If you are not familiar with the anatomy of the male genitourinary tract (bladder, seminal vesicles, testes, prostate, urethra, etc.), consult your text or other diagram. The prostate is located anterior to the rectum at the base of the bladder, and the urethra runs through it. The seminal vesicles are located posterior and superior to the prostate. An enlarged prostate compresses the urethra and results in difficulties in urination (dribbling, hesitancy, feeling of urgency). An enlarged prostate can be palpated upon rectal examination due to the proximity of these two structures. It is difficult to feel the prostate by abdominal exam, since the pubic bone is in the way.

I.               DEFINITIONS

• Azotemia (=uremia): accumulation of nitrogenous wastes (including urea and creatinine) in the blood
• Pyuria: pus in the urine
• Hematuria: blood in the urine
• Cylindruria: a cast of the kidney tubule that is formed by protein and sometimes cells and is found in the urine
• Proteinuria (=albuminuria): protein (chiefly albumin) in the urine
• Oliguria: diminished production of urine (< 400 ml in 24 hours)
• Anuria: no production of urine (< 50 ml in 24 hours). Usually means that the "pipes" are blocked or both kidneys are completely non-functional.
• Polyuria: production of abnormally large amounts of urine (as in diabetes)
• Dysuria: pain during the act of urination

II.             URETHRA AND TESTES

Congenital abnormalities: The development of the genitourinary tract (particularly in the male) is very complicated, and mistakes occur very commonly (~1% of births). In the congenital conditions hypospadias and epispadias, the urethral opening is located at the wrong place on the penis. This problem predisposes to infection, but, fortunately, it can be corrected surgically. During development, the testes descend from the abdomen. Location of testes outside of the abdominal cavity facilitates sperm production, which requires a temperature lower than 37 degrees C. If the testes remain in the abdominal cavity (a condition called cryptorchidism), sterility will result (due to the sperm being immature).

Note: A congenital condition is present at birth and results from errors in normal embryonic development. A hereditary condition is inherited, passed on from generation to generation in the genome, and may develop either early or later in life.

Infections:  In the kidneys and the lower urinary tract (bladder and urethra), the primary protection from infection is the flow of urine. The chief source of infection is bacteria from one’s own colon due to the proximity of the anus and urethra. Normally, the flow of urine will wash the bacteria away and prevent them from ascending up the urinary tract. [It was noted that bacteria from the air will readily grow in urine samples, so urine specimens taken for culture should be sent to the lab immediately or stored in the cold.] If the flow of urine is stopped (due to a kidney stone, cyst, tumor, pregnancy, or enlarged prostate), the patient will be predisposed to infection. Urethritis is considered largely a venereal disease. Its major cause is Chlamydia; gonorrhea and Trichomonas are other common causes (refer to the lecture on infectious diseases). The symptoms include burning upon urination and urethral discharge. If not treated, these infections may spread to the epididymis or to the prostate, causing an acute prostatitis. Prostatitis can also be chronic, but this form often has an autoimmune causation. Infection in the prostate may lead to formation of an abscess, which may extend to involve the rectum as well. Herpes virus infections may cause ulcers on the penis. The primary lesion in syphilis is a painless ulcer on the penis, called a chancre, which is highly infectious. It heals even without treatment. However, untreated primary syphilis will progress to the secondary form of the disease. In the secondary stage, wart-like plaques (condyloma lata) may be seen in the genital area, and systemic, flu-like symptoms may appear. The warty penile lesions caused by papilloma virus are also called condyloma.

Trauma, etc.: Trauma can result in accumulation of blood in the scrotal sac (hematocele), which can be very painful. The veins of the testis can undergo changes similar to those seen in varicose veins of the legs. These dilated veins (varicoceles) have been proposed to cause infertility, but this has been a matter of controversy. Torsion (twisting) of the testis may cut off its blood supply. This is a medical emergency that must be treated promptly to prevent infarction of the testis. The torsion usually occurs in children and is very painful.

Tumors: Tumors may arise from germ cells in the testes of males, just as they arise from germ cells in the ovaries of females. These tumors occur with highest incidence in relatively young men. The most common of these tumors is called a seminoma. Many of these tumors are discovered by the patients themselves.  Young men with cryptorchidism are at increased risk for developing cancer of the testis. Testicular cancers may also occur in young men without this condition. These tumors are often curable if detected early. Treatment is with surgery and chemotherapy.

III.           PROSTATE

Disease of the prostate will eventually affect almost every man who lives long enough. The prostate sits anterior to the rectum, beneath and below the bladder. It surrounds the urethra, so its enlargement may cut of the flow of urine. Enlargement is usually due to one of two causes:

• Benign prostatic hyperplasia: Enlargement of the prostate due to a benign increase in the number of prostate cells occurs in most men above the age of 60 and may be due to hormonal stimulation. The enlarged prostate may compress the urethra, making it hard to release urine from the bladder. There is a constant feeling of needing to urinate (urgency), but there is no force behind the stream of urine, so that it dribbles out. Initiation of flow of urine may be slow (hesitancy). The bladder may become enlarged and hypertrophic. Prostatic hyperplasia is amenable to treatment and does not predispose to development of prostatic cancer. Retrograde flow of urine to the kidney may predispose to infection.

·       Cancer of the prostate: This is the most common cancer in men (except for skin cancer) and the third in terms of fatality rate. It also occurs with greatest frequency in older men. Some instances of prostate cancer can be fairly inconsequential, while others can be very aggressive and kill quickly. We still do not know how to predict these outcomes with any reliability.  Benign prostatic disease usually occurs in the middle of the prostate, whereas malignant prostatic disease tends to occur posteriorly, where the mass can be readily felt by rectal exam. Because of its location, prostatic cancer is less likely to cause problems with urination than is prostatic hyperplasia. A blood test for PSA (prostate-specific antigen) can be used for diagnosis and for following the success of therapy. In advanced disease, the cancer primarily spreads through the seminal vesicles and to the spine and other bones. Pain in the affected bones often occurs at this point. Cancer of the prostate is hard to treat surgically because of the risks of impotence and incontinence. It is often difficult to decide how aggressively to treat this cancer, since the course of the disease can be quite variable. Routine examination is the best way to catch this malignancy early.

IV.           BLADDER

Infections: Cystitis (inflammation of the bladder) occurs more commonly in females of childbearing age due to trauma during intercourse and the relatively short urethra of women. Some people appear to be genetically predisposed to bladder infections: some types of bacteria attach to certain blood group antigens and therefore colonize more readily in people with those antigens. Bladder infections are usually superficial infections that are easily treated with short courses of antibiotics. Symptoms include a feeling of urgency to urinate, burning upon urination, and blood in the urine (which is usually bright red rather than cola-like). Putting anything in the bladder (e.g., a catheter) increases the chance of infection. Untreated lower urinary tract infections can be self-limiting, but they may also become chronic or ascend upward through the ureters, leading to pyelonephritis.

Carcinoma of the bladder: is thought in over 90% of cases to be caused by environmental factors (e.g., chemicals, cigarette smoke). Urine containing carcinogens excreted by the kidney is stored in the bladder. The epithelium lining the bladder thus has prolonged contact with these carcinogens. There is a high incidence of bladder cancer among workers in the aniline dye industry (10%). Carcinomas of the bladder generally grow into the lumen, and the first symptom is usually frank bleeding into the urine. There are two forms: one is very aggressive; the other is a more benign, recurring form. Staging is important for determining therapy.

V.             KIDNEYS

A.  Functions

• Elimination of soluble wastes, such as urea, creatinine, and uric acid, is the principal function. Urea and creatinine are formed by the breakdown of proteins, whereas uric acid is produced by the degradation of nucleic acids.
• Regulation of water excretion (water can also be lost through the GI tract, the skin, and respiration)
• Regulation of salt balance, including sodium, potassium, and chloride. A kidney problem can therefore result in a salt imbalance.
• Regulation of blood pH. The kidney and the lung both play a role in regulating blood pH.
• Detoxification. Many small molecules, including drugs, are reabsorbed or excreted by the kidneys. During processing, these molecules may be changed. If a kidney malfunctions, the drugs may stay in the circulation for a longer period of time. Consequently, it may be necessary to change dosages for patients with kidney disease.
• Production of erythropoietin. The kidney also plays a role in the production of red blood cells by making erythropoietin, a maturation factor for RBCs. If kidney function is lost, anemia may develop due to the lack of this factor. In these cases, patients can be treated with synthetic erythropoietin.
• Regulation of blood pressure: Most hypertension is related to disturbances in renal function. The kidney secretes substances that are important in vasoconstriction (e.g., renin) as well as substances that are important vasodilators. The kidney regulates blood pressure for its own purposes, not for the good of the whole body. If there is a blockage in the filtering units (the glomeruli), not as much filtrate will come out. The kidney then raises the blood pressure to push more blood through the glomeruli. This increase in blood pressure is beneficial to the kidneys but may result in damage to the rest of the body (heart and nervous system). The brain and the kidney are the organs that are most susceptible to damage from loss of blood and decreases in blood pressure. The kidney, however, has more capacity to regenerate than does the brain.
• Regulation of calcium and phosphate metabolism. The kidney also plays a role in regulating bone. First, it controls the excretion of Ca²⁺ (calcium) and PO₄ (phosphate), the building materials of bone. Secondly, the kidney has a role in metabolism of vitamin D, which is also required for proper formation of bone. Vitamin D is taken in from the diet in an incomplete form that is lacking two hydroxyl groups. One hydroxyl group is added in the liver, and the second is added in the kidney. A lack of properly processed vitamin D may result in osteoporosis. The already processed form of vitamin D (called dihydroxy vitamin D) must be administered to patients with chronic kidney disease, since they are incapable of synthesizing it themselves.
• Metabolism of hormones (e.g., insulin)

B. Structure

The functional unit of the kidney is called a nephron. The nephron has two parts, the glomerulus and the tubule. The glomerulus is the filtering unit of the kidney. Blood enters the glomerulus via an arteriole, which branches into capillaries, which then converge to form another arteriole. (This is the only capillary bed in the body to have arterioles on both sides, rather than the more usual arrangement of an arteriole on one side and a venule on the other.) The arterioles can regulate pressure by their capacity to constrict. The filtered waste fluid goes into the tubules. Arterioles adjacent to the tubules can dilate or constrict depending on the composition of the filtrate in the tubule. In the tubules, reabsorption (e.g., of water) and additional excretion of some substances can occur to form concentrated urine.

If tubules are damaged, they can regenerate. In the case of glomerular damage or vessel obstruction, however, glomeruli will not regenerate. Damage to a unit is not always a problem because each healthy person has approximately two million glomeruli, many more than is necessary for normal kidney function. That is why it is possible to donate a kidney and still remain healthy. A person can lose up to 75% of his or her glomeruli and still be OK, because there is lots of reserve. If more than that is lost, permanent dialysis or a kidney transplant are the only solutions.

The kidneys receive 25% of cardiac output ­ they need a lot of energy to do their job. Cardiac disease may therefore lead to acute renal failure due to ischemia. There are several classes of renal syndromes. Acute renal failure may result in production of less than normal amounts of urine (oliguria) or no urine (anuria). The nephrotic and nephritic syndromes are discussed in detail below. Isolated hematuria (blood in the urine) could be due to a tumor in the bladder or kidney or to diseases of the tubules and glomeruli. Lastly, metabolic defects of the tubules may result in failure to excrete or retain certain substances properly.

C.  Infections

• Acute pyelonephritis (inflammation of the kidney): usually results from an infection with one’s own flora that ascends from the lower urinary tract, but less commonly may arise from blood-borne bacteria. Obstructing stones and reflux of urine due to improper functioning of valves in the urinary tract are important risk factors. Diabetes and spinal cord disease affecting bladder contraction are also predisposing factors. Women are more susceptible, since their urethras are shorter and wider and are located closer to the rectum. Pregnancy may compromise the ureters and alter the flow of urine. In addition, the prostate secretes antibacterial substances. Clinical signs include fever, chills, neutrophils in the urine, pain in the flank, and a burning sensation during urination. An infected kidney can become swollen and contain areas of yellow (abscesses containing pus) and red (due to hyperemia). In most cases, a kidney infection is treatable. Some parts are damaged, but a large portion is not involved; therefore, kidney function can be restored. It is difficult to eliminate infections from the kidney, particularly in the medulla, so often an extensive course of antibiotic treatment is necessary.

• Chronic pyelonephritis: If the acute infection is not eliminated, chronic pyelonephritis may occur. This can destroy the kidney (vessels, glomeruli, and tubules), leading to chronic renal failure with all the attendant symptoms. These may include hypertension, discomfort, and anemia (since the kidney makes erythropoietin, which is needed for maturation of RBCs.) The urine may contain bacteria and casts, which are molds of the tubules that result from slow flow of the urine and large amounts of cells and protein in the urine. The kidneys may have stones (which can be a cause or a result of the infection). Eventually (over the course of one to two years), the kidney may become a scarred, non-functional bag of pus. The symptoms of acute infection are striking, and a patient would have to ignore them repeatedly before the kidney reaches this state.

To summarize, infections of the urinary tract are usually progressive: untreated cystitis can spread upward to cause acute pyelonephritis. If this is not treated, chronic pyelonephritis can occur. Cystitis is very common; acute pyelonephritis is not.

D.  Tumors

• Nephroblastoma (Wilms' tumor) is the second most common (after neuroblastoma) solid tumor in children. It occurs most commonly in children less than two years of age and is often detected during well baby exams by palpation. This tumor is responsive to treatment by surgery and chemotherapy, and a complete cure is often possible.
• Renal cell carcinoma:  may grow into the renal vein. Patients have a good prognosis if the tumor is treated before it metastasizes.
• Adenocarcinoma of the kidney: is also called clear cell carcinoma and occurs fairly commonly in adults (most frequently in the late 50’s or older). It may cause hematuria and can be detected by x-ray or by the presence of tumor cells in the urine. It metastasizes readily through the blood to the lung, liver, and bone. Treatment is usually surgical, but the prognosis is poor because symptoms often appear only late in the course of the disease.

E.  Congenital and hereditary diseases

Some babies are born with a horseshoe kidney, a congenital problem in which both kidneys are fused together. Usually, this condition does not cause functional problems. Dysplastic kidney is a congenital problem that often results from obstruction of the ureter in fetal life. Cysts in the kidney form due to lack of proper flow of urine or to various structural defects. This condition may be unilateral or bilateral. It is not hereditary, but rather a developmental problem.

Adult polycystic kidney disease is a common inherited disorder, affecting 1 in 500 people. It is inherited in an autosomal dominant fashion (i.e., it is not sex-linked). It usually manifests itself in one’s late 40’s or early 50’s. It is frequently a cause of chronic renal failure; some 10 to 15% of dialysis patients suffer from adult polycystic disease. The kidneys become greatly enlarged (as much as ten times the normal size) due to formation of numerous cysts. The cysts compress the normal parts of the kidney, destroying them. As the filtration apparatus is destroyed, patients develop hypertension and hematuria. Chronic renal failure may ensue. The condition occurs bilaterally. Hypertension may also lead to cardiac failure. In about one-third of patients, this disease is associated with brain aneurysms called berry aneurysms. Aneurysms and hypertension are not a good combination, and strokes may result. Patients can be treated by clipping off the aneurysms and by using anti-hypertensive drugs.

Simple cysts may form in the kidney with age as a result of dilation of a tubule. These are very common and usually of no consequence, but sometimes they may be mistaken for a tumor.

F.  Glomerular disease

The glomerulus is the only capillary network with arterioles on both sides. Tubules loop around to the incoming arteriole to monitor pressure. If pressure is too low, specialized cells respond by secreting renin, which will constrict the arterioles and increase pressure. In the glomerulus, blood is filtered through a layer of endothelial cells (which line the capillary loops), the underlying basement membrane, and a layer of epithelial cells located on the opposite side of the basement membrane. The endothelial cells that line the capillaries have large separations so that fluid and small molecules can pass through; cells and large molecules cannot. Waste passes into the epithelial-lined urinary space on the other side of the basement membrane. The electrical charge of a molecule is also important; small molecules that are negatively charged will not get through. Even normally, a tiny amount of protein leaks through. However, a major target in renal disease is this filtering apparatus. The normal charge of the filter may be lost or large holes may develop, resulting in "selective" or "nonselective" proteinuria, respectively. If the filtering apparatus is damaged, one of two fundamental patterns of kidney disease, the nephrotic syndrome or the nephritic syndrome, may result.

The six major clinical findings associated with glomerular disease are:

1.     Hematuria

2.     Proteinuria

3.     Azotemia

4.     Oliguria

5.     Hypertension

6.     Edema

Nephrotic syndrome: In the nephrotic syndrome, the glomerular filtering apparatus is sufficiently leaky (due to damage) to allow large molecules to pass through into the urine, resulting in proteinuria. Albumin and other proteins may be lost through excretion faster than the liver can replace them. When the amount of albumin the blood decreases, so does the oncotic pressure. As a result, fluid that leaks out from the capillary bed into the tissues is not reabsorbed properly: the blood has too little protein to "draw" the fluid back in. Consequently, edema will develop. In congestive heart failure, edema tends to develop in areas where pressure is lowest (e.g., feet and legs). In kidney failure, the lack of protein in the blood is everywhere, so the edema tends to be more generalized. This type of generalized edema, which includes the face, is called anasarca. Damage to the tubule, rather than the glomerulus, seldom results in enough leakage of protein to cause edema.

To summarize, the nephrotic syndrome is characterized by proteinuria and edema. Azotemia is not seen, since the problem is too much filtration. Therefore, nitrogenous wastes do not build up. Due to complex metabolic changes, hyperlipidemia and lipiduria may also be part of the nephrotic syndrome.

Nephritic syndrome: In the nephritic syndrome, the glomerulus is clogged, resulting in decreased filtration. The urine volume falls (oliguria), and the patient retains salt, water, and nitrogenous wastes (azotemia). There are three principle nitrogenous waste products that are found in high levels in the blood in azotemia: urea and creatinine, which are formed from breakdown of proteins, and uric acid, formed from RNA and DNA. When the filter is blocked, the kidney tries to increase filtration by raising the blood pressure to force more fluid through the capillary network, so with nephritic disease hypertension is frequently seen. Eventually, holes may be produced in the basement membrane that are large enough to let red blood cells through, resulting in hematuria. The hematuria is usually not massive (because not much blood is getting through), resulting in a "Coca-Cola" rather than a bright red appearance. Hematuria is more characteristic of nephritic than nephrotic diseases. Despite the holes in the basement membrane, proteinuria is usually not as marked in the nephritic syndrome as in the nephrotic, since the filter is usually so clogged that not much blood flows through. Edema is usually not seen in the nephritic syndrome.

To summarize, then, the main characteristics of the nephritic syndrome are azotemia, oliguria, hypertension, and hematuria.

Note: The nephrotic and nephritic syndromes are not always completely distinct entities. A single patient may commonly display elements of both, but the degree of each that is present helps greatly in dagnosis.

Nephritic syndrome diseases:

Important point: Most nephritic disease is immune-mediated and affects the glomeruli. It occurs when antigen-antibody complexes get trapped in the filter of the glomerulus. The complement system is activated and C5a is released, which attracts neutrophils. The neutrophils attempt to eat the immune complexes by the process of frustrated phagocytosis, and, in so doing, release substances that damage the glomerular basement membrane. (This should all sound very familiar ­ if not, review the immunology and inflammation lectures. Also recall that this is a Type III hypersensitivity reaction). Fluorescent probes that can be used for microscopic detection of antibodies are useful in diagnosis.

Examples of diseases that are dominated by the nephritic syndrome include:

·       Acute (poststreptococcal) glomerulonephritis: Usually occurs in children, since they are most likely to get strep throats. If they are not treated, children with strep throats caused by Group A, b-hemolytic strains raise antibodies to the bacteria, and immune complexes that result may get stuck in the glomerulus. The scenario described above then ensues in about 1-3% of cases, usually about two weeks after the strep throat. Children with this disease get hypertensive, have blood in the urine, and become azotemic. Luckily, 95% will recover completely, but 5% may progress to chronic renal disease. Note that this disease does not involve infection of the kidney itself with strep; it is the antigen-antibody complexes that are causing the damage. Although strep throats will usually resolve on their own, it is imperative to treat them quickly to prevent antibodies from forming. If antibodies are not produced, both poststreptococcal glomerulonephritis and rheumatic fever (see the cardiovascular system lecture) will be prevented.

·       IgA nephropathy (Berger disease): is the most common primary renal disease in most of the US and world. It tends to affect young adults. This also tends to be a focal rather than generalized disease, tends to follow upper respiratory infections, and is caused by immune complexes. In a kidney biopsy, the predominant immunoglobulin seen deposited is IgA. The disease results in a nephritic picture, often with a lot of blood in the urine, but it often presents with nephrotic elements as well. Occasionally, some systemic symptoms, such as a rash, may occur when IgA activates complement in skin vessels. The kidneys may become swollen and have focal hemorrhages (petechiae or "flea bites") due to damage to the basement membranes, although petechiae are not as common as in rapidly progressive glomerulonephritis.  (Note: such hemorrhages may also occur due to hypertension.) From 25% to 50% of patients will slowly progress to chronic renal failure over the course of 20 years.

·       Rapidly progressive glomerulonephritis: is characterized by severe and rapid destruction of the glomeruli, not just inflammation. If left untreated, this condition may lead to complete renal failure within weeks to months. "Flea-bite" hemorrhages are often seen in the affected kidneys. There are several forms of this disease, all of which lead a similar outcome. The cause(s) are not entirely known, but are thought to be immunological in origin. This disease is a medical emergency. Rapid treatment is a must; therapies include steroids, immunosuppressive drugs, and plasmapheresis to remove antibodies from the blood.

Nephrotic syndrome diseases:

In general, symptoms of kidney diseases characterized by the nephrotic syndrome include anorexia, fatigue, and a general lousy feeling (malaise). Protein loss may cause white bands to develop across the fingernails. Of course, proteinuria is seen, as well as edema in the tissues and pleural and abdominal cavities. The nephrotic syndrome may occur in many conditions, including primary kidney disease or secondary to metabolic diseases (e.g., diabetes), lupus, sickle cell anemia, drugs (e.g., gold therapy for rheumatoid arthritis), allergies, infections, pre-eclampsia, or eclampsia. Examples of some primary nephrotic kidney diseases, listed from least to most severe, include:

·       Lipoid nephrosis: occurs mainly in children (2 to 6 years old) and, indeed, is the most common kidney disease of childhood.  It occurs when the epithelial layer of the glomerulus becomes very leaky, perhaps due to factors secreted by lymphocytes.  Although lymphocytes may cause the disease, they do not accumulate in the kidney, and there is no inflammation.  Large amounts of albumin are lost in the urine.  The liver, in its attempt to compensate for the decrease in albumin, produces excessive amounts of lipid products.  Some of this lipid accumulates in the kidney tubules, hence the name "lipoid nephrosis."  When viewed in the light microscope, specimens from kidneys of patients with this disease look essentially normal (leading the condition to sometimes be called nil disease), but the functional alterations are great.  This disease responds well to treatment with steroids or may regress on its own.

·       Membranous glomerulonephropathy: usually occurs in adults. It is an immunological disease that results when immune complexes damage the cells that make the glomerular basement membrane. The basement membrane gets leaky, resulting in a nephrotic syndrome. (Note that although both poststreptococcal glomerulonephritis and membranous glomerulonephropathy are caused by immune complexes, the immune complexes have different pathogenic effects in the two diseases.) Immunofluorescent microscopy can be used to detect the presence of immune complexes in this disease, and electron microscopy can be used to view the damage to the basement membrane.

·       Focal segmental sclerosis (focal glomerulonephritis): usually occurs in adults and is so named because initially only a portion of glomeruli, rather than all, is involved. There are many causes, and it is very commonly seen in patients with AIDS. It can also occur in conjunction with systemic lupus erythematosus, IV drug abuse, obesity, and many other conditions. However, perhaps the largest percentage of cases has no known cause (i.e., they are idiopathic).  The frequency of this disease is increasing and may soon surpass that of IgA nephropathy. This illness may lead eventually to chronic renal failure.

G.  Vascular disease

Infarcts: usually, infarcts in the kidney have little consequence due to the great amount of reserve function.

Hypertension: As we have learned, the kidney may cause hypertension. However, it (along with the brain) is also a major target of damage due to hypertension. In fact, because hypertension is so common, it is probably the most common cause of renal disease. There are two types of hypertension, benign and malignant. Benign (also called essential) hypertension is the most common form (~95% of cases) and involves chronic and modest elevations in pressure. This chronic elevation can cause arterioles in the kidney to thicken in an attempt to cope with the increased pressure. This thickening may reduce blood flow through the kidney. The kidney may shrink, display granular bumps on its surface due to scarring, and have fat at the hilum. The damage to the kidney may progress to the point where dialysis is required, but it is important to remember that this is a preventable condition in most cases. Benign hypertension may also lead to hypertrophy of the heart, retinopathy, and strokes.

Approximately 5% of patients with hypertension have the malignant form. It can occur by itself or superimposed on benign hypertension. Malignant hypertension is more acute than benign and involves more severe rises in pressure. These very high pressures can cause hemorrhages from the kidney arterioles (which do not have time to adapt by thickening), as well as from vessels in the brain, eyes, and elsewhere. In malignant hypertension, the kidney is normally sized and has a large number of small, dark discolorations ("flea-bites" or petechiae) on the surface, which result from hemorrhages from the damaged vessels. Areas of the kidney may become necrotic. Patients with malignant hypertension are prone to heart failure, and the condition may rapidly lead to renal failure.  Malignant hypertension is a medical emergency.

H.  Miscellaneous kidney conditions

Systemic diseases: can result in damage to the kidney. Diabetes is just one example. Fluctuations in blood glucose levels can damage basement membranes; blood vessels in glomeruli are a major target (see the lecture on the endocrine system). Since diabetes is so common, it is the most frequent underlying cause of renal disease leading to dialysis. Patients with renal disease due to diabetes usually present with nephrotic syndrome, at least initially. Another example is the autoimmune disorder systemic lupus erythematosus. Immune complexes that form in this disease may deposit in the kidney and lead to damage.

Tubulointerstitial diseases and acute renal failure: involve the kidney tubules and the spaces between them. Diffuse interstitial nephritis is quite common and is often caused by drugs (such as streptomycin) or toxins. These may injure tubular cells directly during their excretion. Also, allergic reaction to drugs can result in this condition. As a drug is cleared, the kidneys may change it into a form that can cause an allergic reaction. In essence, the kidneys have formed the antigen. Antibodies are formed that react with the antigen, and T cells and eosinophils may infiltrate the tissue. If administration of the drug is halted, the patient will get better. Urine of patients who are receiving drugs known to cause this condition should be monitored carefully. The kidneys may appear a little swollen and nodular, but the body does not become edematous.

The most common causes of acute renal failure are shock (which may be due to blood loss or sepsis), trauma, and toxins (e.g., mercury, antifreeze). When the kidney stops functioning acutely, two major problems occur. First, water is retained, and a patient can literally drown in his or her own secretions. Secondly, the finely balanced regulation of potassium in the body is perturbed, which can lead to stoppage of the heart. Most cases of acute renal failure result from damage to the tubules (acute tubular necrosis). However, tubules, unlike glomeruli, can regenerate. Therefore, if a patient in acute renal failure can be maintained on dialysis for a week or two to regulate water and potassium excretion, kidney function may return.

I.  End-stage renal disease

The end-stage of either nephritic or nephrotic diseases may be chronic renal failure. In chronic renal failure, the worst problem is the build-up of nitrogenous wastes in the blood (azotemia) to the point where clinical signs appear (uremia). Uric acid crystals may deposit on the tongue or eyelids. The GI tract may malfunction (constipation or diarrhea, nausea and vomiting). The neuromuscular system may be affected, causing muscle tetany and weakness (due to calcium dysregulation), headache, delirium, convulsions, or even coma. The cardiovascular system also may be involved (pericarditis, anemia, hypertension). The retina of the eyes may be damaged by accumulation of wastes and/or hypertension. Skin rashes and pulmonary edema may be seen. Casts, cells, and protein may be present in the urine. The patient may give off an odor of urine in the body secretions as well.

The causes of chronic renal failure are multiple. Some cases are due to primary renal disease, which can affect the glomeruli, the tubules, or the vascular system of the kidney (e.g., infarction, atherosclerosis, embolus). Infection or obstruction in the kidney may also lead to chronic failure. Chronic renal failure also may occur secondary to diseases in other organs or in systemic disease such as lupus. Metabolic diseases (a good example being diabetes) may also damage the kidneys, as may certain genetic diseases. The course of chronic renal failure is often long, stretching over the course of years.

Once damage to the kidney reaches a certain point, the loss of function tends to be progressive and difficult to treat. Treatment needs to be started as early in the course of the disease as possible. Often, dialysis or transplants become the only options.

J.  Kidney transplantation

Kidneys may be transplanted from cadavers or from living donors (since there is a lot of kidney function to spare). Transplanted kidneys may be rejected by one or more of several processes. Hyperacute rejection (fortunately uncommon) occurs when preformed antibodies in the recipient attack the transplanted organ as soon as it is connected. Antibodies attack the endothelium, and the vessels of the transplanted kidney become occluded. Acute rejection may result if the recipient has T lymphocytes that are sensitized to antigens on the transplanted organ. These lymphocytes may infiltrate into the donated kidney and destroy it over a period of weeks to months. Acute rejection may be prevented with drugs such as cyclosporin or corticosteroids. Chronic rejection is due to production of antibodies and sensitization of lymphocytes long after the time of transplantation. The donated kidney atrophies and appears pale and small. It is difficult to treat and may require a second transplant.

For the greatest chance of success, the transplanted organ must match the recipient with respect to both ABO blood group and major histocompatibility (MHC) antigens (see the immunology lecture if you’ve forgotten what the MHC is!). The success of transplants is generally better in Europe than in the US, because the populations are more homogeneous. It is more difficult to find good matches in a country where there is a diverse ethnic and genetic mix. Imperfect matches mean that the recipient must be on immunosuppressive drugs chronically, and these drugs carry their own risks (such as increased risk of infection).

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