HDP400: Human Disease Process II Professor Joe Gordon Room 107 Extension: 5240 email: [email protected] What you need to know Breakdown: In-class Quizzes 20% Test #1 20% Test #2 25% Test #3 15% Test #4 20% 100% Resources: 1) Text Books – Copstead 2) Blackboard site (http://my.senecacollege.ca) 3) Library/Resource Centre References and Other Sources 1) Marieb EN. Human anatomy and physiology, 5th Ed. San Francisco, CA: Addison Wesley Longman Inc. (2001). 2) Marieb EN. Essentials of human anatomy and physiology, 6th Ed. San Francisco, CA: Addison Wesley Longman Inc. (2000). 3) Gould BE. Pathophysiology for the health-related professions. Philadelphia, PA; W.B. Saunders Company (1997). 4) Porth CM. Pathophysiology: concepts of altered health states, 5th ed. Philadelphia, PA: LippincottRaven Publishers (1998). 5) Lewis SM, Heitkemper MM, Dirksen SR. Medical-Surgical Nursing, 5th. St. Louis, MS: Mosby, Inc. (2000). 6) Ganong WF. Review of medical physiology, 19th Ed. Stamford, Connecticut: Appleton and Lange (1999). 7) Ingraham JL, Ingraham CA. Introduction to microbiology, 2nd. Pacific Grove, CA: Brooks/Cole. (2000). 8) McPhee SJ, Lingappa VR, Ganong WF, Lange JD. Pathophysiology of Disease, 3rd. New York, NY: McGraw-Hill Co. (2000). 9) Atlas of pathophysiology. Springhouse, PA: Springhouse Corp. (2002). 10) Bear MF, Connors BW, Paradiso MA. Neuroscience: exploring the brain. Media, PA: Williams and Wilkins (1996). 11) Lodish H, Baltimore D, Berk A, Zipursky SL, Matsudaira P, Darnell J. Molecular Cell Biology, 3rd Ed. New York, NY: Scientific American Books (1995). Urinary System The major roles of the kidneys are to: 1) Filter metabolic wastes from the blood (eg. Urea, uric acid, and creatinine) and excrete them from the body in the urine. 2) Regulate the blood volume and blood pressure by altering the volume of urine produced, and by releasing the enzyme renin into the blood, which activates angiotensin II promoting vasoconstriction and aldosterone secretion. 3) Production of erythropoietin in response to low blood O2 levels. Erythropoietin stimulates erythrocyte proliferation and maturation in the bone marrow. 4) Regulate the amount of electrolytes (ie. Na+, K+, Cl-, Ca++, phosphate) in the blood and extracellular fluid by altering the urine concentration and composition. In addition, the kidneys are responsible for activating vitamin D, which promotes Ca++ absorption in the small intestine. 5) Regulate the body’s pH by controlling the amount of H+ secreted and HCO3- reabsorbed from the filtrate. Anatomy of the Urinary System • The kidneys lie towards the posterior surface, and are partially protected by the lower ribs. • The kidneys receive blood from the renal arteries, which branch directly from the aorta, and return their ‘cleansed’ blood to the inferior vena cava through the renal veins. • Urine produced in the kidneys travels down the ureters to the urinary bladder for storage. • Urine leaves the body through the urethra during contraction of the bladder. (2) Anatomy of the Urinary System Continued (1) • The kidneys are located posterior to the peritoneum (ie. The connective tissue surrounding the GI tract) in the retroperitoneal area. • Each kidney is covered by a fibrous capsule and a layer of adipose tissue. • Because there are no pain receptors within the kidney, pain is only present when there is impingement on the renal capsule or ureter. The Kidney • Blood enters the kidney and is transported by smaller arteries to the outer portion of the kidney, called the cortex. The majority of blood is filtered here. • The inner portion of the kidney, called the medulla, alters the composition of the filtrate and forms urine. This area is susceptible to ischemic damage since it is very metabolically active, yet has a low O2 tension. The medulla is arranged in triangular shaped structures called medullary pyramids. • The urine drains into collecting ducts in the medulla and eventually passes to the renal pelvis and into the ureters for transport to the urinary bladder. (2) The Nephron • The urine producing apparatus in the kidney is called the nephron. • The nephron consists of a glomerulus, that filters the blood and forms a filtrate, and a tubule, that converts the filtrate into urine by reabsorbing water and electrolytes from the filtrate. • The tubule has three distinct regions. 1) The proximal tubule; 2) the loop of Henle, which enters into the medulla of the kidney; and 3) the distal tubule. • The distal tubule drains into a common collecting duct that makes some final modifications to the urine and ultimately transports the urine into the ureters. (1) Blood Supply to the Nephron • Blood flows into the glomerulus through the afferent arteriole, which divides into the glomerular capillaries. • These capillaries are very porous and allow large amounts of blood plasma to filter out into the glomerular capsule and into the proximal tubule. • Blood leaves the glomerulus through the efferent arteriole, which divides into the peritubular capillaries. These capillaries surround the tubule and function to absorb water and electrolytes from the filtrate. (1) Renal Blood Pressures (1) • Blood to the kidney is regulated to maintain filtration, and not to satisfy the metabolic needs of the tissue. At rest the kidneys receive 25% of the cardiac output (1.3 L/min). These numbers are decreased with exercise and exertion. •The blood pressure in the glomerular capillaries is about 55 mmHg. This high pressure is maintained by the flow through the afferent arteriole (BFG) and the high resistance to flow in the efferent arteriole (RG). The glomerular blood pressure (BPG) is the driving force to create filtration, and determined by: BPG = BFG x RG Where, BFG is increased with afferent arteriolar dilation and decreased with constriction, and RG is increased with efferent constriction and decreased with dilation. When BPG is increased, filtration is increased, and when BPG is decreased, filtration is decreased. Urine Formation The nephron uses 3 processes to produce urine and control its volume and composition: 1) Filtration: Water and dissolved solutes smaller than 8 nm are filtered through the glomerular capillaries and into the tubule. 2) Reabsorption: Water, glucose, amino acids and selected electrolytes are transported into the tubular cells an enter into the peritubular capillary blood. 3) Secretion: H+, K+, some metabolic wastes and drugs are secreted from the tubular cells into the filtrate. (2) The Glomerulus (1) • The glomerular capillaries are formed from the afferent arteriole. • Like most capillaries, the glomerular capillaries are comprised of endothelial cells; however, these cells have ‘holes’ called fenestrations and are covered by epithelial cells call podocytes. • The glomerular capillaries are surrounded by Bowman’s capsule, which is continuous with the renal tubule. • Associated with the afferent and efferent arterioles is the juxtaglomerular apparatus. The juxtaglomerular cells secrete renin in response to low blood pressure or SNS stimulation. The macula densa is part of the distal tubule and senses changes in the concentration of the filtrate, and can dilate or constrict the arterioles appropriately. The Glomerulus Continued • The fenestrations in the glomerular capillaries only allow particles less than 8 nm to pass; however, the capillary basement membrane contains negatively charged proteoglycan. This effectively repels other anions, like the protein albumin. • The glomerulus is commonly injured by immune complexes (ie. Antibody-antigen complexes). This produces an inflammatory response in an attempt to destroy the immune complex by phagocytosis. (1) • If the immune complexes are within the endothelial layer, they are accessible to phagocytes. This is common in nephritic syndrome. If the immune complexes lie within the epithelial cells (ie. On the other side of the basement membrane) they are not accessible to phagocytes and this creates nephrotic syndrome. • Inflammation of the glomerulus allows protein to enter the filtrate and urine; however, in nephritic syndromes there are blood cells in the urine and in nephrotic syndromes there are not. The Glomerular Filtration Rate • Filtration through the glomerular capillaries is governed by the same forces as any other capillary in the body. Blood hydrostatic pressure pushes fluid out and the colloid osmotic pressure pushes fluid into the capillary. (1) • The glomerular capillaries are fenestrated to increases their permeability, also the blood pressure is quite high compared to other capillaries. • The glomerular filtration rate (GFR) is the amount of blood plasma filtered through the capillaries in one minute (125 mL/min). GFR is regulated primarily by altering the glomerular blood pressure (BPG). Increasing flow through the capillaries (ie. Afferent dilation) and increasing the resistance to flow (ie. Efferent constriction) increases GFR; whereas, decreasing flow and decreasing resistance decreases GFR. Regulating GFR (1) The Renal Tubule (2) • The renal tubule is responsible for reabsorbing glucose, amino acids, electrolytes and water from the filtrate. • Other substance (ie. K +) may be secreted into the filtrate. • Reabsorption and secretion may occur passively or by active processes. • Passive processes include diffusion and osmosis; whereas, active processes require ATP either directly (primary active) or indirectly (secondary active or cotransport). • 180 L/day of water is filtered through the glomerulus and the normal urine volume is only about 1 L/day. Therefore, more than 99% of the filtrate is normally reabsorbed. The Proximal Tubule (1) • Most reabsorption in the proximal tubule occurs by Na+ co-transport. • A Na+ concentration gradient is created by the Na+/K+ pump on the basal surface of the tubule cells. This gradient is used to power the absorption of other molecules like glucose. • The glucose transporter is called the sodium-dependent glucose transporter (SGLT). • Cl- ions diffuse passively through Cl- channels and maintain electrochemical neutrality. • Water is reabsorbed by the osmotic gradient created by reabsorption of solutes. Water passes the plasma membrane through pores created from the protein aquaporin-1. The Loop of Henle • The primary function of the loop of Henle is to remove water from the filtrate. • This is achieved by a highly concentrated interstitial fluid (ISF) that becomes more concentrated deeper into the medullary pyramid. This concentration gradient is maintained by the peritubular capillaries. • As filtrate descends into the loop, water is pulled out by osmosis because of the ISF concentration. (1) • The loss of water creates a highly concentrated filtrate. As the filtrate ascends the loop, Na+ and Cl- are actively reabsorbed to reduce the filtrate concentration. • The net result is a greatly diminished filtrate volume. Aldosterone and Vasopressin (Antidiuretic Hormone) Tubule Lumen Tubule Epithelial cell • Both aldosterone and vasopressin (ADH) exert the majority of their effects on the collecting ducts of the kidneys. • Released from the adrenal cortex in response to angiotensin II, aldosterone increases the production of the epithelial sodium channel (ENaC). This increases the sodium absorption from the collecting duct. Water follows osmotically through aquaporin-1. • ADH is released from the posterior pituitary in response to high extracellular fluid osmolarity or low blood pressure. ADH causes a vesicle bound aquaporin-2 to move to the plasma membrane and increase the absorption of water. Interstitial fluid Aldosterone Na+ + K+ K+ Na+ H 2O ADH + H 2O Renal Control of Acid-Base Status (1) • The proximal tubule cells utilize the enzyme carbonic anhydrase to help regulate the body’s pH. • This enzyme converts CO2 and H2O into H+ and HCO3-, and vise versa. • CO2 from the peritubular capillaries or from filtered HCO3- is converted into H+ and HCO3- within the cells. • H+ is then secreted into the filtrate through the Na+/ H+ exchanger, while HCO3- is reabsorbed. • This system is regulated by the PCO2 in the peritubular capillaries. • If PCO2 is elevated, more H+ is secreted and HCO3- absorbed. Additionally, K+ tends to be conserved when more H+ is secreted. If PCO2 is decreased, less H+ is secreted and HCO3- absorbed. • H+ secretion and HCO3- absorption are therefore intimately linked. Metabolic Acidosis (3) Normal Values: pH = 7.4 HCO3- = 24 mmol/L H2CO3 = 1.2 mmol/L Ratio = 20:1 PCO2 = 40 mmHg • Renal disorders can result in failure of the tubules to secrete H+ and reabsorb bicarbonate. This results in a metabolic acidosis. • Bicarbonate is reduced and the normal 20:1 is depressed to about 18:1 due to a bicarbonate level less than 24 mM/L. • The respiratory system has a limited ability to compensate for this by increasing the respiratory rate. This effectively reduces the PCO2 to less than 40 mmHg and the H2CO3 to less than 1.2 mM/L, and restores the 20:1 ratio. • If persistent, the compensation is insufficient and decompensation results. Renal Disorders Renal disorders commonly manifest as elevated blood urea nitrogen (BUN), elevated serum creatinine, and failure to maintain Na+, K+, water, and acidbase balance. These manifestations can result in complications such as hypertension, symptoms of CHF, peripheral edema, and death. Azotemia: When metabolic products that are normally excreted by the kidneys accumulate in the blood. Examples include urea, creatinine, and other toxic metabolic products. Uremia: A complex group of symptoms that occur due to inadequate renal function. Can be caused by accumulating metabolic toxins, fluid and electrolyte imbalances, acidosis, and anemia. Oliguria and anuria: Oliguria is a diminished urine volume; whereas, anuria is an absence of urine production. Diuresis or polyuria: Increased urine production. Renal disease can be categorized by the site of the lesion (eg. Glomerulus vs. tubule), by the etiology (eg. Immumologic, infectious, hemodynamic, etc.), or a combination of the two (eg. Prerenal, intrarenal, and postrenal). 1) Prerenal Disease: Results from inadequate blood flow to the nephron. Examples include hypovolemia, hypotension, drug-induced reduction in perfusion, septic shock, and stenosis of the renal arteries. Renal Disorders Continued 2) Intrarenal Disease: Result from intrinsic damage to the nephron. Examples include acute tubular necrosis, glomerulonephritis, nephrotic syndrome, vasculitis, malignant hypertension, diabetic nephropathy, and pyelonephritis. 3) Postrenal Disease: Result from urinary tract obstruction. Examples include ureter obstruction, prostate disease, malignancy, and calculi. Renal failure can be managed by attempting to treat the cause, conservative dietary manipulation, dialysis, and renal transplant. If anemia is present, erythropoietin is used to stimulate bone marrow production of red blood cells. If inflammation is present, corticosteroids are often used. Acute Renal Failure • Acute renal failure (ARF) represents a group of disorders that cause in rapid deterioration in renal function resulting in azotemia. • ARF presents as rapidly rising BUN/ creatinine and a diminished urine volume (ie. oliguria). • Sepsis is one of the most common causes of ARF. In addition to hypotension caused by systemic vasodilation, and patients with sepsis are often exposed to nephrotoxic antibiotics. • Patients with preexisting renal hypoperfusion (ie. CHF, diabetes, renal stenosis) may develop ARF by ingesting NSAIDs or ACE inhibitors, as prostaglandins dilate the afferent arteriole and angiotensin II acts to constrict the efferent arteriole. (4) • Other causes include eclampsia, hemolysis, and muscle damage due to trauma (ie. Hypermyoglobinemia/rhabdomyolysis), as filtered heme-containing molecules damage the renal tubules. Acute Renal Failure Continued • In the early stages of prerenal disease, GFR is decreased due to renal hypoperfussion (ie. Prerenal azotemia). • Regardless of the etiology, ARF will likely result in necrotic death of the tubule epithelial cells (ie. acute tubular necrosis) without successful treatment. • Manifestations of ARF are a result of tubule obstruction by necrotic tissue. This increases the intratubule pressure and offsets the filtration pressure. The result is a dramatic reduction in GFR. • Acute tubular necrosis results in a loss of tubular function and failure to concentrate urine. • Cell debris and protein can be formed to together within the tubule to forms casts, which are excreted in the urine. (3) Acute Tubular Necrosis (9) Manifestations of ARF Initial signs/symptoms include: 1) Elevated BUN and creatinine (ie. azotemia) because of decreased GFR. BUN increases rapidly with increased protein catabolism (eg. Fever and sepsis). Creatinine is unusually high if rhabdomyolysis is the cause. 2) Oliguria caused by decreased GFR and/or tubule obstruction. However, roughly 25% of patients will not have oliguria, especially when ARF is caused by nephrotoxins. 3) Hyperkalemia occurs if GFR is greatly reduced and there is significant acidosis. Typical ECG changes can occur and predispose to arrhythmias. 4) Fatigue and malaise likely due to water intoxication (ie. Hyponatriemia), hyperkalemia, acidosis, and elevated metabolic wastes (ie. Toxicity). Later symptoms include: 1) Dyspnea, orthopnea, rales, and third heart sound caused by fluid overload. 2) Edema caused by fluid overload. 3) Altered mental status occurs when metabolic wastes become increasingly elevated in the blood. Although elevated BUN is not toxic itself, it is a good indicator toxicity. Altered electrolytes and acidosis contribute. 4) Urinalysis may show hematuria, proteinuria, and pyuria. With acute tubular necrosis cast are present and the urine is very dilute (low specific gravity). Mortality rates and Resolution • Since ARF commonly affects people with serious illness, mortality rates are rather high, ranging from 42%-88% even with dialysis. Immunosuppression and bleeding can occur because of toxicity, and often contribute to mortality. • ARF is potentially reversible even when complicated by tubule necrosis, since these cells are epithelial. Most patients who recover will eventually regain a normal renal status; however, if the damage to the kidneys is extensive, entire nephrons could be lost and chronic renal failure can ensue. Therefore, prevention and early treatment must be emphasized to prevent acute tubular necrosis whenever possible. • Resolution of ARF is characterized by a phase of diuresis, which begins a few days to weeks after the onset of azotemia and oliguria. Diuresis usually begins before the nephrons have fully recovered; therefore, BUN and electrolytes remain abnormal indicating decreased GFR and tubular dysfunction. Careful monitoring to prevent fluid depletion and low electrolytes is indicated. • In ARF clearance of medication is often altered. Careful monitoring for signs of drug toxicity must be done during the oliguric and diuretic phases. Chronic Renal Failure • Chronic renal failure results from the gradual irreversible destruction of nephrons and loss of renal function. • This results in an increased workload on the remaining nephrons, increased glomerular filtration pressure, and hyperfiltration. (8) • Hyperfiltration predisposes to fibrosis and scaring (glomerulosclerosis) and increases the rate of nephron destruction. • End-stage renal failure presents as a complex of symptoms called uremia. Uremia is caused by retained fluid, electrolytes, waste products and hormones, and loss of renal endocrine function. Additionally, BMR is reduced (hypothermia) and blood lipoproteins are increased (probably due to decreased Na+/K+ ATPase activity and lipoprotein lipase activity). • Uremia produces clinical abnormalities in fluid and electrolyte balance, bone metabolism, CNS, cardiovascular, skin, GI, hematologic, and metabolic control. Chronic Renal Failure Continued Occurs in three stages: 1) Reduced renal reserve: Up to 50% of nephrons can be lost without producing signs and symptoms. However, if the cause is not detected, damage will continue. 2) Renal insufficiency: Occurs when more than 20% of nephrons remain. There is a decrease in GFR, reabsorption and secretion capacity, resulting in moderate azotemia (ie. Elevated BUN). (3) 3) End-stage renal failure (uremia): Occurs when less than 20% of nephrons remain. GFR and tubular function are greatly reduced resulting in oliguria/ anuria, marked azotemia, and failure to concentrate urine. Manifestations of Renal Insufficiency The manifestations of this stage are predominately due to decreased GRF, and hyperfiltration of remaining nephrons. 1) Hyponatriemia and hypokalemia. 2) Mild azotemia: Due to decreased GFR. 3) Mild acidosis: Due to decreased tubular function resulting in diminished H+ secretion and HCO3- reabsorption. 4) Generalized weakness and fatigue: Likely due to azotemia, mild acidosis, electrolyte abnormalities, and possibly mild anemia (decreased erythropoietin production). 5) Increased blood pressure: Falling renal perfusion stimulates the overproduction of renin, increasing systemic vasoconstriction and aldosterone secretion. * Any condition that increases H+, decreases body fluid, or alters electrolytes will induce uremic symptoms. Examples include vomiting, diarrhea, infection, diminished respiration, stress, dehydration, increased catabolism or nephrotoxic drugs. Manifestations of Uremia 1) Fluid, Na+, and K+: Sodium and volume overload are common in uremia. Excess ingestion of sodium contributes to circulatory congestion, hypertension, ascites, edema, and weight gain. Excess water can causes hyponatriema. There is also a diminished reserve to conserve sodium and water in the during time of loss (ie. Vomiting and diarrhea). This can lead to circulatory shock. Hyperkalemia can become a serious problem is GFR falls below 5 mL/min. Hemolysis, acidosis, and infection increase the risk of hyperkalemia. 2) Metabolic acidosis: Occurs only moderately when GFR is ↓ Vitamin D greater than 20 mL/min, which can be compensated by increased respirations. Will become decompensated if GFR falls below 20 mL/min or if exposed to other acid loads (ie. ↓ Blood Ca++ Lactic acidosis, infection or pneumonia). 3) Bone and Mineral: Decreased activation of Vitamin D results ↑ PTH in decreased absorption of calcium from the gut, and a fall secretion in serum calcium levels. This stimulates PTH secretion and bone breakdown in an attempt to raise serum calcium. Chronic acidosis also contribute to bone breakdown. ↑ Bone Calcifications occur due to increased Ca2+ x phosphate. breakdown Manifestations of Uremia Continued 4) Cardiovascular and Pulmonary: Symptoms of circulatory congestion, hypertension, and pulmonary edema occur because of sodium and volume overload, and hyperreninemia. Irritation by uremic toxins can cause pericarditis. Atherosclerosis is accelerated resulting in MI, stroke, and PVD. This is mostly due to elevations in blood pressure and hyperlipidemia caused by inhibition of lipoprotein lipase. 5) Hematological: Decreased production of erythropoietin causes anemia with hematocrits of 20-25%. This is not corrected by dialysis, and requires erythropoietin treatment. Abnormal hemostasis and white cell function are also common in uremia, resulting in bleeding and immunosuppression. 6) Neurological: Symptoms include sleep disorders, poor concentration, loss of memory, seizures, hiccups, twitching, and coma. Sensory peripheral neuropathy can also occur. Neurological effects were believed to be due to urea; however, it is likely that they are caused by elevated organic acids or phenols, mostly derived from protein catabolism (ie. Protein restricted diet). BUN corresponds well with the degree of CNS disturbance. 7) GI and skin: Common findings include anorexia, nausea, and vomiting. Bad breath (uremic fetor) can occur when saliva enzymes breakdown urea into ammonium. Skin changes include uremic frost and colour. Diabetic Nephropathy • Diabetes is the leading cause of end-stage chronic renal failure requiring dialysis and transplant. • Diabetic nephropathy primarily involves the glomerular capillaries. In the early stages, loss of negatively charged proteoglycan in the basement membrane allows small amounts of albumin to filter into the tubules and enter the urine (ie. Microalbuminuria). • Fibrosis and thickening of the capillary basement membrane occurs, and is referred to as glomerulosclerosis. As this process continues, the glomerulus is destroyed, an inflammatory response is initiated, and the nephron is lost. • This results in an increased workload on the remaining nephrons, and hyperfiltration to maintain GFR. Hyperfiltration predisposes to more glomerulosclerosis and increases the rate of nephron destruction. As the number of glomerular lesions increase, massive proteinuria occurs. • Eventually, the loss of nephrons is so great that renal failure occurs. Hypertension increases glomerular hyperfiltration and can accelerate nephron loss. Type II diabetics often have hypertension at the time of diagnosis, but type Is usually do not develop hypertension until after the onset of nephropathy. Nephropathy occurs in 25% of type Is, but only 5% of type IIs. Urinary Tract Infections • UTIs are the second most common infections seen by health care providers. • Lower UTIs include cystitis (bladder) urethritis (urethra); whereas, upper UTIs involve the kidney, and are called pyelonephritis. • Most UTIs are ascending and arise from microbes entering the urethra; however, some causes of pyelonephritis are blood-borne. • The major host defense against ascending infection is the ‘flushing’ effect of urine flow. (3) Therefore, stasis of urine is a major contributing factor causing UTI. • An Escherichia Coli opportunist infection is the most common cause of UTI, including nosocomial infections. Fecal proteus bacteria are second. Etiology of UTI • E. coli’s ability to cause UTIs is related to its pili and ability to bind to urinary epithelial cells. Urine flow tends to prevent this. Some bacterial strains can use urea as an energy source, liberating free ammonium (eg. Proteus). Glucosuria (eg. Diabetes) provides an additional energy source. (7) • Females are generally more susceptible to UTIs due to anatomical vulnerability (eg. Short, wide urethra, and proximity to the anus). However, older males often suffer from prostate hypertrophy which causes retention of urine and frequent UTIs. • Other factors that predispose to UTIs are incomplete bladder emptying and obstruction of urine flow. Examples include incontinence, pregnancy, scar tissue, congential defects of the ureter, or impaired blood supply to the bladder. Catheterization and sexual intercourse also increases the risk of UTI. • A relationship exists between UTIs and renal calculi. Calculi can obstruct urine, causing infections, while ammonium liberated by infection makes the urine more alkaline and predisposes to calculi formation. Cystitis Manifestations: 1) Pain: Abdominal pain and pain during micturition (dysuria) are common in cystitis. 2) Frequency and urgency (Irritative symptoms): Inflammation and swelling of the bladder reduce its capacity often resulting in frequent and urgent urination. (9) 3) Systemic signs of infection (ie. Fever, malaise, nausea, and leukocytosis). 4) Urinalysis: Bacteriuria, pyuria, and microscopic hematuria are common creating cloudy urine with an unusual odor. Treatment: • Antibiotic therapy combined with increased fluid intake help eliminate evading organisms. Cranberry and blueberry juice contain tannins that interfere with the pili of E. coli and prevent binding to urinary epithelia. Pyelonephritis • Pyelonephritis can result from an ascending infection from the bladder or from bacteriemia. • Often the infection involves the renal pelvis and medullary tissue, resulting in inflammation and possibly necrosis. • If severe, exudate and pus compress the renal vessels resulting in ischemia and hypertension, while compression of the ureter obstructs urine flow. (9) Manifestations: • Pain associated with distension of the renal capsule is described as dull aching in the lower back or flank area. Systemic signs are marked with symptoms of cystitis (ie. Dysuria). Urinalysis includes casts (leukocyte and epithelia), failure to concentrate the urine, and bacteriuria similar to cystitis. Bilateral obstruction is likely to cause acute renal failure. Chronic or repeat infection can lead to chronic failure. Glomerulonephritis Glomerulonephritis can be classified according to the clinical presentation, which can be nephritic syndrome or nephrotic syndrome. They are caused by disorders of the kidney or systemic diseases that affect the kidney. Nearly all causes are immune mediated. Most common include: postinfectious disease (eg. Streptococci, pneumococci, hepatitis B, mononucleosis, measles, mumps, malaria), sepsis, endocarditis, lupus, rheumatic disease, and idiopahtic autoimmune. The common clinical presentation of nephritic syndrome involves hematuria, proteinuria, reduced GFR, and hypertension. However, nephritic syndrome generally follows one of three paths: 1) Acute glomerulonephritis: An abrupt onset of symptoms, often resulting in acute renal failure, followed by full recovery of renal function. 2) Rapidly progressive glomerulonephritis: An abrupt onset of symptoms, in which recovery from acute renal failure does not occur. Over weeks to months this disorder progresses to chronic renal failure. 3) Chronic glomerulonephritis: Acute glomerulonephritis which progresses slowly over a period of years (ie. 5-20) to chronic renal failure. * It is unclear why nephritic syndromes can take alternatives courses Acute Poststreptococcal Glomerulonephritis • APSGN occurs because of an immune attack on a streptococcal antigen results in immune complex and complement deposits in the glomerular capillaries. • Nephritic manifestations usually occur 7-10 days after the onset of a pharyngeal or cutaneous infection with group A streptococcus (ie. Streptococcal pyogens), and resolve over a period of weeks. • APSGN usually effects children between ages 3-7 years, and is more common in boys. Manifestations: • Damage to the glomerular capillaries gives rise to hematuria and proteinuria. • Glomerular infiltration with inflammatory cells results in a fall in GFR, causing oliguria and azotemia. (4) APSGN Manifestations Continued • Pain in the flank or lower back is attributed to distension of the renal capsule. • Hypertension and edema (ie. Typically facial and periorbital) are a consequence of fluid and salt overload due to a reduced GFR. Hyperreninemia and decreased colloid osmotic pressure may also contribute. • Blood analysis reveals an elevation of antibodies to streptococcal antigens (ie. Antistreptolysin O; ASO, and antistreptokinase; ASK). Metabolic acidosis may also be present. • Urine analysis reveals proteinuria, hematuria, and erythrocyte casts. Resolution: • Most cases resolve with a diuretic phase after treatment for the infection (ie. Especially in children). In adults, it may not be as easily resolved. Some cases ultimately progress to chronic renal failure. (3) Nephrotic Syndrome • Nephrotic syndrome occurs secondary to a number of disorders including infection, lupus, exposure to nephrotoxins, neoplasia, diabetic nephropathy, and immune-mediated. • This syndrome commonly presents with marked proteinuria, hypoalbuminemia, generalized edema, hyperlipidemia, and lipid in the urine (milky appearance with increased specific gravity). (3) • Nephrotic syndrome results from inflammation of the glomerulus with immune complexes within the glomerular basement membrane or foot processes, but without the presence of cellular immune cells. • Reduced colloid osmotic pressure results in massive edema in dependent areas, ascites, weight gain and effusions. Blood pressure is not usually elevated due to third-spacing and hypovolemia. Hypovolemia can manifest as syncope, circulatory shock, and acute renal failure. Impaired capillary exchange may cause skin breakdown and infection. Nephrotic Syndrome Continued • Hyperlipidemia appears to result from the decreased colloid osmotic pressure. This stimulates the liver to increase production of lipoproteins, resulting in elevated plasma LDL and VLDL. • Loss of plasma proteins other than albumin can cause : deficient phagocytosis and opsonization (loss of antibodies and complement), hypercoagulability (loss of plasma anticoagulants like antithrombin), secondary parathyroidism (loss of vitamin D binding proteins), iron deficiency (loss of transferrin) and abnormal thyroid function (loss of thyroid binding protein). • Some cases of nephrotic syndrome are considered a minimal change disease, where all manifestations are due to proteinuria and progression to uremia does not occur. • Sometimes the distinction between nephrotic and nephritic forms of glomerulonephritis is difficult or impossible to make. Treatment: • Usually treated with glucocorticoids to reduce glomerular inflammation. Reoccurrence is common. Urinary Calculi • The most common cause of urinary tract obstruction is urinary calculi or nephrolithiasis • Stones can be made of various solutes the kidney normally excretes. Stone formation requires a nucleus to initiate formation and an environment that encourages precipitation • There are generally four types of stones that can form in the urinary tract. 1) Calcium (phosphate or oxalate) 2) Struvite (magnesium, ammonium, and phosphate) 3) Uric acid 4) Cystine (9) Urinary Calculi Continued • Approximately 75% of all stones contain calcium, and most are due to idiopathic hypercalciuria. Other causes include hyperparathyroidism, and immobility. • Uric acid stones account for 10% of stones with hyperuricosuria, gout, chemotherapy, obesity, a diet high in organ meats, red meat, and acidic urine acting as contributing factors. • Struvite stones represent nearly 15% of stones. They occur primarily because of a chronic or recurrent UTI with urea metabolizing bacteria where the urine pH is alkaline. Cell debris may also act as a nucleus for stone formation. • Cystine stone are very rare. They usually result from inherited disorders of amino acid metabolism Pathogenesis: • Renal stones occur when organic salts precipitate in the urinary tract. This can result from saturation (ie. Too much solute, not enough solvent), or due to a change in the solubility of a salt (ie. Change in pH). • Dehydration favours stone formation by increasing urine concentration and decreasing the Ca++ transit time. High Na+ and high protein diets; as well as hypertension also predispose to stone formation. Manifestations of Urinary Calculi • Impingement of the renal capsule results in lower back and flank pain; whereas distension of the ureter causes the pain to radiate into the groin, perineum, or scrotum. This acute, intermittent, excruciating pain is often called renal colic. As the stone moves into the bladder and urethra, lower abdominal pain occurs. • Oliguria, hematuria occur with and without fever. If stones obstruct both kidneys, there is underlying renal disease, or if the patient has only one kidney, post-renal azotemia (ie. acute renal failure) and anuria result. Other signs of hydronephrosis and hydroureter may occur. Treatment: • Passage of a stone usually requires fluids, bed rest, and analgesics. Occasionally, diuretics, antibiotics, alkali therapy, or aggressive stone removal is required. If possible, a sample of the stone should be kept to identify the underlying pathophysiology and prevent reoccurrence. Alterations in diet are often useful. Low sodium and protein intake often prevents stone formation, while decreasing calcium intake is only helpful a few sufferers. In others, diminished calcium intake may accelerate stone formation. A reduction of dietary organ meats, red meat, and caffeine is useful for uric acid stones. Supplementation of citrate magnesium, and dietary fibre is also useful. Urinary Obstruction • Renal calculi and prostate disease are the more common causes of urinary obstruction. • The two most damaging effects of obstruction are stasis of urine, which predisposes to infection, and increased backpressure, which can impair renal blood flow and damage renal tissue. Obstruction can be either partial or complete. • Impedance to urinary flow increases the pressure within the renal pelvis and calices. This can obstruct blood flow to the medulla and cause ischemic damage and necrosis. • Irreversible nephron damage can occur within a few days of complete obstruction; whereas, recovery can take weeks after the obstruction is removed. • Dilation of the ureters (ie. Hydroureter) and renal pelvis (ie. Hydronephrosis) occurs with prolonged obstruction. (4) Urinary Obstruction Continued • Renal colic occurs due to distention of the bladder, ureter, or renal capsule. Pain is usually more severe in acute obstructions. • A disruption of visceral innervation may impair GI mobility causing abdominal distension and paralytic ileus. • Early diagnosis and treatment is important because failure to restore urinary flow can result in permanent renal damage. A bilateral obstruction can result in renal failure. (9) Benign Prostate Hyperplasia • BPH is nonmalignant growth of prostate. Testosterone • The cause is unknown; however, aging and hormonal factors play a role. • As the name suggests, the growth of the prostate is related to increased cell number and not increased cell size (ie. Hypertrophy). • BPH effects 40% of men in their fifties, 70% in their sixties, and 90% in their eighties. One-third of men over 65 are symptomatic. Estrogen + Growth Factors • The normal prostate contains both epithelial and smooth muscle cells. Circulating testosterone acts to produce protein growth factors (eg. FGF, IGF) that act to maintain normal prostate size. Even though serum testosterone decreases as the male ages, serum estrogens tend to rise. Estrogens increase the number of testosterone receptors and increase prostate sensitivity. Prostate smooth muscle contains α1- receptors that stimulate them to contract. Manifestations of BPH Obstruction to urine outflow and bladder dysfunction are responsible for the major manifestation. Symptoms fall into two categories. Irritative symptoms and obstructive symptoms. 1) Irritative symptoms are a result of bladder hypertrophy and dysfunction. They include: frequency, nocturia, and urgency. 2) Obstructive symptoms result from narrowing of the bladder neck and urethra. They include difficulty initiating urination, decreased urinary flow (ie. Force and caliber), intermittency, hesitancy, and dribbling. • Complications include urinary tract infections, hematuria, post-renal azotemia, and chronic renal failure from bilateral hydroureter and hydronephrosis. • Digital rectal exam usually reveals diffuse enlargement of the prostate that does not correlate well with symptoms. Bladder distention and hypertrophy is also common. Treatment: Usually involves α1-blockers, androgen-blockade, prostate stents, and surgery. Prostate Cancer • In 2008, prostate cancer was the most common cancer in males, and was third in number of cancer deaths. The mortality rate is estimated at 15-20%. • The cause of prostate cancer is unknown, although environmental and genetic factors may play a role. Risk factors: Men who have a first-degree and second-degree relative with prostate cancer are at eight times the risk. Prostate cancer is more common in men over the age of 50, but occurs earlier in men of African descent. It is interesting that prostate cancer never develops in men who have been castrated; therefore testosterone is believed to be a risk factor. Dietary fat and red meat are believed to increase the risk, as well as obesity and inactivity. There is no epidemiological data linking BPH or infectious disease to prostate cancer; however, prostatitis may be a risk factor. Manifestations: • Most tumors are asymptomatic. Depending on the size of the tumor, there may be changes in urination similar to BPH. • The prostate produces a protein called prostate-specific antigen (PSA). Although its function is not known, PSA can become elevated in the serum during prostate disease (ie. Cancer, BPH and prostatitis). Prostate Cancer Continued • Since most prostate tumors are asymptomatic, screening is indicated for those at risk. Common screening tests are serum PSA, rectal examination, and ultrasound. Thirty percent of men with elevated PSA have prostate cancer. Rectal exam can detect hard nodular tumors; whereas, ultrasound can detect tumors are small as 5 mm. • The diagnosis is usually confirmed with prostate biopsy. Treatment: • Prostate cancer is usually treated by surgery, radiotherapy, and androgendeprivation therapy.
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