruction and inflammation of the distal tubules and collecting ducts. Calcium in high concentration may also cause interstitial disease by accumulating as stones that obstruct the tubules.

Infections
Culture of specific disease causing organisms is necessary to diagnose and treat infections of the urinary tract. E. coli is the most common offender but others including Staphylococcus may be the culprit. Cystitis, or inflammation of the bladder is more common in women than men, which makes sense as the urethra is much shorter in women so that the bacteria have less distance to cover. Sexual intercourse, trauma or poor hygiene allow the bacteria to gain a foothold in the bladder. Kidney disease, pregnancy, diabetes mellitus and intercourse are all risk factors for the development of a bladder infection. Urinary frequency, urgency, difficulty and pain just above the pubic area are all symptoms of urinary tract infections.
More severe is polynephritis, which occurs when the invading organisms manage to reach the renal pelvis and kidney causing inflammation. Fever, chills, nausea, vomiting, and diarrhea signal such an infection. The infection usually results in the formation of cortical scar tissue. In chronic forms, damage and atrophy of nephrons causes a diminution of function resulting in chronic renal failure. Protein is found in the urine along with white blood cells.

Stones
Kidney stones, also called renal calculi, are crystalline accumulations present in the pelvis of the kidney. They are usually composed of oxalates, phosphates, uric acid, and carbonates ranging in size from small granules to perhaps 2.5 cm in diameter. Sometimes, usually with uric acid stones, the calculi will fill the renal pelvis and is termed a staghorn calculi. Excessive (megadosing) vitamin C can contribute to the formation of stones. Dehydration contributes to stone formation because of the saturation of certain substances in the urine. Crystals form and grow into stones. Blood may be seen in the urine due to the physical damage caused by the stone and intense pain that radiates from the back to the abdomen and groin may occur when the stone is passed.

Renal Failure
Renal failure, the inability of the kidneys to excrete waste products, occurs for various reasons and maybe acute or chronic in nature. Causes include surgery or trauma, pregnancy, various medical conditions, nephrotoxins, or irreversible conditions that diminish nephron function.
Acute renal failure is most often due to a reduced blood volume or perfusion of the kidney. Infections, vascular disease, or damage to renal tissues may cause acute renal failure. Factors outside the kidney, such as obstruction, stones, prostatic hypertrophy and tumors may also cause acute renal failure. Local lack of oxygen due to a lack of blood flow and toxic effects of various agents (including antibiotics) are the most common cause of damage to the nephrons. Heavy metals, solvents and pigments are also toxic to nephrons. Dependent on the cause, severity and medical treatment, 30 to 60% of acute renal failure patients will recover.
Chronic renal failure is irreversible and has at its end, end-stage renal disease and dialysis. Nephrons and glomeruli are damaged so that kidney function is diminished. A decrease in the number of normally functioning nephrons leads to fluid, sodium, potassium, acid-base imbalances as well as an increase in blood urea nitrogen.

Acid-Base Balance
pH is a measure of the acidity of a substance. The normal pH of the blood is between 7.38 and 7.42. The blood must be kept within a narrow pH range (approximately 6.8 to 7.8) in order to be compatible with life. Uncontrolled pH can result in death.
The human body produces a large amount of acid as a result of metabolic processes and from dietary substances. The blood has a buffering capability that is able to prevent wide fluctuations under normal conditions. The lungs also contribute to maintaining pH balance by their ability to expire carbon dioxide, a respiratory acid. The lungs can rapidly respond to changes in pH by increasing or decreasing the rate of respiration. The kidney, however, must ultimately excrete the extra acid that is present and retain basic bicarbonate in the body.
There are four basic classes of pH disturbances that can occur. The first two have respiratory (lung) causes and the other two have metabolic causes. Respiratory acidosis occurs when respirations are impaired, for example with lung disease, sedative overdose or airway obstruction. Because the respiratory acid, carbon dioxide, cannot be exhaled, it is retained resulting in acidosis of respiratory origin. When respiratory acidosis occurs the kidneys compensate by retaining basic bicarbonate.
Respiratory alkalosis can occur when traveling to high altitudes, or with hyperventilation. In these cases, rapid respirations causes excess carbon dioxide to be removed from the body resulting in alkalosis of respiratory origin. The kidneys compensate by excreting more basic bicarbonate in the urine.
Metabolic acidosis often occurs in uncontrolled diabetes when acidic ketones are formed. Due to the inability to use glucose as an energy source, abnormal amounts of fat are broken down resulting in the formation of ketones. Metabolic acidosis can also occur with retention of acids that occurs in kidney failure or with severe diarrhea . In metabolic acidosis, the lungs attempt to compensate by increasing ventilation, thereby removing the respiratory acid carbon dioxide.
Metabolic alkalosis occurs when large amounts of gastric acid are lost during vomiting or via nasogastric drainage. It can also occur with diuretic use. In these cases, the lungs attempt to compensate by decreasing ventilation, causing the respiratory acid carbon dioxide to increase.
In some cases, compensation by the lungs or kidneys is adequate to bring the pH imbalance under control, but in many cases treatment of the underlying medical condition is necessary. For example, in diabetic ketoacidosis elevated blood glucose levels are treated with insulin , fluids lost through excessive urination are replaced, electrolyte imbalances are corrected and the cause of the acidosis such as an infection is treated. In acidosis associated with kidney failure, dialysis may be required, whereas in respiratory acidosis, mechanical ventilation may be needed.

Thirst Mechanism
Thirst is initiated by dry mouth, ingestion of dry food, an increase in plasma osmolarity (concentration) or a decrease in extracellular fluid volume, as in dehydration or blood loss. Receptors in the hypothalamus that sense the osmolarity (osmoreceptors) of the body fluids detect an increase in osmolarity and cause the release of antidiuretic hormone (ADH). A loss of 10% of plasma volume leads to stimulation of thirst and the release of ADH. This posterior pituitary hormone causes the distal convoluted tubules and collecting ducts to become more permeable to water so that more water is resorbed and a more concentated urine is produced.
Hemorrage or low blood volume (hypovolemia) can cause thirst independent of the osmolarity of blood. Low blood volume is sensed by volume receptors at the heart and blood pressure receptors (baroreceptors) of the large arteries (aorta and carotid) as well as at the level of the nephron. The cells of the distal convoluted tubule and afferent arteriole of a nephron are in close contact and are modified to a structure called the macula densa. This structure acts to compare what comes into the glomerulus in the blood to what is leaving via distal convoluted tubule. Modified smooth muscle cells of the afferent arteriole make the enzyme renin and the hormone erythropoietin which stimulates the production of more red blood cells in cases of anoxia (lack of oxygen).
Renin is a part of the renin-angiotensin system. The precursor angiotensinogen is a glycoprotein produced by the liver . When acted upon by renin, it is converted to the decapeptide angiotensin I. An enzyme in the lung called converting enzyme changes it to the octapeptide angiotensin II which is a potent vasoconstrictor. In cases of low blood volume, say due to hemorrage, vasoconstriction makes for a better use of what blood remains and helps to limit further blood loss. Vasoconstriction causes an increased peripheral resistance which increases blood pressure in an effort to see that the brain and vital organs receive necessary blood flow. The renin-angiotensin system is also important to localized control of glomerular filtration rate. Angiotensisn II participates to increase blood volume by stimulating aldosterone secretion and by stimulating thirst.

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