MODULE 17: ROMANCING THE PAIN 1. Enumerate the parts of the urinary system.

Describe the gross and microscopic appearance of each part. Gross Anatomy of the urinary system Kidneys - retroperitoneal organs/ against posterior abdominal wall - right kidney slightly lower than left due to large size of right lobe of liver - upper pole of right rest on 12th rib - left kidney rests on 11th & 12th ribs - each gives rise to a ureter w/c runs vertically down to psoas muscle - on medial concave border is a vertical slit bounded by thick lips of renal substance called the hilum Hilum - extends into a the Renal Sinus - passed by lymph vessels & sympathetic fibers - transmits from front backward the: renal vein 2 branches of renal artery Ureter 3rd branch of renal artery Renal Pelvis - renal pelvis divides into 2 or 3 major calyces - minor calyces arise from the major calyces - funnel-shaped expanded upper end of ureter - each minor calyx is indented by the apex of renal pyramid the renal papilla Renal Papilla - indented by the apex of renal pyramid 2 zones are identifiable in longitudinal section: - cortex - outer zone - extends into the medulla between adjacent pyramids as the renal papilla - medulla - inner zone - composed of about a dozen of renal pyramids w/ base oriented to cortex & its apex, renal papillae, medially - Medullary Rays - striations extending from base of pyramids into cortex - Coverings: 1. Fibrous capsule - surrounds kidney 2. Peritoneal fat - covers fibrous capsule

3. Renal fascia - condensation of CT - outside perirenal fat - encloses the kidneys & suprarenal glands - continuous laterally with fascia transversalis 4. Pararenal fat - external to renal fascia - often in large quantity - forms part of retroperitoneal fat Peritoneal fat, Renal fascia & Pararenal fat - support kidneys & hold them in position on posterior abdominal wall Blood Supply Arteries Aorta Renal Artery 5 Segmental Arteries - enters each hilum - 4 in front & 1 behind renal pelvis Lobar Arteries - arise from each segmental artery one for each renal pyramid 3 Interlobar Arteries - run toward the cortex on each side of renal pyramid Arcuate Arteries - junction of cortex & medulla - arch over bases of pyramid Several Interlobar Arteries - Ascend in the cortex Afferent Glomerular Arterioles - each intracts with glomerular portion of nephron & breaks into capillary network

Glomerulus Efferent Glomerular Arterioles Peritubular Capillaries (surrounds tubules) - reunite to form venous channels through which blood ultimately leaves the kidney Veins Left and Right Renal Vein - emerges from hilum in front of renal artery Inferior Vena Cava Lymph Drainage - lateral aortic lymph nodes around the origin of renal artery Nerve Supply - Renal sympathetic plexus - Afferent fibers that travel through the renal plexus enter the spinal cord in the 10th, 11th & 12 thoracic nerves. Relations of the Right Kidney Anteriorly: Suprarenal gland Liver 2nd part of the duodenum Right colic flexure Posteriorly: Diaphragm Costodiaphragmatic recess of the pleura 12th rib Psoas Quadratus lumborum Transverses abdominis muscles Subcostal (T12), iliohypogastric and ilioinguinal nerves (L1) run downward and laterally Relations of the Left Kidney Anteriorly: - Suprarenal gland - Spleen - Stomach - Pancreas - Left colic flexure

- Coils of jejunum Posteriorly: Diaphragm Costodiaphragmatic recess of the pleura 11th and 12th ribs Psoas Quadratus lumborum Transverses abdominis muscles Subcostal (T12), iliohypogastric and ilioinguinal nerves (L1) run downward and laterally Ureters - muscular tubes - extend from kidneys to posterior surface of urinary bladder - 10 in [25 cm] long - resembles esophagus in having 3 CONSTRICTIONS along its course: where renal pelvis joins the ureter where it is kinked as it crosses the pelvic brim where it pierces the bladder wall Male Ureter Cross bifurcation of common iliac artery in front of sacroiliac joint Pelvis Lateral wall of pelvis in front of internal iliac artery Region of ischial spine Lateral angle of bladder - near termination, crossed by vas deferens - ureter passes obliquely through wall of bladder for about 0 .75 in [1.9 cm] nefore enteriong into bladder

Female Ureter Crosses over the pelvic inet in front of the bifuration of the common iliac artery down & back in front of internal iliac artery & behind ovary

Reaches the region of the iliac spine Turns forward & medially beneath the base of the broad ligament, where it is crossed by the uterine artery Runs forward, lateral to the lateral fornix of the vagina Bladder Relations of Ureter Right Ureter Anteriorly: duodenum - terminal part of ileum - right colic & ileocolic vessels - right testicular or ovarian vessels - root of the mesentery of the small intestine Posteriorly: right psoas muscle (separates ureter form lumbar transverse processes) - bifurcation of right common iliac artery Left Ureter Anteriorly: - sigmoid colon - left colic vessels - sigmoid mesocoon - left testicular or ovarian vessels Posterior: - left psoas mucle (separates ureter from lumbar transverse proceses) - bifurcation of left common iliac artery Blood Supply: Artery: Upper end Renal artery Middle portion Testicular or Ovarian artery Pelvis Superior Vesical artery Veins: - Upper end Renal vein - Middle portion Testicular or Ovarian vein - Pelvis Superior Vesical vein

Lymph Drainage: - lateral aortic nodes - iliac nodes Nerve Supply: - renal - testicular or ovarian - hypogastric plexuses in the pelvis - Afferent fibers travel with sympathetic nerves & enter spinal cord in 1st & 2nd lumbar segments Urinary Bladder - behind pubic bones within pelvis - receptacle for storage of urine - In adult: maximum capacity of about 500 mL - strong muscular wall - Its shape and relations vary according to amount of urine - Empty bladder in adults lies entirely within pelvis - as the bladder fills, superior wall rises up into hypogastric region - In young child, empty bladder projects above pelvic inlet - later when the pelvic cavity enlarges, the bladder sinks into the pelvis to take up adult position - Empty bladder is pyramidal with the ff: having an apex, base & neck 1 superior and 2 inferolateral surfaces Male Urinary Bladder Apex - points anteriorly - behind upper margin of symphysis pubis - connected to umbilicus by MEDIAN UMBILICAL LIGAMENT [remains of urachus] Base / Posterior Surface - faces posteriorly & triangular - superolateral angles joined by ureters - inferior angle gives rise to urethra - 2 vasa deferentia lie side by side on posterior surface of bladder & separate seminal vesicles from each other - upper part covered by peritoneum, w/c forms anterior wall of rectovesical pouch - lower part is separated from rectum by vasa deferentia, seminal vesicles,

- peritoneum is reflected onto lateral pelvic walls Superior Surface - covered with peritoneum - related to coils of ileum or sigmoid colon - along lateral margins of this surface, peritoneum is eflected onto lateral pelvic walls Inferolateral Surface - related in front to retropubic pad of fat and pubic bones - more posteriorly, they lie in contact with the obturator internus muscle above & the levator ani muscle below Neck - lies inferiorly & rests on upper surface of prostate - here, smooth muscle fibers of bladder wall are continuous with those of prostate - held in positionby the: thickenings of the pelvic fascia PUBOPROSTATIC LIGAMENTS in the male PUBOVSICAL LIGAMENTS in the female Trigone - the area of mucous membrane - covers internal surface of base of the bladder - here, mucous membrane is always smooth, even when viscus is empty - mucuos mebrane over the trigone is firmly adherent to underlying muscular coat - SUPERIOR ANGLES correspond to openings of ureters - INFERIOR ANGLE to internal urethral orifice - limited above by a muscular ridge (runs from the opening of one ureter to that of the other & is known as the INTERURETERIC RIDGE) - UVULA VESICAE is a small elevation behind urethral orifice, produced by underlying median lobe of prostate Muscular Coat of the Bladder - composed of smooth muscle & is arranged as 3 layers of interlacing bundles known as the DETRUSOR MUSCLE - at the neck of bladder, the circular component of the muscle coat is thickened to form the SPHINCTER VESICAE Female Urinary Bladder - due to absence of prostate, - lies at a lower level than in male pelvis - neck rests directly on upper surface of urogential diaphragm Apex lies behind the symphysis pubis Base separated by the vagina from the rectum Superior surface - related to uterovesical pouch of peritoneum & to body of uterus

Inferolateral surface - related in front of retropubic pad of fat & pubic - most posteriorly, lie in contact with obturator internus muscle above & levator ani muscle below Neck - rest on upper surface of urogenital diaphragm Blood Supply Arteries - superior & inferior vesical arteries - branches of the internal iliac arteries Veins - form VESICAL VENOUS PLEXUS, w/c communicates below with prostatic plexus - drained into internal iliac vein Lymph Drainage - drain into internal & external iliac nodes Nerve Supply - Inferior Hypogastric Plexus Sympathetic postganglionic fibers - originate in the 1st & 2nd lumbar ganglia & descend to the bladder via the hypogastric plexuses Parasypathetic preganglionic fibers - arise as the pelvic splanchnic nerves from the 2 nd, 3rd, & 4th sacral nerves Urethra Male Urethra - about 8 in [20 cm] long - extends from the neck of the bladder to the external meatus of the glans penis 3 parts: 1) Prostatic, 2) Membranous, 3) Penile Prostatic Urethra - about 1 in [3 cm] long - begins at the neck of the bladder - passes through the prostate from base to apex, where it becomes continuous w/ membranous part of urethra - wider & most dilatable portion of entire urethra urethral crest - longitudinal ridge on post. wall prostatic sinus - groove on each side of urethral crest - where the prostate glands open prosatic utricle - depression on summit of urethral crest - analog of uterus & vagina in females Openings of 2 ejaculatory ducts

- on ridge of mouth of utricle Membranous Urethra (about in [1.25 cm]) - lies within urogenital diaphragm surrounded by sphincter urethrae muscle - least dilatabe portion of urethra Penile Urethra (about 6 in [15.75 cm]) - enclosed in bulb & corpus spongiosum of penis external meatus - the narrowest part of urethra fossa terminalis - lies within the glans penis bulbourethral glands - open into penile urethra below urogenital diaphragm Female Urethra - 1 in [3.8 cm], prone to UTI due to shortness/nearness to vagina - extends from neck of bladder to externak meatus, where it opens into vestibule about 1 in below clitoris - traverses sphincter urethrae - lies immediately in front of vagina - openings of ducts of parauretral glands sides of external urethral meatus - dilated relativley easy Microscopic Appearance of the urinary system Kidneys - Divisions: Outer Cortex Inner Medulla - Consists of 10-18 conical or pyramidal structures/medullary pyramids - From base of each medullary pyramid, parallel arrays of tubules called medullary rays penetrate cortex - Each kidney is composed of 1-4 million nephrons Each nephron consists of: - dilated portion renal corpuscle - proximal convoluted tubule - thin & thick limbs of Henles loop - distal convoluted tubule - collecting tubules & ducts The nephron is the functional unit of the kidney Renal Corpuscle ( IN CORTEX) - Consists of a tuft of capillaries called the glomerulus - glomerular (Bowmans) capsule double-walled epithelial capsule surrounding glomerulus

- 2 layers: Internal (visceral layer) - envelopes capillaries of glomerulus - cells are called podocytes & have a cell body from which arise several primary processes Each primary process gives rise to numerous secondary processes called pedicels, that embrace capillaries of the glomerulus At adistance of 25 nm, secondary processes are in direct contact with basal lamina & interdigitate, defining elongated spaces about 25 nm wide called the filtration slits The cell bodies of podocytes and their primary process do not touch basement membrane External (parietal) layer - outer limit of renal corpuscle - simple squamous epithelium supported by basal lamina and a thin layer of reticular fibers Urinary space - between two layers w/c receives fluid filtered through capillary wall & visceral layer - each has 2 poles: Vascular pole where afferent arteriole enters &efferent arteriole leaves Urinary pole proximal convoluted tubule begins - epithelium changes to a simple cuboidal or low columnar (epithelium characteristic of proximal tubule Podocytes - have bundles of actin microfilaments in their cytoplasm that give them a contractile capacity Pedicels - secondary processes of podocytes which are in contact with basal lamina - interdigitate to form filtration slits Basement membrane - fusion of capillary - podocyte produced basal laminae - between the fenestrated endothelial cells of glomerular capillaries &podocytes that cover their external surfaces - believed to be the filtration barrier that separates urinary space and blood in capillaries - Derived from fusion of capillary & podocyte-produced basal lamina - filtration barrier where:

lamina densa - as physical filter - network of type IV collagen and laminin - larger than d= 10 nm do not readily cross - negatively-charged proteins with a molecular mass greater than that of albumin (69 kDa) pass across sparingly lamina rarae - as charge barrier - composed of fibronectin Note: - Blood flow in the 2 kidneys of an adult amounts to 1.2 to 1.3 L of blood per minute - This means that all the circulating blood in the kidney passes through the kidneys every 4-5 minutes - The glomeruli are composed of arterial capillaries in which the hydrostatic pressure about 45 mmHg is higher than that found in other capillaries Glomerular filtrate formed in response to: - Hydrostatic pressure in glomeruli - Osmotic/oncotic pressure of plasma colloids - Hydrostatic of fluids in Bowmans capsule - has a chemical composition similar to blood plasma but contains almost no protein because macromolecules do not readily cross the glomerular filter - The largest protein molecules that can cross glomerular have a molecular mass of about 70 kDa, and small amounts of plasma albumin appear in the filtrate Endothelial cells of glomerular capillaries - are of fenestrated variety - but lack thin diaphragm that spans openings of other fenestrated capillaries Mesangial cells - adhere to glomerular capillaries - contracts and have receptors for angiotensin II; when these receptors are activated, glomerular flow is reduced - also have receptors for natriuretic factor increase blood flow - other functions: structural support to glomerulus synthesize ECM endocytose & dispose normal & pathogenic molecules trapped by glomerular basement membrane

produce chemical mediators such as prostaglandins Extraglomerular mesangial cells In the vascular pole but outside the glomerulus Form part of juxtaglomerular apparatus

cytokines

and

RENAL TUBULES Proximal convoluted tubules (IN CORTEX) - longer than distal - cuboidal or low columnar epithelium - acidophilic cytoplasm due to numerous elongated mitochondria - absorbs all glucose and amino acids and 85% NaCl and H 2O, phosphate and calcium - secrete creatinine, PAH, penicillin cell apex - abundant w/ microvilli forming brush border cell base - abundant with membrane invaginations & lateral interdigitations w/ neighboring cells - mitochondra concentrated here Henles Loop (IN MEDULLA) - consists of thick & thin descending & ascending limbs - thick limbs similar to distal - 60 m, squamous epithelial cells whose nuclei protrude into lumen - thin limbs 12 m - 1/7 of nephrons are located near juxtamedullary nephrons, others are cortical - Juxtamedullary nephrons ( bent to hairpin loop) Prime importance in establishing gradient of hypotonicity in medullary interstitium basis of kidneys ability to produce hypertonic urine Very long Henles loops - short, thick descending limbs - long thin descending and ascending limbs - thick ascending limbs - cortical nephrons (no order/ gubot kaau) long segments, 85% very short thin descending limbs no ascending limbs - water retention - descending limb - permeable to water

- ascending limb - impermeable to water Distal convoluted tubules (IN CORTEX) - simple cuboidal epithelium - no brush border - no apical canaliculi - smaller cells - more nuclei - elaborate basement membrane invaginate - associated mitochondria indicative of ion-transporting fxn - in juxtaglomerular region, cells become columnar & nuclei are closely packed, most have Golgi complex in basal regions macula densa Macula densa - sensitive to ioniccontent & H20 volume of tubular fluid - producing signals that promote liberation of rennin in circulation Collecting Tubules and Ducts (IN MEDULLA) - cuboidal epithelium - become more columnar deep into medulla - in medulla, are major component of urine concentrating mechanism - epithelium is responsive to arginine, vasopressin (or ADH) Juxtaglolmerular (JG) Cells - Modified smooth muscle cells of T. media of afferent arteriole, adjacent to renal corpuscle - Have a cytoplasm full of secretory granules - Secretions play a role in the maintenance of BP - Show characteristic of protein-secreting cells, including Abundant rough endoplasmic reticulum Highly developed Golgi complex - Secretory granules of 10-40 nm in diameter - Produce enzyme rennin, which acts on a plasma protein angiotensin to produce an inactive decapeptide angiotensin I Juxtaglomerular (JG) Apparatus (IN MEDULLA) - Formed by region of afferent arteriole that contains the JG cells and macula densa of the distal convoluted tubule - modified smooth muscle cells in tunica media of afferent arteriole adjacent to renal corpuscle - cytoplasm is full of secretory granules secretions for maintenance of BP - secretes rennin - composed of JG cells + macula densa + extraglomerular mesangial cells or lacis cells

Renal Insterstitium - The space between uriniferous tubules,blood&lymph vsl. - Occupies a very small volume in cortex but s in medulla - small amount of CT with fibroblasts, some collagen fibers and (mainly in the medulla) a highly hydrated ground substance rich in proteoglycan - In the medulla, interstitial cells (secreting cells) are found Contain cytoplasmic lipid droplets Implicated in the synthesis of prostaglandins and prostacyclin Urinary Bladder and Ureter - transitional epithelium - lamina propria loose to dense CT surrounded by dense woven sheath of smooth muscle - muscular layers in calyce, renal pelvis and ureters in helical arrangement - muscular layers in bladder in longitudinal arrangement In Tunica Muscularis: Inner longitudinal Distal to bladder neck Middle circular layer around prostatic urethra & prostatic parenchyma Outer longitudinal layer end of prostate & external urethral meatus in women intravesical ureter - only longitudinal muscle fibers urinary passages - covered externally by adventitial membrane, except upper part of bladder which is covered by a serous peritoneum Male Urethra - Consists of 4 parts: Prostatic,Membranous,Bulbous,Pendulous - Initial part passes through prostate(close 2 bladder) & ducts that transport secretions of prostate open into prostatic urethra Prostatic Urethra - In dorsal and distal part, there is an elevation called verumontanum that protrudes into its interior - A closed tube called the prostatic utricle opens into tip of verumontanum; tube has no known function - The ejaculatory ducts open sides of verumontanum - seminal fluid enters proximal urethra through these ducts to be stored just before ejaculation

- Lined with transitional epithelium Membranous Urethra - Extends for only 1 cm - stratified or pseudostratified columnar epithelium - Surrounding this part of urethra is a sphincter of striated muscle, the external sphincter of urethra - The voluntary striates sphincter adds further closing pressure to that exerted by the involuntary urethral sphincter (formed by continuation of internal longitudinal muscle of the bladder) Bulbous and Pendulous Urethra - Located in corpus spongiosum of penis - The urethral lumen dilates distally, forming fossa navicularis - The epithelium is mostly pseudostratified and columnar, with stratified& squamous areas Littres Gland - Mucous glands found along entire length of urethra but mostly in pendulous part - secretory portions of some of these glands are directly linked to the epithelial lining of the urethra; others have secretory ducts Female Urethra - 4-5 cm long - stratified squamous epithelium and areas of pseudostratified columnar epithelium - Mid part surrounded by external striated voluntary sphincter BLADDER AND URINARY PASSAGES - Store urine formed in kidneys& conduct it to exterior - Calyces, renal pelvis, ureter, and bladder have the same basic histologic structure with the walls of the ureters becoming thicker as proximity to the bladder increases - Mucosa of these organs consists of transitional epithelium and a lamina propria of loose to dense CT - Surrounding the lamina propria of these organs is a dense woven sheath of smooth muscle - The transitional epithelium of the bladder in distended state is 5 or 6 cells in thickness; the superficial cells are rounded and bulge into the lumen - Cells are frequently polyploidy or binucleate - When epithelium is stretched, epithelium is only 3 or 4 cells in thickness, and the superficial cells become squamous

- The superficial cells of the transitional epith. have special membrane of thick plates separated by narrow bands of thinner membrane responsible for osmotic barrier between urine & tissue fluids - When bladder contracts, the membrane folds along the thinner regions, and the thicker plates invaginate to form fusiform cytoplasmic vesicles - The muscle fibers of the bladder run in every direction (without distinct layers) until they approach the bladder neck, where 3 distinct layers can be identified: Internal longitudinal layer - distal to bladder neck - Becomes circular around the prostatic urethra and prostatic parenchyma in men Middle layer (middle circular layer) - Ends at the bladder neck Outer longitudinal layer - Continues to end of prostate in men and to external urethral meatus in women - Urinary passages are covered externally by adventitial membrane, except for upper part of bladder, which is covered by serous peritoneum 2. Identify the functions of the kidney. FUNCTIONS of the kidney Process the plasma portion of blood by removing substances from it and adding substances to it. Resulting to following functions: 1. Regulation of water and inorganic-ion balance - H20 concentration, inorganic-organic composition, & volume of internal environment by excreting just enough water& inorganic ions to keep amounts of substances in body relatively constant. 2. Removal of metabolic waste products from the blood and their excretion in the urine - excrete metabolic waste products into urine as far as they are produced - These keeps toxic waste products from accumulating - The metabolic wastes include: urea from the catabolism of protein uric acid from nucleic acids creatinine from muscle creatine end products from hemoglobin breakdown (which give urine much of its color) many others

3. Removal of foreign chemicals in the blood and their excretion in the urine. - drugs, pesticides & food additives & metabolites 4. Gluconeogenesis - During prolonged fasting, kidneys synthesize glucose from amino acids& other acids% release it into blood. - kidneys can supply approx. 20%as much glucose as the liver does at such times. 5. Secretion of hormones ( as endocrine glands) - synthesize and secrete the following: Erythropoietin - controls erythocyte production Renin - controls formation of angiotensin - influences BP and sodium balance - BP regulation 1,25 dihydroxyvitamin D3 - influences calcium balance vasopressor renal medullary lipids (Vitamin E) Maintainance of acid-balance of the blood maintenance of Blood Osmolality - Osmolality = Solutes Solvent - ex. H20 in blood, osmolality 3. Discuss glomerular filtration, taking into consideration the following: a. Relationship of structural characteristics of the glomerulus to glomerular filtration Blood from the afferent arteriole enters the glomerulus located within the Bowmans capsule Glomerulus consists of a coil of approximately eight capillary lobds referred to as the capillary tuft Glomerulus serves as a nonselective filter of plasma substances with molecular weights of less than 70,000 Factors influence the actual filtration process. Cellular structure of the capillary walls and Bowmans capsule Hydrostatic and oncotic pressure Feedback mechanisms of the rennin-angiotensinaldosterone system Plasma filtrate must pass through three cellular layer

Capillary wall membrane The endothelial cells of the capillary wall membrane differ from those in other capillaries by containing pores and are referred to as fenestrated. Fenestra 600-1000 Angstroms in diameter Basement membrane ( basal lamina) - Homogenous and acellular Consists of glycoprotiens and mucopolysaccharides Visceral Epithelium of the Bowmans capsule - Capsular epithelial cells are called podocytes which posses foot processes called pedicels. Pedicels interdigitate with each other and reduce the diameter of the path through which solutes pass to about (240 Angstrom). Pedicels coated with a thick layer glycosialprotiens with further occlude the path Extremely thin diaphragm bridge the slits at the surface of the basement membrane. In order to be freely filtered a solute must be lesser than 100 Angstroms Glomerular membranes are freely permeable to water and to crystalloids but are relatively impermeable to colloids, especially plasma proteins. This is sometimes called steric hindrance Electrical change is also important in the process of movement of a solute across the glomerular capillary. The cell coats of the epithelium, the basement membrane, and the cell coats of the podocytes are polyanions. Negatively charged molecules are restricted from entering and moving through the filtration barrier. This is called electrical hindrance Every minute approximately 120mL of water containing lowmolecular weight substances are filtered through the 2 million glomeruli Filtration is nonselective Filtrate has a specific gravity of 1.010 Difference between compositions of filtrate and plasma is absence of: Plasma protein Any protein bound substance

Cells b. Factors affecting: i. Glomerular plasma flow rate Glomerular plasma flow rate Changes in blood pressure lead to changes in glomerular filtration rate by changing capillary hydrostatic pressure, However because of autoregulation, arterial pressure changes have very little effect on glomerular filtration rate.Autoregulation is brought about by 2 mechanisms: Myogenic mechanism An increase in arterial pressure causes stretch of the smooth muscles of the renal arteries, which respond to the stretch contraction. The renal artery constricts and as a result, the possibility of increased filtration is minimized Tubuloglomerular feedback More popular mechanism, which explains autoregulation of renal blood flow. Increased blood pressure Increased renal arterial pressure Increased glomerular filtration rate Increased rate of fluid flow to the proximal tubule and loop of Henle Increased rate of fluid flow to the macula densa Stimulation of macula densa cells Release of adenosine Adenosine constricts the renal arteries Adenosine constricts the renal arterioles Decreased glomerulus filtration rate

ii. Glomerular Ultrafiltration Coefficient At any given net filtration pressure, glomerular filtration rate is proportional to the glomerular ultrafiltration coefficient ( the product of hydraulic water permeability of glomerular membranes and the surface area available for filtration). Any factor that decreases glomerular ultrafiltration coefficient reduces glomerular filtration rate. Substances that decreas glomerular ultrafiltration coefficient o o o o o o o o o o Angiotensin II ADH PG E and PG 12 Acetylcholine Bradikinin Histamine Parathyroid hormone Papaverine High plasma levels of calcium Low plasma levels of protein

iii. Starlings Forces The net filtration pressure (NFP) across the glomerular capillaries is the algebraic sum of the forces that induce filtration (hydrostatic pressure in the glomerular capillaries and osmotic pressure in the bowmans capsule), and the forces that oppose filtration (hydrostatic pressure in the Bowmans capsule and the osmotic pressure in the glomerular capillaries). At the region of the afferent arteriole, the net filtration pressure is high, and allows fluid to be filtered into the Bowmans capsule. At the region of the efferent arteriole, the net filtration pressure is zero, and fluid is not filtered. Thus, fluid is only filtered at the capillary near the region of the afferent arteriole. iv. Podocyte structure Glomerular filtration rate is measured using a test substance. Such substance must posses the following criteria o It must be freely filtered at the glomerulus o It must be reabsorbed at the tubules

o It must not be secreted by the tubules o It must not be synthesized by the tubules o It must not be degraded by the tubules The substance used inulin meets all the criteria The amount of inulin secreted per unit time must be equal to the amount of the substance filtered per unit time. Quantitation of inulin is technically difficult so clinically other substances are used as substitutes. Urea is one substitute o Does not fill all the criteria since it is reabsorbed Creatinine and para-amino hippurate are also used o However they are both secreted by the tubules o Descripancy isnt large so they are frequently used Using inulin the normal GFR (assuming the body surface area is 1.73 sq. meters o Male 125ml/min o Female 110ml/min

other substances are used as substitutes. One test substance used as a substitute is urea. Urea does not fulfill are the criteria for test substance since urea is reabsorbed. Two other substances used as substitutes are creatinine and paraaminohippurate. These two substances are however, secreted by the tubules. Nevertheless, since the discrepancy is not large, they are frequently used a s substitute for inulin. d. The test substances involved in measurement of GFR and their characteristics Inulin Is a polymer of fructose that can be used to measure GFR It is not produced by the body, thus should be administered intravenously It is freely filtered across the glomerulus into the Bowmans space and not reabsorbed, secreted, or metabolized by the cells of the nephron The amount of inulin excreted in the urine per minute equals the amount on inulin filtered at the glomerulus each minute Quantitation of inulin is technically difficult Urea A substitute test substance Does not fulfill one criteria for test substance since it is reabsorbed Creatine Used to estimate the GFR in the clinical practice Creatine is a by product of skeletal-muscle creatine metabolism Creatine has advantage over inulin because it is produced endogenously and thus obviates the need for intravenous infusion as is required for inulin However, it is not a perfect substance to measure GFR because it is secreted to a small extent in the proximal tubule Para-amino Hippurate - Secreted by the tubules 4. Discuss the tubular reabsorption, taking into consideration the following: a. Relationship of structural characteristics of the different parts of the tubule to tubular reabsorption Bowmans capsule cells of the epithelium are called podocytes

c. Measurement of Glomerular Filtration Rate (GFR) Clearance = Urine w( measured substance concentration) X Volume (24 hour urine) Plasma w (measured substance concentration) Clearance= Uw X V Pw . 1.72m2 A 110ml/min for 1.73m2

Normal value: 125 ml/min for adult male adult female 1.73m2

Glomerular Filtration Rate (GFR) is measured using a test substances. Such substance must process the following criteria: 1. It must be freely filtered at the glomerulus 2. It must not be reabsorbed at the tubules 3. It must not be synthesized by the tubules 4. It must not be degraded by the tubules If there is such substance, then the amount of the substance excreted per unit time must be equal to the amount of the substance filtered per unit time. Fortunately, a such test substance exists, inulin. However, quantitation of inulin is technically difficult, and so clinically,

 pedicels of podocytes interdigitate with each other to form filtration slits along the capillary wall Proximal tubule lining epithelium is made up of cuboidal cells connected by tight junctions Luminar border of cells due to the presence of numerous microvilli Loop of Henle Descending limb o epithelium consists of flat cells o impermeable to ions but permeable to water Ascending limb o epithelial cells are cuboidal o impermeable to water but permeable Distal Tubule lining epithelium- cells lower than that of the proximal tubule few microvilli; no dense brush border reabsorption is less Collecting ducts epithelium is of two cell types: o Principal cells tall, with few organelles involves in H2O and Na H2O reabsorption is ADH-dependent; Na is aldosterone- dependent o Intercalated cells possess microvilli concerned primarily w/ acid-base balance b. Characteristics of: i. Passive tubular reabsorption transport of subs without the use of energy may occur via diffusion, w/c requires an electrochemical gradient diffusion may occur via water filled channels between cells, or if the solute is lipid soluble, via the plasma membrane of the cells ii. Active Tm-limited tubular reabsorption

o involves transport maximum: the maximum amt of subs. that can be absorbed by the tubule o TL- the maximum amt of subs that reaches the tubule if Tm is equal to TL, the subs is completely reabsorbed if Tm is greater than TL, the subs is completely reabsorbed if Tm is less than TL, the subs is partly reabsorbed, partly excreted iii. Active gradient-time tubular reabsorption o time at w/c the subs is in the tubule o involves the transport of solute against an electrochemical gradient primary active transport the energy comes directly from the splitting of ATP secondary active transport 2 or more subs interact simultaneously w. the same carrier and both are translocated across the membrane one of the subs undergoes only downhill transport, while the other manifests uphill movement against an electrochemical gradient c. The substances reabsorbed by the above-mentioned mechanisms MECHANISMS SUBSTANCES Passive Tubular Reabsorption - Water - Chloride - Urea Active Tm Limited Tubular - Glucose Reabsorption - Phosphate - Sulfate - Amino Acids - Vitamin C - Uric Acid - Protein Active Gradient Time Tubular - Sodium Reabsorption - Chloride

d. Splay and its mechanisms SPLAY occurs when reabsorb able substance may appear in the urine before Tm value is reached or exceeded 2 mechanisms: 1.Carrier-mediated mechanisms kinetic similar to enzyme systems so that maximal activity is substrate dependent 2.Not all nephrons have the same Tm value for a particular solute, so that actually, the Tm value is an average rather than an absolute value

Passive tubular secretion via SIMPLE DIFFUSION Involves movement of a solute down its concentration gradient, from the interstitium to the tubular lumen. Substances secreted via this type of secretion: o Potassium (K+) 2. Diffusion trapping Passive tubular secretion via DIFFUSION TRAPPING Involves transport of weak acids and weak bases Luminal membrane of the tubular cell is permeable to o weak acids when the urine is alkaline, and to o weak bases when the urine is acidic Substances secreted: o Weak acids salicyclic acid or aspirin o Weak bases ammonia Mechanism: Once within the tubular lumen, the weak acid/base is converted to ionic forms by interaction with Hydrogen ions. Luminal membrane is impermeable to the ionic forms of weak acids & bases Ionic form is now trapped in the tubular lumen and is then eliminated
Tubular lumen Tubular cell

5. Discuss tubular secretion, taking into consideration the following: a. Relationship of structural characteristics of the different parts of the tubule to tubular secretion Tubular secretory processes transport substances from the capillary lumen to the tubular lumen (opposite the direction of tubular reabsorption). The overall secretory process for any given substance begins with its diffusion out of the peritubular capillaries into the interstitial fluid. The substance makes its way into the tubular lumen via: o Paracellular route crosses the tight junctions (between the cells) o Transcellular route via the basolateral and luminal membrane of the cell (across the cell) Secretion from the interstitial space into the tubular fluid (which draws substances from the peritubular capillaries) is a mechanism to improve the efficiency of the kidney to dispose of substances at a higher rate than the filtered load. b. Characteristics of: i. Passive tubular secretion Passive since energy is not utilized in the process of the transport 1. Simple diffusion

H+ + NH3 NH4-

H+ NH3

If no buffers exist in the lumen, H+ pump will continue The moment H+ pump stops, renal tubular cell will secrete ammonia (NH3) reacting with hydrogen forming ammonium ion (NH4-). Although it is PERMEABLE to ammonia (a weak base) it is IMPERMEABLE to ionic ion (ammonium). Hence it is trapped (ionic form of weak acids and bases) and is therefore ELIMINATED.

5.2.2 Active Tm-Limited tubular secretion - Involves transport of solutes via a mechanism similar to active Tm-limited tubular reabsorption - Different only from Tm-limited tubular reabsorption in terms of the following: Direction of movement of the solute Carriers are less specific Only 1 carrier for all organic anions Only 1 carrier for all organic cations 1. Bile salts 2. Fatty acids 3. Hippurtaes 4. Hydroxybenzoates 5. Drugs: - Acetazolamine - Chlorthiazide - Ethacrynate - Furosemide 6. Oxalate 7. Prostaglandins 8. Urate Penicillin Probenecid Saccharin Sulfonamides

5.2.3

Organic cations; endogenous substances such as: 1. Acetycholine 2. Choline 3. Creatinine 4. Dopamine 5. Epinephrine 6. Drugs: Atropine Isoproterenol Cimetidine Meperidine Morphine Procaine Quinine Tetraethylammonium 7. Guanine 8. Histamine 9. Serotonin 10. Norepinephrine 11. Thiamine Active-Gradient time limited tubular secretion Involves hydrogen (H+) Transport of a substance depends upon the time the intraluminal fluid (which contains the substance) is in contact with the tubular epithelium

c. The substances reabsorbed by then abovementioned mechanisms Mechanisms Substance(s) Reabsorbed Simple Diffusion Potassium Diffusion Trapping 1. weak acids (exemplified by salicylic acid or aspirin) 2. weak bases (exemplified by ammonia) Tm-limited secretion 1. organic anions: Endogenous substances such as bile salts, fatty acids, hippurates, hydrobenzoates, oxalate, prostaglandins, urates; and drugs such as acetazolamide, chlorothiazide, ethacrynate, furosemide, penicillin, probenecid, saccharin, sulfonamides

Gradient-time limited secretion Passive tubular reabsorption

2. organic cations: Endogenous substances such as acetylcholine, choline, creatinine, dopamine, epinephrine, guanine, histamine, serotonin, norepinephrine, thiamine, and drugs such as atropine, isoproterenol, cimetidine, meperidine, morphine, procaine, quinine, and tetraethylammonium 3. carboxylic or sulfonic acid 4. EDTA Hydrogen 1. water 2. Chloride 3. Urea

Ascending Limb: permeable to ions, impermeable to H2O Cl- is actively absorbed while Na+ is reabsorbed passively Fluid becomes more dilute and is hypotonic to plasma when it reaches the top because Na + and Cl- movement out of the tubular lumen Osmolarity decreases (hypo-osmolar)

6.

Discuss the reabsorption of sodium, chloride and water at the proximal tubule, Loop of Henle, Distal tubule and collecting duct, taking into consideration the following: a. Permeability characteristics of the part of the tubule b. Osmolarity changes in the fluid in that part of the tubule c. Amount of sodium, chloride and water reabsorbed at each part Proximal Tubule Site of greatest Na+ and H2O reabsorption Approximately 65% of the filtered Na +, H2O and Cl- is reabsorbed by the time the fluid reaches the end of the proximal tubule Na+ is actively transported Cl- and H2O are passively transported as a result of active Na + reabsorption Fluid osmolarity remains the same as that of plasma ( isosmolar) Loop of Henle Reabsorbs about 25% of filtered Na + and Cl- (ascending limb) and 15% of filtered H2O (descending limb) Descending Limb: impermeable to ions, permeable to H2O fluid becomes hypertonic as H2O moves into the hypertonic interstitium

Distal Tubule Only about 10% of Na+ & Cl- and 20% of H2O remains in the tubule as it enters distal tubule Na+ and Cl- reabsorption continues, but H2O is reabsorbed more. Fluid that leaves the distal tubule to enter the collecting duct is isosmolar Collecting Duct Na+ and Cl- continue to reabsorbed at the principal cells in the presence of aldosterone Reabsorption of H2O at the principal cells also continues in the presence of ADH Changes in osmolarity and volume depends on the amount of ADH and aldosterone acting on the duct Fluid that leaves the collecting duct to enter the ducts of Bellini may be either: Hyperosmolar ADH and aldosterone present Concentrated urine, volume Hypo-osmolar ADH and aldosterone absent Dilute urine, volume 7. Explain briefly the following: a. Countercurrent multiplication of osmolar concentration Concentration of urine takes place at the medullary collecting ducts, in the presence of ADH. Such action of ADH however, can only take place in the hyperosmolarity is called the countercurrent multiplier system, and takes place at the loop of henle of juxtamedullary nephrons. Assume that a loop of henle is filled is filled with isosmolar fluid. At the ascending limb, chloride and sodium reabsorption takes place. In the process, there is a decrease in osmolarity of the fluid within the

ascending limb, but there is an increase in osmolarity of the fluid at the interstitium. This increase in osmolarity at the interstitium causes water from the descending limb to move towards the interstitium. Since the loop of henle of juxtamedullary nephrons are long, it is logical to assume that intratubular fluid becomes progressively concentrated as it flows down the descending limb, and that medullary interstitial fluid also progressively becomes concentrated to the same degree. Although a gradient of 200 m0sm/L is maintained across the ascending limb at any given horizontal level in the medulla, there is much larger osmotic gradient from the top of the medulla to the bottom. In other words, the gradient of 200 m0sml/L established by active chloride transport has been multiplied because of the countercurrent flow. The moment the loop countercurrent multiplier system causes the interstitial fluid of the medulla to become concentrated, in the presence of adequate ADH, fluid is drawn out of the collecting ducts, and the fluid within the collecting ducts thud becomes concentrated b. Countercurrent exchange One characteristic feature of the peritubular capillaries of the juxtamedullary nephrons is their peculiar arrangement- that of hairpin loops- which run parallel to the loops of henle and medullary collecting ducts, and are called the vasa recta. Blood that enters the vasa recta at an osmolarity of 300 m0sm/L, and as it flows down the capillary loop deeper into the medulla, sodium and chloride diffuse into, and water out of, the capillary loop. However, after the bend of the loop, as blood flows up the ascending capillary loop, the process is now reversed. Sodium and chloride diffuse out of the capillary, while water diffuses into the capillary. Thus, the capillary loop acts as a countercurrent exchanger which prevents the gradient at the interstitium from being dissipated. Since the capillary loop does not create the medullary gradient itself but only protects it. It is therefore completely passive. And is thus the reason why it is called an exchanger instead of multiplier. 8. Explain briefly the mechanisms involved in concentration and dilution of urine. State the cells of the collecting duct involved in the concentration of urine. In the presence of ADH, the principal cells of the collecting duct become permeable to water o Water moves out of the collecting duct, attracted by a hyperosmolar interstitium, and eventually is absorbed by the vasa recta

As a result of water movement out of the collecting duct, the fluid within the collecting duct progressively becomes hyperosmolar, and thus, concentrated In the absence of ADH, the principal cells of the collecting duct are impermeable to water o Water accumulated in the collecting duct and is not reabsorbed o Fluid in the collecting duct becomes dilute o

9. Discuss micturition, taking into consideration the following: Definition: Micturition refers to the periodic complete emptying of the urinary bladder, under voliuntary control, except during infancy (up to 2-3 years of age). The act of micturition involves the coordinated activity of the detrusor muscle, the muscles of the abdominal wall, muscles of the pelvic floor, fixation of the chest wall and diaphragm and relaxation of the internal and external sphincter. a. Physiological processes involved and relationship of these processes to structural characteristics End of micturition, urinary bladder is empty and intra vesicle pressure is equal to the intraabdominal pressure

Bladder slowly fills with urine coming from the urethra via peristaltic wave motion. Discoidal vesicle at the mucosa of the bladder are reinserted into the membrane at the luminal surface (mucosal fold unfold) Intravesical volume rises and the pressure remains low Bladder volume reaches 100 150 ml (sensation of bladder filling is experienced) Bladder continues to be filled with urine Bladder volume reaches 150 250 ml (first desire to void)

Afferent impulses are sent to the cerebral cortex If access to the toilet is difficult, afferent impulses are sent by the cerebral cortex to the spinal cord (S2 S4) Efferent impulses are sent to the pudendal nerve Contraction of the external vesical sphincter Bladder continues to fill with urine Bladder volume reaches 450 ml (max. bladder volume) Involuntary micturition occurs when bladder volume exceeds 450 ml for most individuals Involuntary relaxation of the external urinary sphincter, followed by the internal sphincter (also relax) Small amount of urine reaches the proximal urethra Afferent impulses signals the cerebral cortex that voiding is imminent Voluntary control of micturition by the cerebral cortex is lifted Suprapontine and pontine centers no longer inhibit parasympathetic fibers that innervate the detrusor Detrusor muscles of the bladder contract causing expulsion of the urine

Voluntary contractions of abdominal muscles raise bladder pressure and further enhance emptying b. When micturition is involuntary and when it becomes a reflex. When micturition is involuntary and when it becomes a reflex? - for majority of individuals, the maximum amount of urine that canbe tolerated without discomfort is 250 450 ml, beyond this amount involuntary control of micturition becomes a reflex. -micturition is normally controlled by micturition reflex. Stretch and contraction of muscles of bladder wall causes excitement of mechanoreceptors in the wall. The accumulation of urine brings about distention of the wall of the urinary bladder, then mechanoreceptors begin to discharge. Pressure in the urinary bladder is low during filling ( 5 -10 cmH2O), but increases abruptly when micturition begins. Bladder afferent fibers 1. excite neurons projecting to the brainstem and activate the micturition center (rostral pons barringtons center) 2. inhibit sympathetic preganglionic neurons that prevent voiding SPINAL REFLEX PATHWAY - operational in newborn infants - maturation: supraspinal control pathways take on dominant role in triggering micturition - spinal cord injury: human adults lose bladder control(urinary incontinence) and may lead to urinary infections. Micturition through spinal reflex Bladder fills with urine Pressure within bladder increases Stimulation of the stretch receptors in the bladder wall Afferent fibers from the receptors enter the spinal cord Stimulation of the parasympathetic neuron

 Pelvic nerve Detrusor muscle contracts Reflex inhibition of the sympathetic neurons to the internal urethral sphinchter (hypogastric nerve) Reflex inhibition of the somatic motor neurons to the external urethral sphincter (pudendal nerve) Opening of the external urethral sphincter