Urinary system

The urinary system consists of the kidneys, ureters, bladder, and urethra. The many purposes of the urinary system include:- regulates blood volume and blood pressure, control levels of electrolytes and metabolites, regulate blood pH ( acid-base balance), and waste removal from the body.

 

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Structure of the Urinary system

1. Human urinary system: 2. Kidney, 3. Renal pelvis, 4. Ureter, 5. Urinary bladder, 6. Urethra. (Left side with frontal section)
7. Adrenal gland

Vessels: 8. Renal artery and vein, 9. Inferior vena cava, 10. Abdominal aorta, 11. Common iliac artery and vein

Transparent: 12. Liver, 13. Large intestine, 14. Pelvis

Reference:- https://en.wikipedia.org/wiki/Urinary_system

 

The kidney serves as part of the homeostasis of the whole body. It regulates acid and bases in the body as well as the electrolyte concentration. It also regulates blood pressure. In specific terms, the kidney excretes metabolism products that include the nitrogenous wastes known as urea. The urea is removed from catabolism, uric acid, and nucleic acid. The kidney also helps in the reabsorption of the vital molecules required by the body. These include glucose, water, among others.

The human body is adapted to remove waste in the following ways. The first is exhalation that removes carbon dioxide from the body through the lungs. The skin regulates salt in the body and removes wastes from the body through sweating. The skins also remove dead skin. The kidneys also remove urea from the body.

 

The kidneys are situated behind the peritoneum on the back of the abdominal wall. The renal arteries supply the kidney with blood to be filtered and toxic substances to be removed in the urine. Each kidney has a renal pelvis that causes urine to drain into the ureters. Ureters in adults are 25-30 cm in length. Ureters are made of smooth muscle, when there is a smooth muscle contraction, causing urine to be pushed down the ureters into the bladder. The capacity for a full adult bladder is half a liter or two cups

 

Males and females have a fundamental difference in their urethra. A female urethra is narrow and 4 cm in length. The urethra starts at the bladder neck and finishes at the external urethral orifice in the vestibule of the vagina.

A male urethra is 17.5 – 20cm in length. The three sections of the urethra are:- prostatic urethra (the widest portion), membranous urethra (the narrowest part), and the spongy urethra (the longest portion).  Males urethra has a dual purpose of urine and semen to be expelled out of the body. The urethra starts at the bladder neck through the prostate and finishes at the external urethral orifice of the penis.

 

Urine production in a healthy adult is between 1 – 2 litres a day. Factors that can manipulate this can be due to hydration, activity level, environmental factors, weight, and general well-being.

Medical consideration should be taken if:-

Polyuria excess production of (> 2.5 L/day)

Oliguria when < 400 mL per day

Anuria when < 100 mL per day.

 

Cardiac output of between 12 to 30% is received by the kidney; on average, the kidney receives 20% equivalent to 1.25L/min

The nephron is the main functional components of the kidney. It is located within the kidney. Its primary function is to regulate the concentration of the sodium salts and water filtered from the blood. It reabsorbs the vital molecules in the process of filtration of the blood in the kidney. It also excretes and eliminates waste from the body. It is allowing for the regulation of blood pressure and volume. Bowman’s capsule is the first part of the nephron; blood is taken from the circulatory system and filtered. Filtration can include water, small molecules, and ions that can move freely through the filtration membrane. The filtration membrane stops large molecules such as protein and blood cells from crossing the barrier. Urination in healthy humans is of voluntary control. As the body ages or with neurological injury, urination becomes an involuntary reflex. Coordination between the central, autonomic, and somatic nervous systems for physical ability to urinate.

 

The function of the urinary system is influenced by the circulatory, nervous, and endocrine systems. The endocrine system affects the urinary system’s regulationby releasing hormones such as aldosterone, vasopressin, and parathyroid hormone.

 

Aldosterone

Alderstone is a steroid hormone, one of the main mineralocorticoid hormones. The zona glomerulosa cells allow for the production, instructed by the adrenal cortex, located in the adrenal glands. Aldosterone is responsible for conserving sodium in the kidneys, salivary glands, sweat glands, and colon. It is responsible for homeostasis regulation of blood pressure, plasma sodium (Na+), and potassium (K+) levels. Potassium excretion and reabsorption of sodium on the kidneys are influenced by aldosterone. With an indirect influence on water retention /loss, blood pressure, and blood volume.

 

Vasopressin

Vasopressin is also known as antidiuretic hormone (ADH), arginine vasopressin (AVP), or argipressin. The hypothalamus produces vasopressin. The nephrons of the kidneys require the vasopressin to be released to increase the amount of solute free water available for circulation. As it causes reabsorption of water, this causes a reduction in urine output and urine concentration. It is responsible for raising arterial blood pressure by constricting arterioles, causing an increase in peripheral vascular pressure.

 

Parathyroid hormone

Parathyroid hormone (PTH) is also parathormone or parathyrin. The parathyroid gland produces parathyroid hormone, and the parathyroid chief cells are responsible for the production of the hormone. PTH is responsible for regulating serum calcium through the body, including bone, kidneys, and intestines.

 

In the bones, PTH stimulates the release of calcium from the reserves within the bone. As bone resorption occurs, osteoclasts to start rebuilding the bone. As this happens, PTH binds to the osteoblasts as they rebuild the bone.

 

In the kidneys, calcium ions are influenced for reabsorption of calcium ions in the distal tubules and renal collection ducts. PTH stops the phosphate (HPO42) reabsorption from the tubular fluid, therefore creating a reduction in the plasma phosphate concentration. Activated Vitamin D stimulated calcium to be uptaken from the intestines.

 

From the kidneys, absorption of calcium from the intestines is improved by PTH and increasing the production of active Vitamin D. The process of creating activated Vitamin D occurs in the kidneys.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

The function of the Urinary system

Urinary system main functions include:-

  • Regulate blood volume and compositions (i.e. sodium, potassium, and calcium)
  • Regulate pH homeostasis of the blood
  • Contributes to the production of red blood cells by the kidneys
  • Store waste products ( urea and uric acid ) before it and other products are removed from the body.

 

The kidney is responsible for the production of hormones, including

  • Renin
  • Erythropoietin
  • Calcitriol
  • Thrombopoietin

 

Erythropoietin (EPO)

The kidneys produce Erythropoietin (EPO) as a response to hypoxia at the cellular level. This allows for red blood cell production from the bone marrow to occur through erythropoiesis. Kidney and liver produce Erythropoietin throughout the lifespan of a human. The liver is responsible through the fetal and perinatal period; throughout adulthood, the kidney continues the production.

 

Thrombopoietin (THPO)

Thrombopoietin (THPO) is known as a megakaryocyte growth and development factor (MGDF). Thrombopoietin is a  glycoprotein hormone that is produced by the liver and kidneys. It is responsible for the regulation of the production of platelets. The production of Thrombopoietin stimulates megakaryocyte production. At a cellular level, Megakaryocytopoiesisis responsible for the production of platelets.

 

 

 

 

 

Renin

 

                                      The relationship of Renin on the body

Reference – https://en.wikipedia.org/wiki/Renin

 

Renin is also known as angiotensinogenase. Renin is secreted from juxtaglomerular kidney cells,  which respond to change in renal perfusion pressure. Renin is the main activation enzyme for the renin-angiotensin-aldosterone system, which is secreted from the kidneys.  Angiotensin II is secreted from the liver, allowing for the response of aldosterone and vasopressin to be secreted from the hypothalamus. Thus, in turn, activated the thirst reflex, leading to an increase in blood pressure. Once this process has occurred, Renin’sprimary function becomes increased blood pressure and adequate pressure to perfuse the kidneys.

 

 

Calcitrol(1,25-dihydroxyvitamin D3)

Vitamin D Metabolism

Reference:- https://www.wikipathways.org/index.php/Pathway:WP1531

 

Calcitriol is the active form of vitamin D3 that is produced by the kidneys. Calcitriol needs parathyroid hormone to helps with cellular functions.

 

Calcitriol works in conjunction with the Parathyroid hormone (PTH) on the body functions. PTH is responsible for the stimulation to produce calcitriol. At the time that PTH is being released causing the kidneys to release phosphate (Pi) and  Ca2+ with an indirect cause of stimulatingosteoclasts to start forming.

 

The gastrointestinal tract absorption of phosphate is stimulated when calcitriol is released. Calcium-binding protein works at a cellular level; when the protein becomes active, it promotes the cells to transport more calcium (Ca2+) into the intestines’ blood. The release of calcitonin is inhibited when calcitriol is released. Calcitonin inhibits the release of calcium from the bone by reducing bone calcium release.

 

Urinary System Development

Development of the urinary system

Reference – https://en.wikipedia.org/wiki/Development_of_the_urinary_system

 

Prenatal development is the beginning of developing the urinary system, sex organs, and reproductive system, continuing the development as a part of sexual differentiation. The intermediate mesoderm is the starting point for the development of the urinary and reproductive organs.

 

 

 

Pronephros and Wolffian duct[edit]

Wolffian duct[edit]

In the outer part of the intermediate mesoderm, immediately under the ectoderm, in the region from the fifth cervical segment to the third thoracic segment, a series of short evaginations from each segment grows dorsally and extends caudally, fusing successively from before backward to form the pronephric duct. This continues to grow caudally until it opens into the ventral part of the cloaca; beyond the pronephros it is termed the Wolffian duct. Thus, the Wolffian duct is what remains of the pronephric duct after the atrophy of the pronephros.

Pronephros[edit]

Main article: Pronephros

The original evaginations form a series of transverse tubules each of which communicates by means of a funnel-shaped ciliated opening with the abdominal cavity, and in the course of each duct a glomerulus also is developed. A secondary glomerulus is formed ventral to each of these, and the complete group constitutes the pronephros. In humans, the pronephros is just rudimentary, and undergoes rapid atrophy and disappears.

Wolffian duct[edit]

Mesonephros[edit]

Main article: Mesonephros

On the medial side of the Wolffian duct, from the sixth cervical to the third lumbar segments, a series of tubules, the Wolffian tubules, develops. They increase in number by outgrowths from the original tubules. They change from solid masses of cells to instead become hollowed in the center. One end grows toward and finally opens into the Wolffian duct, the other dilates and is invaginated by a tuft of capillary bloodvessels to form a glomerulus. The tubules collectively constitute the mesonephros.

The mesonephros persists and form the permanent kidneys in fish and amphibians, but in reptiles, birds, and mammals, it atrophies and for the most part disappears rapidly as the permanent kidney (metanephros) develops beginning during the sixth or seventh week, so that by the beginning of the fifth month only the ducts and a few of the tubules of the mesonephros remain.

Development in male[edit]

Main article: Development of the reproductive system

In the male the Wolffian duct persists, and forms for example the epididymis, the ductus deferens, the ejaculatory ductseminal vesicle and efferent ducts.

In the female, on the other hand, the Wolffian bodies and ducts atrophy, leaving behind only remnants in the adult, involving e.g. the development of the suspensory ligament of the ovary.

Müllerian duct[edit]

Shortly after the formation of the Wolffian ducts a second pair of ducts is developed; these are the Müllerian ducts. Each arises on the lateral aspect of the corresponding Wolffian duct as a tubular invagination of the cells lining the abdominal cavity. The orifice of the invagination remains open, and undergoes enlargement and modification to form the abdominal ostium of the fallopian tube. The ducts pass backward lateral to the Wolffian ducts, but toward the posterior end of the embryo they cross to the medial side of these ducts, and thus come to lie side by side between and behind the latter—the four ducts forming what is termed the common genital cord, to distinguish it from the genital cords of the germinal epithelium seen later in this article. The Müllerian ducts end in an epithelial elevation, the Müllerian eminence, on the ventral part of the cloaca between the orifices of the Wolffian ducts. At a later stage the eminence opens in t

he middle, connecting the Müllerian ducts with the cloaca.

Atrophy in males[edit]

In the male the Müllerian ducts atrophy, but traces of their anterior ends are represented by the appendices testis (hydatids of Morgagni of the male), while their terminal fused portions form the utriculus in the floor of the prostatic urethra.

Development in females[edit]

In the female the Müllerian ducts persist and undergo further development. The portions which lie in the genital cord fuse to form the uterus and vagina. This fusion of the Müllerian ducts begins in the third month, and the septum formed by their fused medial walls disappears from below upward.

The parts outside this cord remain separate, and each forms the corresponding Fallopian tube. The ostium of the fallopian tube remains from the anterior extremity of the original tubular invagination from the abdominal cavity.

About the fifth month a ring-like constriction marks the position of the cervix of the uterus, and after the sixth month the walls of the uterus begin to thicken. For a time the vagina is represented by a solid rod of epithelial cells. A ring-like outgrowth of this epithelium occurs at the lower end of the uterus and marks the future vaginal fornix. At about the fifth or sixth month the lumen of the vagina is produced by the breaking down of the central cells of the epithelium. The hymen represents the remains of the Müllerian eminence.[1]

 

Kidney development

 

The three phases of development of the kidneys

Reference https://en.wikipedia.org/wiki/Kidney_development

The phases of the kidney’s development include:-pronephros, mesonephros, and metanephros.

 

Pronephros

On day 22 of gestation, the paired pronephric appear towards the cranial end of the intermediate mesoderm. Series of tubules called nephrotomes are formed by epithelial cells and join at the lateral aspect of the pronephric duct. The pronephros is nonfunctional in humans as it is fully encapsulated in the embryo with no excrete material leaving the embryo.

 

 

Mesonephros

 

The development of the pronephric duct proceeds in a cranial-to-caudal direction. As it elongates caudally, the pronephric duct induces nearby intermediate mesoderm in the thoracolumbar area to become epithelial tubules called mesonephric tubules. Each mesonephric tubule receives a blood supply from a branch of the aorta, ending in a capillary tuft analogous to the glomerulus of the definitive nephron. The mesonephric tubule forms a capsule around the capillary tuft, allowing for filtration of blood. This filtrate flows through the mesonephric tubule and is drained into the continuation of the pronephric duct, now called the mesonephric duct or Wolffian duct. The nephrotomes of the pronephros degenerate while the mesonephric duct extends towards the most caudal end of the embryo, ultimately attaching to the cloaca.

 

Metanephros

 

During the fifth week of gestation, the mesonephric duct develops an outpouching, the ureteric bud, near its attachment to the cloaca. This bud, also called the metanephrogenic diverticulum, grows posteriorly and towards the head of the embryo. The elongated stalk of the ureteric bud, called the metanephric duct, later forms the ureter. As the cranial end of the bud extends into the intermediate mesoderm, it undergoes a series of branchings to form the collecting duct system of the kidney. It also forms the major and minor calyces and the renal pelvis.

The portion of undifferentiated intermediate mesoderm in contact with the tips of the branching ureteric bud is known as the metanephrogenic blastema. Signals released from the ureteric bud induce the differentiation of the metanephrogenic blastema into the renal tubules. As the renal tubules grow, they come into contact and join with connecting tubules of the collecting duct system, forming a continuous passage for flow from the renal tubule to the collecting duct. Simultaneously, precursors of vascular endothelial cells begin to take their position at the tips of the renal tubules. These cells differentiate into the cells of the definitive glomerulus.

In humans, all of the branches of the ureteric bud and the nephronic units have been formed by 32 to 36 weeks of gestation. However, these structures are not yet mature, and will continue to mature after birth. Once matured, humans have an estimated two million nephrons

 

 

Migration

After the formation of metanephric mesenchyme,the nephric duct’s lower portion migrates downwards, connecting with the bladder and forming the ureters. As the fetus’s development continues and the torso lengthens, the kidneys rotate and migrate the abdomen, increasing the ureters’ length.

 

Urinary bladder

The endodermal cloaca and partially from the ends of the Wolffian ducts form the urinary bladder. The separation of the rectum from the dorsal part of the cloaca, the ventral aspect, allows for the formation of the urogenital sinus. The urogenital sinus division becomes a superficial definitive urogenital sinus and the anterior portion of the vesico-urethral.The vesico-urethral portion absorbs the ends of the Wolffian ducts and the renal diverticula’s associated ends, Creating the urinary bladder and parts of the prostatic urethra.

 

Aging of the Urinary system

As aging occurs, kidneys’ filtering ability and nephrons decrease, causing the kidneys’ overall function to start to slow down its function. As aging occurs, many disorders can occur as a result of the slowing of kidney function. This can result from infection to kidney failure. Urinary cancers, including bladder and prostate, tend to be more come in individuals over 55 years old. As the body continues to age,  events happen in the kidneys. The number of nephrons that filter waste from the blood decreases in number and reduces the overall amount of available kidney tissue. Filtration of the blood is slowed in the situation where the blood vessels supply the kidney harden. The bladder tissue becomes rigid due to the loss of elasticity, causing the bladder to become less stretchy. Muscles become weak in the bladder, causing the bladder to be unable to completely empty when urinating. Due to age, there is an increased risk of acute and chronic kidney failure, urinary incontinence, leakage or retention, and bladder and other urinary tract infections

 

 

 

 

 

 

Common Disorders

Benign prostatic hyperplasia (BPH), also called prostate enlargement,

 

 

Most experts consider androgens (testosterone and related hormones) to play a permissive role in the development of BPH. This means that androgens must be present for BPH to occur, but do not necessarily directly cause the condition.

Dihydrotestosterone (DHT), a metabolite of testosterone, is a critical mediator of prostatic growth. DHT is synthesized in the prostate from circulating testosterone by the action of the enzyme 5α-reductase, type 2. DHT can act in an autocrine fashion on the stromal cells or in paracrine fashion by diffusing into nearby epithelial cells. In both of these cell types, DHT binds to nuclear androgen receptors and signals the transcription of growth factors that are mitogenic to the epithelial and stromal cells. DHT is ten times more potent than testosterone because it dissociates from the androgen receptor more slowly. The importance of DHT in causing nodular hyperplasia is supported by clinical observations in which an inhibitor of 5α-reductase such as finasteride is given to men with this condition. Therapy with a 5α-reductase inhibitor markedly reduces the DHT content of the prostate and, in turn, reduces prostate volume and BPH symptoms.[17][18]

Testosterone promotes prostate cell proliferation,[19] but relatively low levels of serum testosterone are found in patients with BPH.

While there is some evidence that estrogen may play a role in the cause of BPH, this effect appears to be mediated mainly through local conversion of androgens to estrogen in the prostate tissue rather than a direct effect of estrogen itself.[23] In canine in vivo studies castration, which significantly reduced androgen levels but left estrogen levels unchanged, caused significant atrophy of the prostate.[24] Studies looking for a correlation between prostatic hyperplasia and serum estrogen levels in humans have generally shown none.[21][25]

Pathophysiology[edit]

As men age, the enzymes aromatase and 5-alpha reductase increase in activity. These enzymes are responsible for converting androgen hormones into estrogen and dihydrotestosterone, respectively. This metabolism of androgen hormones leads to a decrease in testosterone but increased levels of DHT and estrogen.

Both the glandular epithelial cells and the stromal cells (including muscular fibers) undergo hyperplasia in BPH.[2] Most sources agree that of the two tissues, stromal hyperplasia predominates, but the exact ratio of the two is unclear.[36]:694

Anatomically the median and lateral lobes are usually enlarged, due to their highly glandular composition. The anterior lobe has little in the way of glandular tissue and is seldom enlarged. (Carcinoma of the prostate typically occurs in the posterior lobe – hence the ability to discern an irregular outline per rectal examination). The earliest microscopic signs of BPH usually begin between the age of 30 and 50 years old in the PUG, which is posterior to the proximal urethra.[36]:694 In BPH, the majority of growth occurs in the transition zone (TZ) of the prostate.[36]:694 In addition to these two classic areas, the peripheral zone (PZ) is also involved to a lesser extent.[36]:695 Prostatic cancer typically occurs in the PZ. However, BPH nodules, usually from the TZ are often biopsied anyway to rule out cancer in the TZ.[36]:695 BPH can be a progressive growth that in rare instances leads to exceptional enlargement.[37] In some males, the prostate enlargement exceeds 200 to 500 grams.[37] This condition has been defined as giant prostatic hyperplasia (GPH).[37]

 

Urinary incontinence

 

Urinary incontinence can be an effect of urologic or non-urologic causes.

Urologic causes can include

  • Bladder dysfunction or urethral sphincter
    • Detrusor overactivity
    • Poor bladder compliance
    • Urethral hypermobility

 

Non- urologic causes can include

  • Infection
  • Medication or drugs
  • Psychological factors
  • Polyuria
  • Stool impaction
  • Restricted mobility

 

 

 

Women[edit]

 

The most common types of urinary incontinence in women are stress urinary incontinence and urge urinary incontinence. Women that have symptoms from both types are said to have “mixed” urinary incontinence. After menopauseestrogen production decreases and, in some women, urethral tissue will demonstrate atrophy, becoming weaker and thinner, possibly playing a role in the development of urinary incontinence.[4]

Stress urinary incontinence in women is most commonly caused by loss of support of the urethra, which is usually a consequence of damage to pelvic support structures as a result of pregnancy, childbirth, obesity, age, among others.[12]

Stress incontinence is characterized by leaking of small amounts of urine with activities that increase abdominal pressure such as coughing, sneezing, laughing and lifting. This happens when the urethral sphincter cannot close completely due to the damage in the sphincter itself, or the surrounding tissue. Additionally, frequent exercise in high-impact activities can cause athletic incontinence to develop.

 

For example, stress urinary incontinence is usually a result of the incompetent closure of the urethral sphincter. This can be caused by damage to the sphincter itself, the muscles that support it, or nerves that supply it. In men, the damage usually happens after prostate surgery or radiation,[14] and in women, it’s usually caused by childbirth and pregnancy.[19] The pressure inside the abdomen (from coughing and sneezing) is normally transmitted to both urethra and bladder equally, leaving the pressure difference unchanged, resulting in continence. When the sphincter is incompetent, this increase in pressure will push the urine against it, leading to incontinence.

 

 

Another example is urge incontinence. This incontinence is associated with sudden forceful contractions of the detrusor muscle (bladder muscle), leading to an intense feeling of urination, and incontinence if the person does not reach the bathroom on time. The syndrome is known as overactive bladder syndrome, and it’s related to dysfunction of the detrusor muscle.

Men[edit]

Urge incontinence is the most common type of incontinence in men.[14] Similar to women, urine leakage happens following a very intense feeling of urination, not allowing enough time to reach the bathroom, a condition called overactive bladder syndrome. In men, the condition is commonly associated with benign prostatic hyperplasia (an enlarged prostate), which causes bladder outlet obstruction, a dysfunction of the detrusor muscle (muscle of the bladder), eventually causing overactive bladder syndrome, and the associated incontinence.[14]

Stress urinary incontinence is the other common type of incontinence in men, and it most commonly happens after prostate surgery.[15] Prostatectomytransurethral resection of the prostateprostate brachytherapy, and radiotherapy can all damage the urethral sphincter and surrounding tissue, causing it to be incompetent. An incompetent urethral sphincter cannot prevent the urine from leaking out of the urinary bladder during activities that increase the intraabdominal pressure, such as coughing, sneezing, or laughing.

 

 

 

 

 

 

 

Bladder cancer

Bladder cancer is any of several types of cancer arising from the tissues of the urinary bladder.[1] Symptoms include blood in the urinepain with urination, and low back pain.[1]

Risk factors for bladder cancer include smoking, family history, prior radiation therapy, frequent bladder infections, and exposure to certain chemicals.[1] The most common type is transitional cell carcinoma.[1] Other types include squamous cell carcinoma and adenocarcinoma.[1] Diagnosis is typically by cystoscopy with tissue biopsies.[4] Staging of the cancer is determined by transurethral resection and medical imaging.[1][5][6]

Treatment depends on the stage of the cancer.[1] It may include some combination of surgery, radiation therapy, chemotherapy, or immunotherapy.[1] Surgical options may include transurethral resection, partial or complete removal of the bladder, or urinary diversion.[1] The typical five-year survival rates in the United States is 77%, Canada is 75%, and Europe is 68%.[2][7][8]

Bladder cancer, as of 2018, affected about 1.6 million people globally with 549,000 new cases and 200,000 deaths.[3] Age of onset is most often between 65 and 84 years of age.[2] Males are more often affected than females.[2] In 2018, the highest rate of bladder cancer occurred in Southern and Western Europe followed by North America with rates of 15, 13, and 12 cases per 100,000 people.[3] The highest rates of bladder cancer deaths were seen in Northern Africa and Western Asia followed by Southern Europe.[3]

Causes[edit]

Tobacco smoking is the main known contributor to urinary bladder cancer; in most populations, smoking is associated with over half of bladder cancer cases in men and one-third of cases among women,[13] however these proportions have reduced over recent years since there are fewer smokers in Europe and North America.[14] There is an almost linear relationship between smoking duration (in years), pack years and bladder cancer risk. A risk plateau at smoking about 15 cigarettes a day can be observed (meaning that those who smoke 15 cigarettes a day are approximately at the same risk as those smoking 30 cigarettes a day). Smoking (cigar, pipe, Egyptian waterpipe and smokeless tobacco) in any form increases the risk for bladder cancer.[15] Quitting smoking reduces the risk. Risk of bladder cancer decreases by 30% within 1–4 years and continues to decrease by 60% at 25 years after smoking cessation.[16] However, former smokers will most likely always be at a higher risk of bladder cancer compared to people who have never smoked.[14] Passive smoking also appear to be a risk.[17][18]

Opium consumption increases the risk of bladder cancer by 3-fold and concurrent use of opium and smoking increases the risk of bladder cancer by 5 times compared to the general population.[19]

Thirty percent of bladder tumors probably result from occupational exposure in the workplace to carcinogens. Occupational or circumstantial exposure to the following substances has been implicated as a cause of bladder cancer; benzidine (dyes manufacturing), 4-aminobiphenyl (rubber industry), 2-naphtylamine (azo dyes manufacturing, foundry fumes, rubber industry, cigarette smoke and cancer research), phenacetin (analgesic), arsenic and chlorinated aliphatic hydrocarbons in drinking water, auramine (dye manufacturing), magenta (dye manufacturing), ortho-toluidine (dye manufacturing), epoxy and polyurethane resin hardening agents (plastics industry), chlornaphazinecoal-tar pitch.[20][21][22][23][24] Occupations at risk are bus drivers, rubber workers, painters, motor mechanics, leather (including shoe) workers, blacksmiths, machine setters, and mechanics.[25][26] Hairdressers are thought to be at risk as well because of their frequent exposure to permanent hair dyes.[27]

Infection with Schistosoma haematobium (bilharzia or schistosomiasis) may cause bladder cancer, specially of the squamous cell type.[28] Schistosoma eggs induces a chronic inflammatory state in the bladder wall resulting in tissue fibrosis.[29] Higher levels of N-nitroso compounds has been detected in urine samples of people with schistosomiasis.[30] N-Nitroso compounds have been implicated in the pathogenesis of schistosomiasis related bladder cancer. They cause alkylation DNA damage, specially Guanine to Adenine transition mutations in the HRAS and p53 tumor suppressor gene.[31] Mutations of p53 are detected in 73% of the tumors, BCL-2 mutations accounting for 32% and the combination of the two accounting for 13%.[32] Other causes of squamous cell carcinoma of the bladder include chronic catheterizations in people with a spinal cord injury and history of treatment with cyclophosphamide.[33][34]

Ingestion of aristolochic acid present in many Chinese herbal medications has been shown to cause urothelial carcinoma and kidney failure.[35] Aristolochic acid activates peroxidase in the urothelium and causes transversion mutation in the TP53 tumor suppressor gene.

People who undergo external beam radiotherapy (EBRT) for prostate cancer have a higher risk of developing invasive bladder cancer.[36]

In addition to these major risk factors there are also numerous other modifiable factors that are less strongly (i.e. 10–20% risk increase) associated with bladder cancer, for example, obesity.[37] Although these could be considered as minor effects, risk reduction in the general population could still be achieved by reducing the prevalence of a number of smaller risk factor together.[38]

Genetics[edit]

Mutations in FGFR3TP53PIK3CAKDM6AARID1AKMT2DHRASTERTKRASCREBBPRB1 and TSC1 genes may be associated with some cases of bladder cancer.[39][40][41] Deletions of parts or whole of chromosome 9 is common in bladder cancer.[42] Low grade cancer are known to harbor mutations in RAS pathway and the fibroblast growth factor receptor 3 (FGFR3) gene, both of which play a role in the MAPK/ERK pathwayp53 and RB gene mutations are implicated in high-grade muscle invasive tumors.[43] Eighty nine percent of muscle invasive cancers have mutations in chromatin remodeling and histone modifying genes.[44] Deletion of both copies of the GSTM1 gene has a modest increase in risk of bladder cancer. GSTM1 gene product glutathione S-transferase M1 (GSTM1) participates in the detoxification process of carcinogens such as polycyclic aromatic hydrocarbons found in cigarette smoke.[45] Similarly, mutations in NAT2 (N-acetyltransferase) is associated with increased risk for bladder cancer. N-acetyltransferase helps in detoxification of carcinogens like aromatic amines (also present in cigarette smoke).[46] Various single-nucleotide polymorphisms in PSCA gene present on chromosome 8 have shown to increase the risk for bladder cancer. PSCA gene promoter region has an androgen response region. Loss of reactivity of this region to androgens is hypothesized as a cause of more number of aggressive tumors in women (unlike in men who have higher amount of androgen).[47]

Muscle invasive bladder cancer are heterogeneous in nature. In general, they can be genetically classified into basal and luminal subtypes. Basal subtype show alterations involving RB and NFE2L2 and luminal type show changes in FGFR3 and KDM6A genes.[48] Basal subtype are subdivided into basal and claudin low-type group and are aggressive and show metastasis at presentation, however they respond to platinum based chemotherapy. Luminal subtype can be subdivided into p53-like and luminal. p53-like tumors of luminal subtype although not as aggressive as basal type, show resistance to chemotherapy[49]

 

Currently, the best diagnosis of the state of the bladder is by way of cystoscopy, which is a procedure in which a flexible or rigid tube (called a cystoscope) bearing a camera and various instruments is introduced into the bladder through the urethra. The flexible procedure allows for a visual inspection of the bladder, for minor remedial work to be undertaken and for samples of suspicious lesions to be taken for a biopsy. A rigid cystoscope is used under general anesthesia in the operating room and can support remedial work and biopsies as well as more extensive tumor removal. Unlike papillary lesion, which grow into the bladder cavity and are readily visible, carcinoma in situ lesion are flat and obscure. Detection of carcinoma in situ lesions requires multiple biopsies from different areas of interior bladder wall.[50] Photodynamic detection (blue light cystoscopy) can aid in the detection of carcinoma in situ. In photodynamic detection, a dye is instilled into the bladder with the help of a catheter. Cancer cells take up this dye and are visible under blue light, providing visual clues on areas to biopsied or resected.[51]

However, visual detection in any form listed above, is not sufficient for establishing pathological classification, cell type or the stage of the present tumor. A so-called cold cup biopsy during an ordinary cystoscopy (rigid or flexible) will not be sufficient for pathological staging either. Hence, a visual detection needs to be followed by transurethral surgery. The procedure is called transurethral resection of bladder tumor (TURBT). Further, a rectal and vaginal bimanual examination should be carried out before and after the TURBT to assess whether there is a palpable mass or if the tumour is fixed (“tethered”) to the pelvic wall. The pathological classification and staging information obtained by the TURBT-procedure, is of fundamental importance for making the appropriate choice of ensuing treatment and/or follow-up routines.[52]

Classification[edit]

 

Histopathology of urothelial carcinoma of the urinary bladder. Transurethral biopsy. H&E stain

Type Relative incidence Subtypes
Transitional cell carcinoma 95%[62][63] Papillary (70%[62])
Non-papillary (30%[62])
Non-transitional cell carcinoma 5% [62][63] Squamous cell carcinomasadenocarcinomassarcomassmall cell carcinomas, and secondary deposits from cancers elsewhere in the body.[63]

Non-papillary carcinoma includes carcinoma in situ (CIS), microinvasive carcinoma and frankly invasive carcinoma.[64] Carcinoma in situ (CIS) invariably consists of cytologically high-grade tumour cells.[65]

Transitional cell carcinoma can undergo differentiation (25%) into its variants.[64][66][67] When seen under a microscope, papillary transitional cell carcinoma can present in its typical form or as one of its variations (squamous, glandular differentiation or micropapillary variant). Different variations of non-papillary transitional cell carcinoma are listed below.

Variant Histology Percentage of non-papillary cases Implications[68]
Squamous differentiation Presence of intercellular bridges or keratinization 60% Outcomes similar to conventional transitional cell carcinoma
Glandular differentiation Presence of true glandular spaces 10%
Sarcomatoid foci Presence of both epithelial and mesenchymal differentiation 7% Clinically aggressive[69]
Micropapillary variant Resembles papillary serous carcinoma of the ovary or resembling micropapillary carcinoma of breast or lung[70] 3.7% Clinically aggressive, early cystectomy recommended
Urothelial carcinoma with small tubules and microcystic form Presence of cysts with a size range of microscopic to 1-2mm Rare
Lymphoepithelioma-like carcinoma Resembles lymphoepithelioma of the nasopharynx
Lymphoma-like and plasmacytoid variants Malignant cells resemble cells of malignant lymphoma or plasmacytoma
Nested variant Histologically look similar to von Brunn’s nests Can be misdiagnosed as benign von Brunn’s nests or non-invasive low-grade papillary urothelial carcinoma
Urothelial carcinoma with giant cells Presence of epithelial tumour giant cells and looks similar to giant cell carcinoma of the lung
Trophoblastic differentiation Presence of syncytiotrophoblastic giant cells or choriocarcinomatous differentiation, may express HCG
Clear cell variant Clear cell pattern with glycogen-rich cytoplasm
Plasmacytoid Cells with abundant lipid content, mimic signet ring cell adenocarcinoma of stomach/ lobular breast cancer Clinically aggressive, propensity for peritoneal spread
Unusual stromal reactions Presence of following; pseudosarcomatous stroma, stromal osseous or cartilaginous metaplasia, osteoclast-type giant cells, lymphoid infiltrate

Staging[edit]

Diagram showing the T stages of bladder cancer

Stage N1 bladder cancer

Advanced bladder cancer (M1b)

Lymph nodes in the pelvis. Bladder cancer commonly spreads to obturator and internal iliac (not labelled)

Lymphatic drainage of the bladder (lateral view).Tumors on the superolateral bladder wall spread to external iliac lymph nodes

Bladder cancer is staged (classified by the extent of spread of the cancer) and graded (how abnormal and aggressive the cells appear under the microscope) to determine treatments and estimate outcomes. Staging usually follows the first transurethral resection of bladder tumor (TURBT). Papillary tumors confined to the mucosa or which invade the lamina propria are classified as Ta or T1. Flat lesion are classified as Tis. Both are grouped together as non-muscle invasive disease for therapeutic purposes.

In the TNM staging system (8th Edn. 2017) for bladder cancer:[71][72]

T (Primary tumour)

  • TXPrimary tumour cannot be assessed
  • T0No evidence of primary tumour
  • TaNon-invasive papillary carcinoma
  • TisCarcinoma in situ (‘flat tumour’)
  • T1Tumour invades subepithelial connective tissue
  • T2aTumour invades superficial muscle (inner half of the detrusor muscle)[73]
  • T2bTumour invades deep muscle (outer half of the detrusor muscle)[73]
  • T3Tumour invades perivesical tissue:
    • T3aMicroscopically
    • T3bMacroscopically (extravesical mass)
  • T4aTumour invades prostateuterus or vagina
  • T4bTumour invades pelvic wall or abdominal wall

N (Lymph nodes)

  • NXRegional lymph nodes cannot be assessed
  • N0No regional lymph node metastasis
  • N1Metastasis in a single lymph node in true pelvis (hypogastric, obturator, external iliac, or presacral nodes)
  • N2Metastasis in multiple lymph nodes in true pelvis (hypogastric, obturator, external iliac, or presacral nodes)
  • N3Metastasis in common iliac lymph nodes

M (Distant metastasis)

  • MXDistant metastasis cannot be assessed
  • M0No distant metastasis
  • M1Distant metastasis.
    • M1a:The cancer has spread only to lymph nodes outside of the pelvis.
    • M1b: The cancer has spread other parts of the body.

The most common sites for bladder cancer metastases are the lymph nodes, bones, lung, liver, and peritoneum.[74] The most common sentinel lymph nodes draining bladder cancer are obturator and internal iliac lymph nodes. The location of lymphatic spread depends on the location of the tumors. Tumors on the superolateral bladder wall spread to external iliac lymph nodes. Tumors on the neck, anterior wall and fundus spread commonly to the internal iliac lymph nodes.[75] From the regional lymph nodes (i.e. obturator, internal and external lymph nodes) the cancer spreads to distant sites like the common iliac lymph nodes and paraaortic lymph nodes.[76] Skipped lymph node lesions are not seen in bladder cancer.[75]

 

 

 

 

Pyelonephritis

Pyelonephritis is inflammation of the kidney, typically due to a bacterial infection.[3] Symptoms most often include fever and flank tenderness.[2] Other symptoms may include nauseaburning with urination, and frequent urination.[2] Complications may include pus around the kidneysepsis, or kidney failure.[3]

It is typically due to a bacterial infection, most commonly Escherichia coli.[2] Risk factors include sexual intercourse, prior urinary tract infectionsdiabetes, structural problems of the urinary tract, and spermicide use.[2][3] The mechanism of infection is usually spread up the urinary tract.[2] Less often infection occurs through the bloodstream.[1] Diagnosis is typically based on symptoms and supported by urinalysis.[2] If there is no improvement with treatment, medical imaging may be recommended.[2]

Pyelonephritis may be preventable by urination after sex and drinking sufficient fluids.[1] Once present it is generally treated with antibiotics, such as ciprofloxacin or ceftriaxone.[4][6] Those with severe disease may require treatment in hospital.[2] In those with certain structural problems of the urinary tract or kidney stones, surgery may be required.[1][3]

Causes[edit]

Most cases of “community-acquired” pyelonephritis are due to bowel organisms that enter the urinary tract. Common organisms are E. coli (70–80%) and Enterococcus faecalisHospital-acquired infections may be due to coliform bacteria and enterococci, as well as other organisms uncommon in the community (e.g., Pseudomonas aeruginosa and various species of Klebsiella). Most cases of pyelonephritis start off as lower urinary tract infections, mainly cystitis and prostatitis.[9] E. coli can invade the superficial umbrella cells of the bladder to form intracellular bacterial communities (IBCs), which can mature into biofilms. These biofilm-producing E. coli are resistant to antibiotic therapy and immune system responses, and present a possible explanation for recurrent urinary tract infections, including pyelonephritis.[13] Risk is increased in the following situations:[9][14]

 

 

Kidney failure

Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys are functioning at less than 15% of normal.[2] Kidney failure is classified as either acute kidney failure, which develops rapidly and may resolve; and chronic kidney failure, which develops slowly and can often be irreversible.[6] Symptoms may include leg swelling, feeling tired, vomiting, loss of appetite, and confusion.[2] Complications of acute and chronic failure include uremiahigh blood potassium, and volume overload.[3] Complications of chronic failure also include heart diseasehigh blood pressure, and anemia.[4][5]

Causes of acute kidney failure include low blood pressure, blockage of the urinary tract, certain medications, muscle breakdown, and hemolytic uremic syndrome.[6] Causes of chronic kidney failure include diabeteshigh blood pressurenephrotic syndrome, and polycystic kidney disease.[6] Diagnosis of acute failure is often based on a combination of factors such as decrease urine production or increased serum creatinine.[3] Diagnosis of chronic failure is based on a glomerular filtration rate (GFR) of less than 15 or the need for renal replacement therapy.[1] It is also equivalent to stage 5 chronic kidney disease.[1]

Treatment of acute failure depends on the underlying cause.[7] Treatment of chronic failure may include hemodialysisperitoneal dialysis, or a kidney transplant.[2] Hemodialysis uses a machine to filter the blood outside the body.[2] In peritoneal dialysis specific fluid is placed into the abdominal cavity and then drained, with this process being repeated multiple times per day.[2] Kidney transplantation involves surgically placing a kidney from someone else and then taking immunosuppressant medication to prevent rejection.[2] Other recommended measures from chronic disease include staying active and specific dietary changes.[2]

In the United States acute failure affects about 3 per 1,000 people a year.[8] Chronic failure affects about 1 in 1,000 people with 3 per 10,000 people newly developing the condition each year.[1][9] Acute failure is often reversible while chronic failure often is not.[6] With appropriate treatment many with chronic disease can continue working.[2]

Classification[edit]

See also: Hepatorenal syndrome

Kidney failure can be divided into two categories: acute kidney failure or chronic kidney failure. The type of renal failure is differentiated by the trend in the serum creatinine; other factors that may help differentiate acute kidney failure from chronic kidney failure include anemia and the kidney size on sonography as chronic kidney disease generally leads to anemia and small kidney size.

Acute kidney failure[edit]

Main article: Acute kidney injury

Acute kidney injury (AKI), previously called acute renal failure (ARF),[10][11] is a rapidly progressive loss of renal function,[12] generally characterized by oliguria (decreased urine production, quantified as less than 400 mL per day in adults,[13] less than 0.5 mL/kg/h in children or less than 1 mL/kg/h in infants); and fluid and electrolyte imbalance. AKI can result from a variety of causes, generally classified as prerenalintrinsic, and postrenal. Many people diagnosed with paraquat intoxication experience AKI, sometimes requiring hemodialysis.[citation needed] The underlying cause must be identified and treated to arrest the progress, and dialysis may be necessary to bridge the time gap required for treating these fundamental causes.

Chronic kidney failure[edit]

Main article: Chronic kidney disease

Illustration of a kidney from a person with chronic renal failure

Chronic kidney disease (CKD) can also develop slowly and, initially, show few symptoms.[14] CKD can be the long term consequence of irreversible acute disease or part of a disease progression.

Acute-on-chronic kidney failure[edit]

Acute kidney injuries can be present on top of chronic kidney disease, a condition called acute-on-chronic kidney failure (AoCRF). The acute part of AoCRF may be reversible, and the goal of treatment, as with AKI, is to return the person to baseline kidney function, typically measured by serum creatinine. Like AKI, AoCRF can be difficult to distinguish from chronic kidney disease if the person has not been monitored by a physician and no baseline (i.e., past) blood work is available for comparison.

Signs and symptoms[edit]

Symptoms can vary from person to person. Someone in early stage kidney disease may not feel sick or notice symptoms as they occur. When the kidneys fail to filter properly, waste accumulates in the blood and the body, a condition called azotemia. Very low levels of azotaemia may produce few, if any, symptoms. If the disease progresses, symptoms become noticeable (if the failure is of sufficient degree to cause symptoms). Kidney failure accompanied by noticeable symptoms is termed uraemia.[15]

Symptoms of kidney failure include the following:[15][16][17][18]

  • High levels of ureain the blood, which can result in:
    • Vomitingor diarrhea (or both) may lead to dehydration
    • Nausea
    • Weight loss
    • Nocturnal urination (nocturia)
    • More frequent urination, or in greater amounts than usual, with pale urine
    • Less frequent urination, or in smaller amounts than usual, with dark coloured urine
    • Blood in the urine
    • Pressure, or difficulty urinating
    • Unusual amounts of urination, usually in large quantities
  • A buildup of phosphatesin the blood that diseased kidneys cannot filter out may cause:
  • A buildup of potassiumin the blood that diseased kidneys cannot filter out (called hyperkalemia) may cause:
    • Abnormal heart rhythms
    • Muscle paralysis[19]
  • Failure of kidneys to remove excess fluid may cause:
    • Swelling of the hands, legs, ankles, feet, or face
    • Shortness of breath due to extra fluid on the lungs (may also be caused by anemia)
  • Polycystic kidney disease, which causes large, fluid-filled cysts on the kidneys and sometimes the liver, can cause:
    • Pain in the back or side
  • Healthy kidneys produce the hormone erythropoietinthat stimulates the bone marrow to make oxygen-carrying red blood cells. As the kidneys fail, they produce less Erythropoietin, resulting in decreased production of red blood cells to replace the natural breakdown of old red blood cells. As a result, the blood carries less hemoglobin, a condition known as anemia. This can result in:
    • Feeling tired or weak
    • Memory problems
    • Difficulty concentrating
    • Dizziness
    • Low blood pressure
  • Normally proteins are too large to pass through the kidneys. However they are able to pass through when the glomeruli are damaged. This does not cause symptoms until extensive kidney damage has occurred,[20]after which symptoms include:
    • Foamy or bubbly urine
    • Swelling in the hands, feet, abdomen, and face
  • Other symptoms include:
    • Appetite loss, which may include a bad taste in the mouth
    • Difficulty sleeping
    • Darkening of the skin
    • Excess protein in the blood
    • With high doses of penicillin, people with kidney failure may experience seizures[21]

Causes[edit]

Acute kidney injury[edit]

Acute kidney injury (previously known as acute renal failure) – or AKI – usually occurs when the blood supply to the kidneys is suddenly interrupted or when the kidneys become overloaded with toxins. Causes of acute kidney injury include accidents, injuries, or complications from surgeries in which the kidneys are deprived of normal blood flow for extended periods of time. Heart-bypass surgery is an example of one such procedure.

Drug overdoses, accidental or from chemical overloads of drugs such as antibiotics or chemotherapy, along with bee stings[22] may also cause the onset of acute kidney injury. Unlike chronic kidney disease, however, the kidneys can often recover from acute kidney injury, allowing the person with AKI to resume a normal life. People suffering from acute kidney injury require supportive treatment until their kidneys recover function, and they often remain at increased risk of developing future kidney failure.[23]

Among the accidental causes of renal failure is the crush syndrome, when large amounts of toxins are suddenly released in the blood circulation after a long compressed limb is suddenly relieved from the pressure obstructing the blood flow through its tissues, causing ischemia. The resulting overload can lead to the clogging and the destruction of the kidneys. It is a reperfusion injury that appears after the release of the crushing pressure. The mechanism is believed to be the release into the bloodstream of muscle breakdown products – notably myoglobinpotassium, and phosphorus – that are the products of rhabdomyolysis (the breakdown of skeletal muscle damaged by ischemic conditions). The specific action on the kidneys is not fully understood, but may be due in part to nephrotoxic metabolites of myoglobin.

Chronic kidney failure[edit]

Chronic kidney failure has numerous causes. The most common causes of chronic failure are diabetes mellitus and long-term, uncontrolled hypertension.[24] Polycystic kidney disease is another well-known cause of chronic failure. The majority of people afflicted with polycystic kidney disease have a family history of the disease. Other genetic illnesses cause kidney failure, as well.

 

 

 

 

Kidney stone disease

From Wikipedia, the free encyclopedia

Kidney stone disease, also known as nephrolithiasis or urolithiasis, is when a solid piece of material (kidney stone) develops in the urinary tract.[2] Kidney stones typically form in the kidney and leave the body in the urine stream.[2] A small stone may pass without causing symptoms.[2] If a stone grows to more than 5 millimeters (0.2 in), it can cause blockage of the ureter, resulting in severe pain in the lower back or abdomen.[2][7] A stone may also result in blood in the urine, vomiting, or painful urination.[2] About half of people who have had a kidney stone will have another within ten years.[8]

Most stones form by a combination of genetics and environmental factors.[2] Risk factors include high urine calcium levelsobesity; certain foods; some medications; calcium supplementshyperparathyroidismgout and not drinking enough fluids.[2][8] Stones form in the kidney when minerals in urine are at high concentration.[2] The diagnosis is usually based on symptoms, urine testing, and medical imaging.[2] Blood tests may also be useful.[2] Stones are typically classified by their location: nephrolithiasis (in the kidney), ureterolithiasis (in the ureter), cystolithiasis (in the bladder), or by what they are made of (calcium oxalateuric acidstruvitecystine).[2]

In those who have had stones, prevention is by drinking fluids such that more than two liters of urine are produced per day.[4] If this is not effective enough, thiazide diureticcitrate, or allopurinol may be taken.[4] It is recommended that soft drinks containing phosphoric acid (typically colas) be avoided.[4] When a stone causes no symptoms, no treatment is needed,[2] otherwise pain control is usually the first measure, using medications such as nonsteroidal anti-inflammatory drugs or opioids.[7][9] Larger stones may be helped to pass with the medication tamsulosin[10] or may require procedures such as extracorporeal shock wave lithotripsyureteroscopy, or percutaneous nephrolithotomy.[2]

Between 1% and 15% of people globally are affected by kidney stones at some point in their lives.[8] In 2015, 22.1 million cases occurred,[5] resulting in about 16,100 deaths.[6] They have become more common in the Western world since the 1970s.[8] Generally, more men are affected than women.[2] Kidney stones have affected humans throughout history with descriptions of surgery to remove them dating from as early as 600 BC.[1]

Hypocitraturia[edit]

Hypocitraturia or low urinary-citrate excretion (defined as less than 320 mg/day) can cause kidney stones in up to 2/3 of cases. The protective role of citrate is linked to several mechanisms; citrate reduces urinary supersaturation of calcium salts by forming soluble complexes with calcium ions and by inhibiting crystal growth and aggregation. Therapy with potassium citrate or magnesium potassium citrate is commonly prescribed in clinical practice to increase urinary citrate and to reduce stone formation rates.[41]

Supersaturation of urine[edit]

When the urine becomes supersaturated (when the urine solvent contains more solutes than it can hold in solution) with one or more calculogenic (crystal-forming) substances, a seed crystal may form through the process of nucleation.[22] Heterogeneous nucleation (where there is a solid surface present on which a crystal can grow) proceeds more rapidly than homogeneous nucleation (where a crystal must grow in a liquid medium with no such surface), because it requires less energy. Adhering to cells on the surface of a renal papilla, a seed crystal can grow and aggregate into an organized mass. Depending on the chemical composition of the crystal, the stone-forming process may proceed more rapidly when the urine pH is unusually high or low.[42]

Supersaturation of the urine with respect to a calculogenic compound is pH-dependent. For example, at a pH of 7.0, the solubility of uric acid in urine is 158 mg/100 ml. Reducing the pH to 5.0 decreases the solubility of uric acid to less than 8 mg/100 ml. The formation of uric-acid stones requires a combination of hyperuricosuria (high urine uric-acid levels) and low urine pH; hyperuricosuria alone is not associated with uric-acid stone formation if the urine pH is alkaline.[43] Supersaturation of the urine is a necessary, but not a sufficient, condition for the development of any urinary calculus.[22] Supersaturation is likely the underlying cause of uric acid and cystine stones, but calcium-based stones (especially calcium oxalate stones) may have a more complex cause.[44]

Inhibitors of stone formation[edit]

Normal urine contains chelating agents, such as citrate, that inhibit the nucleation, growth, and aggregation of calcium-containing crystals. Other endogenous inhibitors include calgranulin (an S-100 calcium-binding protein), Tamm–Horsfall proteinglycosaminoglycans, uropontin (a form of osteopontin), nephrocalcin (an acidic glycoprotein), prothrombin F1 peptide, and bikunin (uronic acid-rich protein). The biochemical mechanisms of action of these substances have not yet been thoroughly elucidated. However, when these substances fall below their normal proportions, stones can form from an aggregation of crystals.[45]

Sufficient dietary intake of magnesium and citrate inhibits the formation of calcium oxalate and calcium phosphate stones; in addition, magnesium and citrate operate synergistically to inhibit kidney stones. Magnesium’s efficacy in subduing stone formation and growth is dose-dependent.[28][33][46]

 

Kidney cancer

Kidney cancer, also known as renal cancer, is a group of cancers that starts in the kidney.[4] Symptoms may include blood in the urine, lump in the abdomen, or back pain.[1][2][3] Fever, weight loss, and tiredness may also occur.[1][2][3] Complications can include spread to the lungs or brain.[6]

The main types of kidney cancer are renal cell cancer (RCC), transitional cell cancer (TCC), and Wilms tumor.[7] RCC makes up approximately 80% of kidney cancers, and TCC accounts for most of the rest.[8] Risk factors for RCC and TCC include smoking, certain pain medications, previous bladder cancer, being overweight, high blood pressure, certain chemicals, and a family history.[1][2] Risk factors for Wilms tumor include a family history and certain genetic disorders such as WAGR syndrome.[3] Diagnosis maybe suspected based on symptoms, urine testing, and medical imaging.[1][2][3] It is confirmed by tissue biopsy.[1][2][3]

Treatment may include surgery, radiation therapychemotherapyimmunotherapy, and targeted therapy.[1][2][3] Kidney cancer newly affected about 403,300 people and resulted in 175,000 deaths globally in 2018.[5] Onset is usually after the age of 45.[4] Males are affected more often than females.[4] The overall five-year survival rate is 75% in the United States, 71% in Canada, 70% in China, and 60% in Europe.[4][9][10][11] For cancers that are confined to the kidney, the five-year survival rate is 93%, if it has spread to the surrounding lymph nodes it is 70%, and if it has spread widely, it is 12%.[4]

Signs and symptoms[edit]

Paraneoplastic syndromes caused by kidney cancer can be broadly classified as endocrine and non-endocrine. Endocrine dysfunctions include increase in blood calcium levels (hypercalcemia), high blood pressure (hypertension), increased red bloods (polycythemia), liver dysfunction, milky nipple discharge unrelated normal breast-feeding (galactorrhea), and cushings syndrome. Non-endocrine dysfunctions include deposition of protein in tissue (amyloidosis), decrease in hemoglobin or red blood cells (anemia), disorders of nerves, muscles (neuromyopathies), blood vessels (vasculopathy) and blood clotting mechanisms (coagulopathy).[15]

Causes[edit]

Factors that increase the risk of kidney cancer include smoking, high blood pressure, obesity, faulty genes, a family history of kidney cancer, having kidney disease that needs dialysis, being infected with hepatitis C, and previous treatment for testicular cancer or cervical cancer.[16][17]

There are also other possible risk factors such as kidney stones being investigated.[18][19] Some studies have linked regular use of NSAIDs such as ibuprofen and naproxen to increases of kidney cancer risk by up to 51%.

About 25-30% of the kidney cancer are attributed to smoking.[17] Smokers have a 1.3 times higher risk of developing kidney cancer compared to non-smokers. Moreover, there is a dose-dependent increased risk of cancer development. Men who smoke more than 20 cigarettes per day have twice the risk. Likewise, women who smoke more than 20 cigarettes per day have 1.5 times the risk of non-smokers. After 10 years of smoking cessation a substantial reduction is seen in the risk of developing kidney cancer.[20]

 

 

 

 

Prostate cancer

Pathophysiology[edit]

 

The prostate is part of the male reproductive system that helps make and store seminal fluid. In adult men, a typical prostate is about 3 cm long and weighs about 20 g.[58] It is located in the pelvis, under the urinary bladder and in front of the rectum. The prostate surrounds part of the urethra, the tube that carries urine from the bladder during urination and semen during ejaculation.[59] The prostate contains many small glands, which make about 20% of the fluid constituting semen.[60]

Superiorly, the prostate base is contiguous with the bladder outlet. Inferiorly, the prostate’s apex heads in the direction of the urogenital diaphragm, which is pointed anterio-inferiorly. The prostate can be divided into four anatomic spaces: peripheral, central, transitional, and anterior fibromuscular stroma.[61] The peripheral space contains the posterior and lateral portions of the prostate, as well as the inferior portions of the prostate. The central space contains the superior portion of the prostate including the most proximal aspects of the urethra and bladder neck. The transitional space is located just anterior to the central space and includes urethra distal to the central gland urethra. The neurovascular bundles course along the posterolateral prostate surface and penetrate the prostatic capsule there as well.

Most of the glandular tissue is found in the peripheral and central zones (peripheral zone: 70-80% of glandular tissue; central zone: 20% of glandular tissue).[62] Some is found in the transitional space (5% of glandular tissue). Thus, most cancers that develop from glandular tissue are found in the peripheral and central spaces,[63] while about 5% is found in the transitional space. None is found in the anterior fibromuscular stroma since no glands are in that anatomic space.

The prostate glands require male hormones, known as androgens, to work properly. Androgens include testosterone, which is made in the testesdehydroepiandrosterone, made in the adrenal glands; and dihydrotestosterone, which is converted from testosterone within the prostate itself. Androgens are also responsible for secondary sex characteristics such as facial hair and increased muscle mass.

Because of the prostate’s location, prostate diseases often affect urination, ejaculation, and rarely defecation. In prostate cancer, the cells of these glands mutate into cancer cells.

Most prostate cancers are classified as adenocarcinomas, or glandular cancers, that begin when semen-secreting gland cells mutate into cancer cells. The region of the prostate gland where the adenocarcinoma is most common is the peripheral zone. Initially, small clumps of cancer cells remain within otherwise normal prostate glands, a condition known as carcinoma in situ or prostatic intraepithelial neoplasia (PIN). Although no proof establishes that PIN is a cancer precursor, it is closely associated with cancer. Over time, these cells multiply and spread to the surrounding prostate tissue (the stroma) forming a tumor.

Eventually, the tumor may grow large enough to invade nearby organs such as the seminal vesicles or the rectum, or tumor cells may develop the ability to travel in the bloodstream and lymphatic system.

Prostate cancer is considered a malignant tumor because it can invade other areas of the body. This invasion is called metastasis. Prostate cancer most commonly metastasizes to the bones and lymph nodes, and may invade the rectum, bladder, and lower ureters after local progression. The route of metastasis to bone is thought to be venous, as the prostatic venous plexus draining the prostate connects with the vertebral veins.[64]

The prostate is a zinc-accumulating, citrate-producing organ. Transport protein ZIP1 is responsible for the transport of zinc into prostate cells. One of zinc’s important roles is to change the cell’s metabolism to produce citrate, an important semen component. The process of zinc accumulation, alteration of metabolism, and citrate production is energy inefficient, and prostate cells require enormous amounts of energy (ATP) to accomplish this task. Prostate cancer cells are generally devoid of zinc. Prostate cancer cells save energy by not making citrate, and use the conserved energy to grow, reproduce and spread.

The absence of zinc is thought to occur via silencing the gene that produces ZIP1. It is called a tumor suppressor gene product for the gene SLC39A1. The cause of the epigenetic silencing is unknown. Strategies that transport zinc into transformed prostate cells effectively eliminate these cells in animals. Zinc inhibits NF-κB pathways, is antiproliferative, and induces apoptosis in abnormal cells. Unfortunately, oral ingestion of zinc is ineffective since high concentrations of zinc into prostate cells is not possible without ZIP1.[65]

Loss of cancer suppressor genes, early in prostatic carcinogenesis, have been localized to chromosomes 8p10q13q, and 16qP53 mutations in the primary prostate cancer are relatively low and are more frequently seen in metastatic settings, hence, p53 mutations are a late event in the pathology. Other tumor suppressor genes that are thought to play a role include PTEN and KAI1. “Up to 70 percent of men with prostate cancer have lost one copy of the PTEN gene at the time of diagnosis”.[66] Relative frequency of loss of E-cadherin and CD44 has also been observed. Loss of the retinoblastoma (RB) protein induces androgen receptor deregulation in castration-resistant prostate cancer by deregulating ‘E2F1 expression.[67]

RUNX2 is a transcription factor that prevents cancer cells from undergoing apoptosis, thereby contributing to cancer development.[68]

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