Urinary System Anatomy PDF

Urinary system CPTMP 2024-2025 Renal module (Departments) 1. Anatomy 2. Histology 3. Physiology 4. Biochemistry 5. Pharmacology 6. Pathology Revised by Curriculum Committee Tanta Faculty...

Urinary system CPTMP 2024-2025 Renal module (Departments) 1. Anatomy 2. Histology 3. Physiology 4. Biochemistry 5. Pharmacology 6. Pathology Revised by Curriculum Committee Tanta Faculty of Medicine  ‫‪Vision and Mission of Faculty of Medicine‬‬ ‫رؤيةكلية الطب – جامعه طنطا‬ ‫كليه طب ذاتتصنيف متميز محليا وعالميا من خاللبرامجتعليميه متطورة وابحاث‬ ‫تطبيقيه مبتكرة وتنميه مجتمعيه مستدام ه‬ ‫رسالةكلية الطب – جامعه طنطا‬ ‫فعليهلسوق العمل‬ ‫فق مع االحتياجات ال‬ ‫فيه وتطبيقيه متميزةتتوا‬ ‫فاءة معر‬ ‫‪ -‬إعداد اطباء ذو ك‬ ‫المحلي والعالمي‬ ‫فق مع االستراجيات القوميةللعلوم والتكنولوجيا‬ ‫فسي متوا‬ ‫‪-‬تقديمبحث علميتطبيقيتنا‬ ‫فقا معايير الجوده العالميه‬ ‫‪-‬تقديم خدمه مجتمعية مستدامه و‬ ‫‪I‬‬  ILOS AnatomyILOS By the end of this module the student will be able to: 1. Identify the parts of the urinary system. 2. Describe the shape, position, coverings and relation of the two kidneys. 3. Define the position, length and constrictions of the ureters and its blood supply 4. Understand the stages of development of kidneys and ureter and identify the most common congenital anomalies 5. Describe the parts and shape of the urinary bladder. 6. Compare between the male and female urethra. 7. Understand the stages of development of urinary bladder and urethra and identify the most common congenital anomalies. HistologyILOS By the end of this module, the student should be able to: 1. Differentiate between different parts of urinary system. 2. Define the structures and functions of the different segments of the nephron and collecting tubules. 3. Describe the structures present in the cortex and medulla of the kidney. 4. Predict the special types of cells present in juxtaglomerular apparatus. 5. Differentiate between the urinary passages by light microscope. PhysiologyILOS By the end of this module, the student should be able to: 1. List the general functions of kidney and its hormonal control. Outline and identify the mode of handling of different substances in renal tubules. Discuss the mechanism of urine acidification in renal tubules. Summarize the physiological mechanisms of urine concentration & dilution II 2. Clarify the normal value of the renal blood flow and its related dynamics. Distinguish mechanisms of regulation, factors affecting of the RBF and its auto regulatory mechanism. Define, calculate, and predict the clinical significance of plasma clearance. Interpret the dynamics, factor affecting, and fate of GF 3. Relate tubular PH with renal hydrogen buffering capacity. Discriminate the fate and results of hydrogen secretion in different parts of renal tubules. Detect change in renal buffering capacity in acid-base disturbances BiochemistryILOS By the end of this module, the student should be able to: 1. Recognize the importance of acid base balance and understand the intracellular and extracellular mechanisms for buffering changes in body pH. 2. Explain the primary causes and compensatory mechanisms of metabolic acidosis and metabolic alkalosis 3. Outline general steps in the overall synthesis of purine and pyrimidine nucleotides and identify diseases associated with these pathways. 4. Describe metabolic functions of the kidney and metabolic interrelations of renal diseases. 5. Explain relationship between oxidative stress and the pathogenesis of kidney diseases. PathologyILOS By the end of this module, the student should be able to: 1. To identify causes of nephritic and nephrotic syndromes. 2. To identify various types of glomerunephritis diseases and how to differentiate between them on histopathological and electron microscopic basis. 3. To know the predisposing factors of renal tumors. 4. To study the classification of renal tumors and the pathological characteristics of each type. 5. To know the predisposing factors of urinary bladder tumors. III 6. To study the classification of urinary bladder tumors and the pathological characteristics of each type. PharmacologyILOS By the end of this module the student will be able to: 1. Differentiate between diuretic, aquaretic and natriuretic terms 2. Classify diuretics according to efficacy 3. Identify and understand different pharmacological aspects of loop diuretics, thiazide diuretics and K sparing diuretics (kinetics, dynamics, clinical indication, adverse effects, contraindications and drug interactions) 4. Identify and understand pharmacological aspects of carbonic anhydrase inhibitors and osmotic diuretic (mannitol) (kinetics, dynamics, clinical indications, adverse effects and contraindications) 5. Identify aquaretic agents and recognize ADH antagonists 6. Understand the impact of diuretics combinations 7. Recognize and understand the role of diuretics in kidney diseases and renal failure 8. Identify and discuss pharmacological aspects of urinary antiseptic drugs 9. Recognize urine pH modifiers and their indications 10.Recognize common drugs that cause injury to the kidney and the form of injury they produce 11.Understand mechanism and risk factors of drug induced injury 12.Identify measures to minimize injury 13.Identify and discuss drugs used in different types of urinary incontinence 14.Recognize and understand drugs that exacerbate urinary incontinence IV  INDEX Contents Pages 1. Anatomy and development of Kidney and Ureter 1-18 2. Histological structure of glomerular apparatus 19-34 and renal tubules 3. Functions of the kidney 3.1 General functions of the kidney.... 35-34 3.2 Metabolic function of the kidney.... 35-40 4. Tubular functions 41-64 5. Role of kidney in acid base balance 65-72 6. Diuretics 73-86 7. Pathology of glomerular diseases 87-99 8. Drug inducedkidney injury 100-103 9. Pathology of different renal diseases 104-109 10.Anatomy and developmentof urinary bladder 110-123 and urethra 11.Histology of excretory passages 124-129 12.Physiology of urinary bladder 130-133 13.Nucleotide metabolism 134-140 14.Oxidative stressand kidney 141-144 15.Urinary antiseptics 145-149 16.Drugs and urinary incontinence 150-152 17.Tumors of the urinary system 153-160 18.References 161-162 V  CHAPTER 1 Chapter 1 Anatomy and development of Kidney and Ureter The renal system, which is also called the urinary system, is a group of organs in the body that filters out excess fluid and other substances from the blood steam. The renal system organs include the kidneys, ureters, bladder, and urethra. 1- Kidney: Fig 1.1: Renal systemorgans. Shape and size: The kidneys are a pair of bean-shaped organs approximately 12 cm long, 6 cm in breadth and 3cm in thickness. It has: 2 poles;upper and lower. 2 surfaces;anterior and posterior 2 borders;lateral convex and medial concave with a hilum in its middle 1  CHAPTER 1 The hilum transmits from front backward renal vein, renal artery and the ureter that directed downward Vein ; anteriorly Artery ; intermediate Ureter ; posterior and is directed downwards Its dimensionsare: 12cm in length 6 cm in breadth 3 cm in thickness. Fig 1.2: right and left kidneys They lie : - On the posterior abdominal wall. - Behind the peritoneum - On each side of the vertebral column They extend from the level of the 12th thoracic vertebra to the level of the 3rd lumbar vertebra The left kidney lies in an upper position than the right because of its relation to the liver. - The left kidney reaches up to the 11th rib - The right kidney reaches up to the 11th space They lie sloping in the para-vertebral gutters so that the hilum faces somewhat forwards as well as medially 2  CHAPTER 1 They lie obliquely with their upper poles nearer to the median plane than the lower ones. Fig1.3 : The postionsof the kidneys in male and female longitudinal sectionKidney It is composed of an outer cortex and inner medulla. The medulla consists of conical masses called renal pyramids(10 to 18), the base of which are directed towards the renal cortex while their apices (renal papillae) are directed towards the renal sinus. Minor calyxsurrounds one or more renal papillae. The minor calyces (10 to 12 in number) unit to form 2 or 3 major calyces, which unite together forming the renal pelvisinside the renal sinus. Sinusof the kidneyis a central recess within the hilum of the kidney, which contains renal vessels and pelvis. Cortical tissue extends between the pyramids to form the renal columns. Each pyramid with its covering cortex forms a renal lobe. 3  CHAPTER 1 Fig1.4: longitudinal sectionof the kidney Coverings of the kidney: The kidneys have the following coverings from inside to outside: 1- Fibrouscapsule:This surrounds the kidney and is Closely applied to its outer surface. 2-Perirenalfat: This covers the fibrous capsule. 3-Renal fascia:This is a condensation of connective tissue that lies outside the perirenal fat and encloses the kidneys and suprarenal glands; it is continuous laterally with the fascia transversalis. 4-Pararenal fat: This lies external to the renal fascia and is often in large quantity. It forms part of the retroperitoneal fat. The perirenal fat, renal fascia, and pararenal fat support the kidneys and hold them in position on the posterior abdominal wall. Fig 1.5: coveringsof the kidney. 4  CHAPTER 1 Relations of the kidney: Anterior realtions of right and left kidneys Right kidney left kidney - Right suprarenal gland - left suprarenal gland - right lobe of liver - stomach - 2nd part of duodenum - spleen - right colic flexure - pancreas - coils of jejunum - left colic flexure, coils of jejunum Fig 1.6: anterior relations of right and left kidneys Posterior relations of the right and left kidneys Right kidney Left kidney th - 12 ribs -11th and 12th rib - diaphragm, psoasmajor muscleand qudratus lumborum muscle - subcostalnerve and vessels- iliohypogastric and ilioinguinal nerves Fig 1.7: Posterior relations of the right and left kidneys 5  CHAPTER 1 Blood supply of the kidney: There is a network of blood vesselsthroughout the kidneys. The kidneys receive blood from the aorta via the renal arteries. the renal arteries branch into the segmentalarteries,the lobar arteries, and the interlobar arteries. The interlobar arteries branch to form the arcuatearteries The arcuate arteries branch off into interlobulararteries The interlobular arteries branch off into the afferent arterioles. The afferent arterioles lead into the glomerulus Efferent arteriolesleave the glomerulus to form peritubular capillariessurrounding the collecting tubules at the renal nephron.. When the blood leaves the nephron it travels to the interlobular veins, arcuate veins and then the Interlobar veins. there are no segmental veins like the segmental arteries. Blood leaves the kidney via the renal veins An outline of the pathway of blood through the kidneys is as follows 1-Renal artery 2-Segmental arteries 3-Lobar arteries 4- Interlobar arteries 5-Arcuate arteries 6- interlobular arteries 7- Afferent arterioles (Arteries = Afferent) 7-Glomerulus (capillaries) 8- Efferent arterioles (Exit vein = Efferent) 9-Peritubular capillaries 10- Interlobular veins 11- Arcuate veins 12- Interlobar veins 13-Renal vein Fig 1.8: pathway of the blood through the kidney 6  CHAPTER 1 The renal vascular system Renal artery usually gives into 5 segmental based on the distribution of five segmental branches of renal artery, each kidney is divided into five vascular segments. -Apical/ superior - Upper anterior -Middle anterior -Caudal/ inferior -Posterior Fig 1.9: The segmentationof the kidney based on segmental5 arteries Ureter Each ureter is a long tube of about 10 incheslong. The two ureters are muscular tubes that extend from the kidneys to the posterior surface of the urinary bladder. The urine is propelled along the ureter by peristaltic contractions of the muscle coat, assisted by the filtration pressure of the glomeruli Its upper ½ lies in the abdomen& its lower ½ in the pelvis 7  CHAPTER 1 Fig 1.10 parts and courseof the two ureters Abdominal part of the ureter Course: Begins inside the renal sinus as the pelvis of the ureter The pelvis is the funnel shaped expanded upper end of the ureter. It receives 2,3 major calyces. The ureter emerges from the hilum of the kidney and descends vertically behind the peritoneum, on the psoas major opposite the tips of the transverse processes of the lower 4 lumbar vertebrae. It enters the pelvis by crossing the bifurcation of the common iliac artery infront of the sacroiliac joint. Relations Right ureter: Left ureter: Medially: - Inferior vena cava ; - Inferior mesenteric vein Anteriorly: - 2nd part of the duodenum. –Left colic vessels - Right colic vessels -Left gonadal vessels - Gonadal vessels - sigmoid colon - Iliocolic vessels - Simoid mesocolon - Root of the mesentery Posteriorly of both right and left ureters - Psoas major muscle - Genitofemoral nerve - Bifurcation of common iliac artery 8  CHAPTER 1 Fig 1.11 Anterior relations of the right and left ureters Pelvic part of the ureter Course and relations: It enters the pelvic: - Opposite the sacroiliac joint. - Crossing infront of the bifurcation of common iliac artery Its course is divided into 3 parts. 1- From the pelvic brim to the ischial spine: ▫ It passes downwards and backwards along the anterior margin of greater sciatic foramen It crossesthe following from above downwards: External iliac vessels. Superior vesical artery & obliterated umbilical art. Obturator nerve & vessels Inferior vesical artery. Middle rectal artery ◘ In femaleforms the posterior border of ovarian fossa 2 - From the ischial spine to the urinary bladder: At the ischial spine the ureter changes its direction to run forwards and medially on the floor of the pelvis to reach the postero-superior angle of the urinary bladder ◘ In male: - It is crossed by the vas deferens. ◘ In female: - It passes closely lateral to the upper end of vagina - is crossed by the uterine artery from lateral to medial. 9  CHAPTER 1 3-Intramural part of the ureter: - It runs a very oblique course through the bladder wall to open at the supero-lateral angle of the trigone. Fig1.12: pelvic part of the ureter. A:in female B: in male Pelvis Constrictions of the ureter 1-Along its course it has 3 constrictions: 2-At the pelvi-ureteric junction 3-As it crosses the pelvic brim 4-As it pierces the bladder wall (intramural part) Fig 1.13: Sites of constrictions of the ureter 10  CHAPTER 1 Blood supply: 1- Arteries: The ureter is supplied along its course as follows: - Abdominal aorta, renal, gonadal, common iliac & Internal iliac arteries. - Inferior vesical and middle rectal arteries in males. - Twigs from the vaginal and uterine arteries in females. 2- Veins:corresponds to the arteries 3-Lymph Drainage: The lymph drains to the lateral aortic nodes and the iliac nodes. 4-Nerve Supply: The nerve supply is the renal, testicular (or ovarian), and hypogastric plexuses (in the pelvis). Afferent fibers travel with the sympathetic nerves and enter the spinal cord in the 1st and 2nd lumbar segments Fig1.14: Arterial supply of the ureter Development of the Kidneys and Ureters The urinary systemdevelopsfrom -Intermediate mesoderm -Part of cloaca ( urogenital sinus) The urogenital ridge is formed from the intermediate mesoderm At the 4th week, the intermediate mesoderm in the cervical region loses its contact with the somite and forms segmentally arranged cell clusters, known as the nephrotomes.Itgrows in a lateral direction 11  CHAPTER 1 and obtains a lumen (nephrictubules).The nephric tubules open mediallyinto the intra-embyronic coelom and laterally grow in a caudal direction. During the caudal growth, the tubules of succeeding segments unite and form a longitudinal duct on each side of the embryo (pronephric duct).Both ducts open caudally into the cloaca Fig 1.15: The intermediate mesodermand cloaca Development of the Kidney Three different, slightly overlapping kidney systems are formed during intrauterine life in humans :1- Pronephros( rudimentary and non-functional) 2- Mesonephros(may function for a short time during the early fetal period). 3- Metanephros ( permanent kidney) Fig 1.16: The nephric tubules and nephrogenic cord 12  CHAPTER 1 Pronephros: It is the first kidney to appear. It is represented by 7-10 solid cell groups (nephrotomes) in the cervicalregion. As they obtain lumina, they form 7-10 rudimentary pronephric tubules. The medial end of each tubule opens into the coelomiccavity.Theother lateral ends of the tubules join into a longitudinal duct called the pronephricduct which extends downwards to open into the cloaca It is segmentalin arrangement i.e. one pronephric unit develops opposite each somite. The pronephric tubules degenerate early at the end of the 4th week and the pronephric duct persists to the next stage where it is called the mesonephricduct. Fig 1.17: Different stagesof development of the kidney Mesonephros: It is the secondkidney to appear. During regression of the pronephric system, the first excretory tubules of the mesonephros appear. It develops in the intermediate mesoderm of the thoracic, lumbar and upper sacral regions opposite the 14- 28 somites. 13  CHAPTER 1 The intermediate mesoderm undergo segmentation into about 70 solid clusters, on each side. They elongate greatly and become canalized to form S-shaped tubules called the mesonephrictubules The lateral ends of the mesonephric tubules open into the mesonephric duct (previous pronephric duct). The medialend of each tubule is invaginated by a tuft of capillaries forming an internal glomerulus. While the caudal tubules are still differentiating, the cranial tubules and glomeruli show degenerative changes until they disappear by the end of the 2nd month Parts of the mesonephros persist to form very important derivatives: The derivatives of mesonephrosin The derivatives of mesonephrosin male: female: 1) Vasa efferentia 1) Paroophoron 2) Epididymis 2) Epoophoron and its duct 3) Vas deferens (Gartener’s duct) 4) Seminal vesicle 3) Trigone of the urinary 5) Ejaculatory duct bladder 6) Trigone of the urinary 4) Ureteric bud and its bladder derivatives 7) Upper part of the posterior wall of the prostatic urethra 8) Ureteric bud and its derivatives 14  CHAPTER 1 Metanephros: It is the permanentkidney It develops from 2 separate primordia : 1) The ureteric bud : Arise from a diverticulum of the mesonephric duct (collecting units) which gives rise to the entire collecting duct system. 2) The metanephric cap : Arise from the intermediate cell mass of the lower lumbar region , below the 26th somite and the sacral regions (excretory units) nephrons. The ureteric bud : It arises as an outgrowth of the caudal part of the mesonephric duct close to its entrance into the cloaca The bud grows dorsocranially invading the mesoderm of the intermediate cell mass, which condenses around it to form the metanephrogenic cap. Fig 1.18: The origin of permanent kidney from ureteric bud and metanephric cap Development of collecting ducts The ureteric bud forms the ureter,which dilates at this upper end to form the pelvisof the ureter. 15  CHAPTER 1 Later the pelvis gives off branches that form the major calyces, and these in turn divide and branch repeatedly until 12-14 order of branches are established, they form the minor calycesandthe collecting tubules. New collecting tubules continue to be formed until the end of the fifth month of fetal life. Fig 1.19: Development of the collecting tubules The metanephric cap:(excretory part) The mesoderm is segmented into cell clusters in relation to the termination of the collecting tubules. These cell clusters change into renal vesicleswhich elongate to form the different parts of nephron which are: Bowman’s capsule -Proximal convoluted tubule- Loop of Henle and Distal convoluted tubule. The proximal glomerular capsule becomes invaginated by a cluster of capillaries that form the glomerulus.Thedistal convoluted tubule joins the nearest collecting tubule to form a complete uriniferous tubule. 16  CHAPTER 1 Fig 1.20: Development of excretory part of the nephron More signsof kidney development: Location:In the early stages of development, the kidney is located in the pelvicregion, later on it moves upwards. This ascent is caused by a diminution of the body curvature and the growth of the body in the lumbar and sacral regions. Failure of ascent may result in pelvickidneywhich may remain in pelvis or lower lumbar region. Fig 1.21: The different location of the kidney during development Blood supply The kidney changes its blood supply during the ascent. At first it receives its blood supply from the median sacral and the common iliac arteries and then from the lower part of the abdominal aorta. 17  CHAPTER 1 Fig 1.22: The different blood supply of the kidney during development Shape:The foetal kidney is lobulatedwith an irregular surface. This lobulation usually disappear before birth as a result of further growth of the nephrons. Position:In the early stages, the convex border of the kidney look posteriorly and its hilum looks ventrally. Later it rotates about 90 degree medially so that the hilum becomes directed medially Congenital anomalies of the kidney: Horseshoekidney:Occurs when the inferior poles of the kidneys fuse together. Polycystickidney:Thekidney shows many small cysts which become full of urine due to failure of nephrons to join the collecting tubules. RenalAgenesis:(Bilateraland unilateral): Occurs when the ureteric bud fails to develop. Fig.1.23: Different congenital anomalies (agenesis, pelvic and horseshoe) 18  CHAPTER 2 Chapter 2 Histological structure of glomerular apparatus and renal tubules General microscopicstructure of the kidney The kidney is a mixed gland that has endocrine and exocrine functions. It consists of (Figure 1): 1- Stroma; is formed of: a- A thin connective tissue capsule. b- A highly vascular loose connective tissue presents in between renal lobes and lobules. 2- Parenchyma: By light microscopic examination, it is divided into cortex and medulla. The Cortex: - It is the outer, dark-stained part. - It consists of the renal corpuscles, convoluted proximal and distal tubules, and the cortical part of the collecting tubules. The Medulla: - It is deep to the cortex. - It is composed of the straight tubules of the nephron (loop of Henle and the medullary part of collecting tubules and ducts). - Because of the arrangement and the differences in length of the tubules, they form a number of conical structures called medullarypyramids. - The bases of the pyramids face the cortex, and the apices face the renal sinus. - Each medullary pyramid and the associated cortical tissue constitute a renal lobe. - Each human kidney is lobulated and contains 8 to 18 lobes. - The tip of each pyramid opens into a funnel-shaped minor calyx that collects the formed urine. Two to three minor calyces join forming a major calyx. 19  CHAPTER 2 - The major calyces join forming the renal pelvis, which is the expanded, proximal part of the ureter. The parenchyma is a compound tubular gland formed of uriniferous tubules. The uriniferous tubules consist of: a- Nephrons which produce urine. b- Collecting ducts that concentrate urine and deliver it out of kidney. Both components of uriniferous tubules have different embryological origins. General organization of the nephron Definition: - It is the structural and the functional unit of the kidney. Number: - Each kidney is formed of 1-3 million nephrons. - Two or three nephrons can be drained by one collecting tubule that join others to form duct of Bellini. -Each nephron consistsof (Figure 1): 1- Malpighian corpuscle (Renal corpuscle). 2-Proximal convoluted tubule. 3-Loop of Henle. 4-Distal convoluted tubule. -Types of nephrons-there are two types of nephrons; I- Subcapsularor cortical nephronswhich are present high up in cortex. II- Juxtamedullarynephronsare near the medulla. 20  CHAPTER 2 Fig 2.1:General structure of the kidney and nephron components 1-Renal corpuscle(Malpighian corpuscle) - Site: It is found in the cortex (Figure 2). - Structure: - It is a spherical structure consists of: a) The glomerulus (tortuous tuft of capillaries). b) Bowman's capsule (epithelial capsule covering the glomerulus). - It has two poles; vascular and urinary. - The vascularpoleis the site where the afferent arteriole enters and efferent arteriole leaves. 21  CHAPTER 2 - The urinary poleis the site where the proximal convoluted tubule begins. A) The glomerulus Definition: - It is a tuft of anastomosing capillaries formed by the afferent arteriole that enters the renal corpuscle at its vascular pole and gives capillary loops of the glomerulus and unite to form efferent arteriole. Structure of the glomerular capillaries: They are lined by fenestratedendothelium that has no diaphragm. They rest on a thick basementmembrane,300nm thick. EM structure of the basementmembrane: - It is composed of three layers, - The lamina densais the middle dense layer and consists of collagen type IV. -The lamina rarae are the outer and inner layers. They are less electron dense and formed of laminin, fibronectin, and negatively charged proteoglycans. B) Bowman's capsule: -It is a double epithelial capsule that is formed of two layers (Figures 2 and 11); The outerparietallayer is lined with a simple squamous epithelium. The inner viscerallayer is lined with modified cells called podocytes,which are adherent to the glomerular capillaries. The spacebetweenthe parietal and visceral layers is called capsular space/ urinary space that receives the glomerular ultrafiltrate and is continuous with the lumen of the proximal convoluted tubule. 22  CHAPTER 2 Fig 2.2: A diagram showing the cortex of kidney consistsof renal corpuscles, proximal convoluted tubule, distal convoluted tubules and collecting tubules. The Podocyte: - L/M: Podocyte is a star-shaped cell with multiple processes. The basement membrane is well developed and can be demonstrated as PAS+ve line (formed of glycoprotein). - E/M: It is a large cell that consists of body, primary processes (major) and secondary foot processes (minor). The cell body contains a central large indented nucleus with extended chromatin. The cytoplasm contains mitochondria, Golgi body, rough endoplasmic reticulum, microtubules and microfilaments. The cell body gives rise to several primary processesthatextend parallel to the long axis of blood capillaries. Each primary process gives rise to many secondaryfoot processes(the pedicels)that implanted on the basement membrane of glomerular blood capillaries. 23  CHAPTER 2 The pedicelsfromone podocyte embrace more than one capillary and the pedicels of two podocytes alternate in position on a single capillary. The pedicels contain only microtubules & microfilaments. The pedicelshave a well-developed glycocalyx composed of negatively charged proteins. In between the pedicels, there are filtration slits that are covered with slit diaphragms. Slit diaphragmsare a highly specialized type of intercellular junctions mainly formed by nephrin. The podocytes are separated from the glomerular capillaries by subpodocyticspace. Fig 2.3: A diagram showingthe structure of podocyteand blood-renal barrier Function of podocyte: 1- Formation of blood renal barrier. 1- Regeneration of the basement membrane. 24  CHAPTER 2 # Structure of blood-renal barrier: 1. Fenestrated endothelium of the blood capillaries. 2. Thick basement membrane, which is the only continuous layer of the filtration barrier. 3. Filtration diaphragms that cover the filtration slits (60-100nm). # Function of blood-renal barrier: - The principal function of the barrier is the formation of the glomerular ultrafiltrate. - The fenestrated endothelium of the glomerular capillaries allows the passage of plasma holding pack the RBCs, WBCs and platelets. - The lamina densaof the basement membrane restricts the passage of high molecular weight proteins (> 70,000 Da), but small molecular weight proteins (not bearing a negative charge), sugar and amino acids can pass with the filtrate. - The lamina rarae restrict the passage of the negatively-charged (anionic) molecules, even those smaller than 70,000 Da. - Filtration diaphragmsprevent the passage of molecules according to their size and electrostatic charge. Intraglomerular Mesangial cells(Figure 6): - Site:In between the loops of capillaries in the places that lack the podocytes. - Function: 1- Give supportto the capillaries (like pericytes). 2- Phagocytosisofproteins (antigen-antibody complexes) that adhere to the basement membrane. 3- Secretionoffactors important for immune defense as cytokines. 4- May be contractilebecause they respond to the vasoactive substances (angiotensin II) to reduce the blood flow into the glomerulus. 25  CHAPTER 2 Fig.2.4: Electron micrograph of pedicels (P) and slit diaphragms (→) bridging the filtration slits. CL, capillary lumen. Hollow arrow indicates the laminae rara Fig 2.5: A star-shaped podocyte with primary processes and pedicles surroundings two capillaries. The proximal convoluted tubules It begins in the cortex at the urinary pole of renal corpuscle. At first, it is highly convoluted (pars convoluta), then straightens (pars recta) and directed toward the medulla forming thick descending loop of Henle. 26  CHAPTER 2 Fig.2.6: Intraglomerular mesangialcell in betweenthe glomerular capillaries By L/M, acrosssection of proximal convoluted tubule showsthat: - The lumen is narrow. - It is formed of 4-5 pyramidal cells. - The cells are strongly acidophilic - The nuclei are rounded and central. - The apical surface shows brush border. - The basal part has acidophilic striation. - The cell boundaries are indistinct (not clearly evident). Fig 2.7: A diagram showingLM of proximal convolutedtubule, distal convoluted tubule and collecting tubule. 27  CHAPTER 2 By EM showsthe characters of ion transporting cells: The apical surfacehas long, closely packed microvilli (seen as brush border by LM) to facilitate reabsorption, in between microvilli there are tubular invaginations called apical canaliculi. At the base of the microvilli, there are vesiclespresent in between the canaliculi engaged in endocytosis and pinocytosis. The small proteins in the filtrate are reabsorbed by receptor- mediated endocytosis or degraded by the surface peptidases and released at the basolateral side for uptake by capillaries. The basalpart of the cell has basal invaginations (seen as basal striation by LM). Numerous long mitochondria in between the basal infoldings (which is the cause of basal acidophilia). Both brush border and basolateral folds contain many types of transmembrane proteins that mediate tubular reabsorption and secretion. Lateral cell membraneinterdigitations between the adjacent cells (indistinct border by LM). There are tight junctions that seals the intercellular space from the lumen of the tubule, and zonula adherence that maintain the adhesion between neighboring cells. The nucleiare central and rounded with extended chromatin. The cytoplasmcontains small Golgi apparatus, RER, lysosomes. 28  CHAPTER 2 Fig 2.8: A diagram showingEM picture of proximal convolutedtubule cell 2- Loop of Henle - It is U shaped tube present mainly in medulla. - It consists of four parts: 1- Thick descendingpart: It starts in the cortex and extends to the medulla. It is similar to proximal convoluted tubule in structure and function. 2-Thin descendingpart. 3-Thin ascendingparts, Both thin parts are located in the medulla. They are lined by simple squamous epithelium. 4-Thick ascendingpart: It starts in the medulla and extends to the cortex. It is similar to the distal convoluted tubule in structure and function. * Structure of thin parts: - Both thin descending and ascending parts are similar by LM and EM. - The cells lining them have a few short stubby microvilli on the luminal surface. 29  CHAPTER 2 - They have few mitochondria in the cytoplasm, indicating a passive role in transport. - The cross section of the thin limb is similar to the capillary wall of vasa recta, but it may be distinguished by: 1- The thin limb lumen contains no blood cells. 2- The epithelium of the thin limb is thicker than the endothelium of vasa recta capillary wall. 3- Nuclei of thin limb stain less dense than those of the endothelium, and they protrude slightly into the lumen. Fig. 2.9: EM showsthat the simple squamousepithelium (hollow arrow) of the thin limbs (T) is slightly thicker than the epithelium (black arrow) of vasa recta capillaries (C). 4- Distal convolutedtubule - There are three parts of distal tubule. 1. The straight part is continuous with the ascending thick limb of the loop of Henle. 2. Macula densa is present between the afferent and efferent arterioles and it is a part of the juxtaglomerular apparatus. 3. The convoluted part opens in the collecting tubule. 30  CHAPTER 2 By LM, acrosssection of distal convoluted tubule shows: The lumen is wide. It is formed of 6-8 simple cuboidal cells. The cells are acidophilic but less than PCT. Their nuclei are rounded and nearly apical. Their apical surface has no brush border. The basal part has acidophilic striation. Their cell boundaries are more distinct than PCT. By EM, it showsthat: The apical part has a few club-shapedshortmicrovilli(less reabsorption). Their nuclei are rounded and nearly apical with extended chromatin. The basal part contains mitochondria in-between the basal invaginations. Cells of distal tubules have fewer mitochondria than cells of proximal tubules making them less acidophilic by LM. Fig 2.10: A diagram showingEM picture of distal convolutedtubule cell 31  CHAPTER 2 JUXTAGLOMERULAR APPARATUS - It is a specialized sensory structure in the kidney responsible for regulation of blood glomerular flow and makes it constant. It is composedof(Figure 11): 1- Macula densa: 2- Juxtaglomerular cells: 3- Extraglomerular mesangial cells, (polar cushionor lacis cells): 1. Macula densa: -It is a part of the distal tubule present in the concavity between afferent and efferent arterioles of the same nephron. Structure: 1. LM: The cells appear columnar, tall, and narrow with packed nuclei. 2. E/M: The cell has apical numerous microvilli, infranuclear Golgi apparatus, and randomly-oriented, small mitochondria. The cell lacks its basement membrane. 2. Juxtaglomerular cells: -They are modified smooth muscle cells of the tunica media of the afferent arteriole. They are richly innervated by sympathetic nerve fibres. Structure: 1- LM: - The cells are large cubical with rounded nuclei. The cytoplasm contains many secretory granules which are (PAS) +ve. 2- EM: - The cytoplasm contains RER, Golgi apparatus, mitochondria and secretory granules contain renin. The juxtaglomerular cells are in direct contact with the cells of macula densa on the other side due to the absence of the basement membrane of macula densa. 32  CHAPTER 2 3. Extraglomerular mesangial cells, (polar cushionor lacis cells): Structure: The cells are pale staining and occupying the space between afferent and efferent arterioles and the macula densa. Function:May be phagocytic. Fig 2.11: A diagram showingthe juxtaglomerular apparatus. COLLECTING TUBULES - Collecting tubules are not a part of the nephron. - Collecting tubules have three recognized regions: o Cortical. o Medullary. o Papillary. - Cortical collectingtubules:they are made by the union of two or three distal convoluted tubules and run in the medullary rays in cortex. They descend deeper to penetrate the medullary pyramid. - Medullary collectingtubules: they are larger in caliber as they formed by union of several cortical collecting tubules. - Papillary collectingtubules (ducts of Bellini): formed by the union of the medullary tubules that open at the apex of renal papillae into a minor calyx. - Two to four minor calyces join to form a major calyx that opens in the renal pelvis. 33  CHAPTER 2 Structure (Figures 2 and 7): - The tubules have wide lumens and are lined with simple cubical epithelium (in small tubules), or simple columnar epithelium (in large tubules). - There are two cells; the main principal cell (light cell) and the intercalatedcell (dark cell). Principle cell (light cell): The cytoplasm is pale acidophilic (lightly stained). The cell borders are evident (no lateral interdigitations). The nuclei are central. Ther are few sparse microvilli. The cytoplasm has few mitochondria, There are numerous basal invaginations. Responsible for water absorption and urine concentration under the effect of antidiuretic hormone secreted by the posterior pituitary. Intercalated cell (dark cell): - Fewer than the principal cells. - Have dark cytoplasm, apical vesicles and more mitochondria. - Responsible for maintaining acid-base balance by secretion of H+ or HCo3- 34  CHAPTER 3 Chapter 3 Functions of the kidney I- general functions of the kidney 1- Role of the kidney in homeostasis The kidney maintains the internal environment (extracellular fluid) always constant. This action is exerted by the following mechanismsofthe kidney. a- Regulation of the extracellular fluid volume: In overhydration the urine will be increased. In dehydration the urine volume will be decreased. This function is adjusted by antidiuretic hormone. b- Regulation of the blood level of electrolytes: e.g.: By adjustment of Na+ & K+ excretion in the urine. This function is adjusted by the aldosterone. c- Regulation of blood pH: The kidney can regulate pH through: i- Secretion of nonvolatile acids or alkalies. ii- Formation of NH3 & excretion of other buffer system (e.g.) phosphate & bicarbonate. 2- Reabsorption The kidney reabsorbs useful nutrient substances & other elements essential for body functions. 3- Excretory function The kidney has a role in excretion of: i- Waste productsformed in the body (e.g.) uric acid & creatinine. 35  CHAPTER 3 ii- Foreign substancesaftertheir detoxication in the liver by conjugation (e.g.) drugs & toxins. iii- Excess amounts of essential substances (e.g.) excess water, electrolytes & H+. 4- Regulation of the arterial blood pressure(ABP): In conditions of shock or hemorrhage renal ischemia occurs. Renal ischemia leads to stimulation of juxtaglomerularapparatus to secrete renin. Then, renin acts on angiotensinogenformed by the liver to form angiotensinI. Angiotensin I is converted to angiotensin II by the convertaseenzyme (angiotensin converting enzyme). Angiotensin II causes a powerful vasoconstriction of the blood vessels increase ABP. In addition, angiotensinII is stimulant for the secretion of aldosterone hormone which leads to Na+ & water retention increasethe blood volume increaseABP. 5- Erythropoiesis Hypoxia stimulates the kidney to secrete erythropoietin from endothelial cellsof the peritubular capillaries in the renal cortex. Erythropoietinis a powerful stimulant to the bone marrow to produce RBCs. 6- Prostaglandins The kidney secretes prostaglandins(E2& I2). Prostaglandins play a minor role in regulation of the renal blood flow & protection of the kidney from excess renal V.C. during severe cardiovascular stress such as hemorrhage. 36  CHAPTER 3 7- Endocrine function of the kidney The kidneys are endocrine organs they secrete the following: 1. Renin 2. Erythropoietin 3. Kinins (unknown function). 4. Prostaglandins. 5. 1, 25 dihydroxycholecalciferol (1,25-DHCC). 1,25-DHCC is the active form of the vitamin D. II- Metabolic Functionsof the Kidney - Despite that the kidney tissue represents less than 0.5% of the body weight, it receives 25% of the cardiac output & 10 % of O2 are consumed by it. - This is required for the synthesis of ATP needed to reabsorb most of the solutes filtered through glomerular membranes. However, its stores of glycogen, phosphocreatine and lipids are very, so kidney must get its energy requirement from circulating fuel substrates (as glucose, fatty acids & ketone bodies) - Most people know that a major function of the kidneys is to remove waste products and excess fluid from the body, but it also has various metabolic functions that are not less important than its excretory function. 1- Carbohydrate Metabolism in the kidney - Gluconeogenesis: Synthesis of glucose from non-carbohydrate sources as lactate, glycerol & amino acids (esp. glutamine) - Glucose oxidation (Glycolysis) , citric acid cycle & HMP shunt Kidney & glucosehomeostasis - Regarding glucose homeostasis, the kidney can be considered as 2 organs due to the differences in the distribution of various enzymes in renal medulla & renal cortex - Cells of the cortex have considerable amounts gluconeogenic enzymes, BUT have little hexokinase. So, the release of glucose by the normal kidney is 37  CHAPTER 3 exclusively, a result of renal cortical gluconeogenesis. The most important substrates for renal gluconeogenesis are glutamine, lactate & glycerol. - Cells of the medulla have considerable amounts of hexokinase and other enzymes of glycolysis. So, they can take up, phosphorylate & metabolize glucose through glycolysis BUT: don’t have gluconeogenic enzymes nor glucose 6- phosphatase, so they can form glycogen (limited amounts), but cannot release free glucose into the circulation. Renal gluconeogenesis paradoxically increases postprandially due to postprandial increases in sympathetic nervous system activity availability of gluconeogenic precursors (e.g., lactate and amino acids).This increase in renal gluconeogenesis help liver glycogen repletion by suppression of hepatic glucose release. Kidney & GlucoseMetabolism in Fasting: - Early fasting (first hours): source of glucose in blood is mainly by liver glycogenolysis. - 18 – 60 hours of fasting: source of blood glucose is mainly gluconeogenesis (in liver & kidneys). - After 60 hours of fasting: Liver gluconeogenesis release is decreased by 25%. So, liver cannot compensate for the kidney to preserve normal blood glucose levels in patients with renal insufficiency during prolonged fasting. This may explain why patients with renal failure develop hypoglycemia. 2- Lipid Metabolism in the Kidney Lipid metabolic pathways occur in the kidneys: 1- Beta-oxidation of fatty acids. 2- Synthesis of carnitine: for transport of FA to mitochondria for oxidation. 3- De-novo synthesis of fatty acids. 38  CHAPTER 3 4- De-novo synthesis of cholesterol. 5- Activation of glycerol to glycerol 3-phosphate (by glycerol kinase) 3- Protein Metabolism in the Kidney Amino acid metabolic pathways occur in the kidneys: 1- Excretion of ammonia & urea to urine. 2- Degradation of glutamine by glutaminase enzyme. Glutamine produced in most organs (from amino acid metabolism) are degraded into glutamate & ammonia in the kidney. Ammonia produced is important in acid base balance. 3- Amino acids deamination. 4- Creatine synthesis (first step) from amino acids glycine & arginine: a. Formation of guanido acetic acid from amino acids glycine & argenine occurs in the kidney. b. Methylation of guanido acetic acid to creatine occurs in the liver. 4- Production of Erythropoietin It is a glycoprotein hormone that controls erythropoiesis. It is produced by the renal cortex in response to low oxygen levels in the blood. 5- Activation of vitamin D in the Kidney - Renal 1α hydroxylase: The key regulatory enzyme in vitamin D activation is the 1α hydroxylase enzyme produced by the kidney. - Vitamin D3 (cholecalceferol) is hydroxylated in the liver to 25 hydroxycholecalciferol. Then, the renal 1α hydroxylase converts 25 hydroxycholecalciferol to 1, 25 dihydroxycholecalciferol which is the active form of vitamin D in the kidney. Metabolic interrelations of tissuesin kidney diseases 1. In chronic kidney diseases levels of amino acids (proline, glutamin, glysineand citrulline) normally metabolized by kidney are increased, nitrogen end product accumulates (urea, uric acid, creatinine) which are normally metabolized by the kidney. 39  CHAPTER 3 2. High protein intake or increased proteolysis worsens kidney function. 3. In kidney failure protein intake except for essential amino acids should be limited as much as possible, but carbohydrate should be increased which may delay the need for dialysis 4. Patients under dialysis have an increased risk of cardiac and skeletal myopathy due to impaired fatty acid oxidation as a result of carnitine deficiency as: - Carnitine is removed from blood during dialysis. - Dietary source of carnitine (meat) is reduced. - Functional kidney mass is reduced. Fig 3.1: Metabolic interrelationships of tissuesin kidney failure. 40  CHAPTER 4 Chapter 4 General functions of the kidney (1) Role of the kidney in homeostasis: The kidney maintains the internal environment (extracellular fluid) always constant. This action is exerted by the following mechanismsofthe kidney. Regulation of the extracellular fluid volume: In overhydration the urine will be increased. In dehydration the urine volume will be decreased. This function is adjusted by antidiuretic hormone. Regulation of the blood level of electrolytes: e.g.: By adjustment of Na+ & K+ excretion in the urine. This function is adjusted by the aldosterone. Regulation of blood pH: The kidney can regulate pH through: j- Secretion of nonvolatile acids or alkalies. jj- Formation of NH3 & excretion of other buffer system (e.g.) phosphate & bicarbonate. (2) Reabsorption: The kidney reabsorbs useful nutrient substances & other elements essential for body functions. (3)Excretory function: The kidney has a role in excretionof: Waste productsformed in the body (e.g.) uric acid & creatinine. Foreign substancesaftertheir detoxication in the liver by conjugation (e.g.) drugs & toxins. Excess amounts of essential substances (e.g.) excess water, electrolytes & H+. (4) Regulation of the arterial blood pressure In conditions of shock or hemorrhage renal ischemia occurs. Renal ischemia leads to stimulation of juxtaglomerularapparatus to secrete renin. Then, renin acts on angiotensinogenformed by the liver to form angiotensinI. 41  CHAPTER 4 Angiotensin I is converted to angiotensin II by the convertaseenzyme (angiotensin converting enzyme). Angiotensin II causes a powerful vasoconstriction of the blood vessels increase ABP. In addition, angiotensinII is stimulant for the secretion of aldosterone hormone which leads to Na+ & water retention increasethe blood volume increaseABP. (5) Erythropoiesis: Hypoxia stimulates the kidney to secrete erythropoietin from endothelial cellsof the peritubular capillaries in the renal cortex. Erythropoietinis a powerful stimulant to the bone marrow to produce RBCs. (6) Prostaglandins The kidney secretes prostaglandins(E2& I2). Prostaglandins play a minor role in regulation of the renal blood flow & protection of the kidney from excess renal V.C. during severe cardiovascular stress such as hemorrhage. (7) Endocrine function of the kidney The kidneys are endocrine organs they secrete the following: 1. Renin 2. Erythropoietin 3. Kinins (unknown function). 4. Prostaglandins. 5. 1, 25 dihydroxycholecalciferol (1,25-DHCC). 1,25-DHCC is the active form of the vitamin D. 42  CHAPTER 4 Tubular functions In the renal tubules, the glomerular filtrate is changed to urine through the processes of: 1- Reabsorption. 2- Secretion. 1- Reabsorption This process is either passiveor active: (a)Passive reabsorption: This occurs by simple or facilitated diffusion. It requires no energy. It occurs downa concentration, electrical or osmotic gradients. (b)Active reabsorption: It requires energy. It occurs againsta concentration, electrical or osmotic gradients. It needs enzymatic activity & specific carriers. It is either primary or secondary (see later for differentiation between them). 2- Secretion This process is almostonly active. The secreted substances may be: a- Derived from the blood stream e.g. creatinine & K+. b- Synthesizedin the tubular cells then secreted e.g. H+ & NH3. 43  CHAPTER 4 Fig 4.1: Tubular functions The tubular functions include: (I) Functions of PCTs. (II) Functions of Loop of Henle. (III) Functions of DCTs. (IV) Functions of collecting ducts. Functions of the proximal convoluted tubules 1- Reabsorption in PCTs: 1) Sodium reabsorption Na+ reabsorption in the PCTs occurs as following: a) Primary active transport at the basolateral borders of the cells of the PCTs. b) Passivediffusionat the brush borders of the cells of the PCTs. a) Primary active transport: Na+ is reabsorbed by primary active transport as follows: Na+ is pumped at the basolateral borders of the cells into the interstitial fluid. The required energy is obtained directlyfrom ATP breakdown by the activity of the Na+-K+ ATPase enzyme. 44  CHAPTER 4 This energy pump 3 Na+ outsidethe cells in exchange with 2 K+ pumped inside the cells. K+ diffuse almost immediately back again into the interstitium. b) Passive diffusion: The primary active transport of Na+ at the basolateral borders leads to decreasethe intracellular Na+ concentration & the potential inside the cells is kept at about −70mV. This negativeintracellular voltage as well as the low concentrationof Na+ inside the epithelial cells cause Na+ to diffusepassivelyfrom the tubular lumen into the cells by the so called electrochemical gradient. The passivediffusionof Na+ into the cells also occurs by facilitated diffusion (i.e.) Na+ binds to a special Na+ carrier protein at the brush borders of the cells. 2) Water reabsorption The PCTs are highly permeableto water. Water is reabsorbed by passive diffusion (osmosis) following Na+ reabsorption. This is called obligatorywater reabsorption.(See later). It is about 65% of water in the glomerular filtrate. 3) Chloride reabsorption About 65% of Cl- is reabsorbed by passive diffusion in the PCTs secondary to active reabsorption of Na+ to maintain electrical neutrality. 45  CHAPTER 4 Fig4.2: transport of sodiumin PCTs 4) Glucose reabsorption This is usually completein normal condition. It occurs only in the PCTs. Glucose reabsorption at the brush borders occurs by the secondaryactive transport. Then, Glucose reabsorption at the basolatreal borders of the cells of PCTs to the interstitium occurs by facilitated diffusion. Secondaryactive transport as following: The energy of the secondary active transport is not directly provided by breakdown of ATP. But, it is provided by the primary activetransport of Na+ out of the renal tubular cells into the interstitial fluid as follows: The outward Na+ pump greatly decreases the intracellular Na+ concentration this creates a large concentration gradient for Na+ diffusion from the tubular lumen into the tubular cells. This gradient represents diffusionenergy because the increased 46  CHAPTER 4 Na+ diffusion also energizes the transport of other substances along with Na+ through the cell membrane. Both Na+ & glucose are co-transportedintothe cells by binding to a symportcarrier in the brush borders of the cells. Then, glucose moves to the interstitial fluid by facilitateddiffusion (type of passive diffusion). Fig4.3: Glucoseabsorption 5) Amino acid reabsorption Normally, amino acids & other substances of nutritional value (e.g. protein & vitamins) are completelyreabsorbed. Amino acids are reabsorbed by secondaryactive transport at the brush borders of PCTs into the cells. Then, they are transported at the basolatreal borders of the cells of PCTs to the interstitium occurs by facilitated diffusion. Protein is reabsorbed in by pinocytosisthrough the brush border of the epithelial cells then, they are digested into amino acids. 6) K reabsorption 65% K+ of glomerular filtrate is reabsorbed in the PCTs. At the brush bordersof the tubular cells K+ reabsorption occurs by 47  CHAPTER 4 secondaryactive transport with Na+ (co-transport with Na+). At the basolateralbordersof the tubular cells K+ reabsorption occurs by passive diffuse into the interstitium then, to the blood in the peritubular capillaries. 7) Calcium reabsorption: About 60% of filtered Ca++ is reabsorbed in the PCTs. Ca++ transport occurs by secondaryactivetransport at the brush borders of the tubular cells. Then, by passivediffusionat the basolateral borders of the tubular cells. 8) Phosphate reabsorption: Phosphate is reabsorbedonlyin the PCTs. It occurs by secondaryactive transport. It is inhibited by the parathyroid hormone. 9) Bicarbonate HCO3-reabsorption The renal tubules are poorly permeableto HCO3- However, HCO3- is primary reabsorbedin the form of CO2 as follow: a- H+ is formed inside the tubular cells then, secreted in the tubular fluid. b- H+ combines with HCO3- in the tubular fluid forming H2CO3. c- By activity of carbonicanhydraseenzyme(C.A.) at the brush borders of the tubular cells H2CO3 dissociates into CO2 & H2O (the later excreted). d- CO2 diffuses into the cells where it combines with H2O by activity of an intracellularC.A. forming H2CO3. e- H2CO3dissociates into HCO3- and H+. f- HCO3- passively diffuses into the interstitial fluid (then to the blood). g- While, H+ is secreted into the tubular fluid to help more reabsorption of 48  CHAPTER 4 HCO3-. Fig 4.4: Bicarbonate transport in PCT 10- urea reabsorption About 50% of the filtered urea is passivelyreabsorbedin the PCTs (because their walls are partially permeable to urea). 11-Uric acid reabsorption Uric acid is reabsorbedonlyin the PCTs. This occurs by passivediffusion. It is also slightly secreted. Its absorption is more than that of urea (so uric acid clearance is only 14 ml/min.). 2- Secretion in the PCTs 1- H+ ions: H+ ions are actively secreted by secondary active transport (counter- transport with Na+) in the PCTs. This secretion is controlled by H+ ions level in the blood. 49  CHAPTER 4 2- Secretion of creatinine: Small quantities of creatinine are secreted by the PCTs. 3- Secretion of foreign substances: e.g. PAHA, penicillin &metabolites as steroids degradation. 3- Synthesisin the PCTs Synthesis & secretion of NH3 occur in all the renal tubules with the exception of the thin segmentof loop of Henle. The ammonia (NH3) reacts with H+ to form ammonium ions (NH4+). Then NH4+ is excreted into the urine in combination with Cl - ions to from ammonium chloride which is a weak acid. Functions of loop of Henle The loops of Henle act as countercurrentsystem. The loops of Henle of the cortical nephrons are concerned with conservation of water & electrolytes. While, the loops of Henle of the juxtamedullary nephrons are essential for urine concentration. N.B.: (A countercurrent system) It is a system where there is two currents flowing parallel, oppositeand adjacentto each other. There are two types of the countercurrent system include: 1) Countercurrent multiplier system: It is a system that operates activelyto create an osmoticor chemical gradient. The loop of Henle is an example of this type which creates an osmoticgradientin the renal medullary interstitium. 2) Countercurrent exchanger system: It a system that operates passivelyto maintain an osmotic,thermalor chemicalgradient. 50  CHAPTER 4 Examples for countercurrent exchanger systeminclude: The vasa recta are an example of the countercurrent osmotic exchangersystem. The renal countercurrent mechanism This is the mechanism by which urine is concentratedinthe kidneys. It depends on the production & maintenance of a stateof hypersomolarity in the renal medullaryinterstitiumby the action of the structures that pass in the renal medulla. These structures include the following: 1- The loop of Henle of the juxtamedullary nephrons: These constitute a countercurrentmultiplier system. It acts to increaseprogressivelyhyperosmolarityin the renal medulla. So that the osmolarity of the medullary interstitium gradually increase from (300 mOsm/liter) in the renal cortex to (1200-1400 mOsm/liter)at the renal papillae. 2- The vasa recta: These constitute a countercurrent exchangersystemthat operates passively to maintain the hyperosmolarity of the medullary interstitium. 3- The medullary collecting ducts: These establish an osmoticequilibrium between the tubular fluid & the renal medullary interstitium. Thus, it is considered as an osmoticequilibrating device. 51  CHAPTER 4 The countercurrent multiplier system (The loop of Henle) This system consists of the loop of Henle of the juxtamedullarynephrons (which penetrate deeply in the renal medulla). It is concerned with graded hyperosmolarityin the medullary interstitium by the following mechanism: (1)The descendinglimb of loop of Henle: It receives isotonicfluid from the PCTs. Its wall is: (a) Highly permeable to water. (b) Poorlypermeable to solutes (Na+, Cl- and urea). Accordingly, water passivelydiffuseoutwarddownan osmotic gradient into the medullary interstitium. As a result, the tubular fluid because hypertonic. Its hypertonicity increasegraduallyas the tabular fluid flows downwards reaching (1200 up to 1400 mOsm/liter) at the tips of the renal pyramids. The amount of the reabsorbed water in the loop of Henle is about 15% of the filtered water in the glomeruli & it is an obligatoryreabsorption as that occurring in the PCTs. (2)The ascendinglimb of loop of Henle: It receives hypertonicfluid from the descending limb. Then, the following changes occur: (a)The initial thin part is: i) Impermeableto water. ii) Poorly permeableto urea. iii) Highly permeableto Na+ and Cl-: 52  CHAPTER 4 Accordingly, Na+ & Cl- diffuse passively down their concentration gradients into the medullary interstitium. Therefore, the tonicity of the tubular fluid progressively decreasesasit moves up (becoming iso then hypotonic). While, hyperosmolarity is developed in the medullary interstitium. (b)The distal thick part is: i) Impermeableto water. ii) Poorly permeableto all solutes. iii) However, both Na+ & Cl- are activelytransportedfromthe tubular fluid into the medullary interstitium. This produces: Hyperosmolarity in the medullary interstitium. The tubular fluid becomes more hypotonicwith an osmolarity about 150 mOsm/literwhen delivered to the DCTs. Fig 4.5: The Renal Counter Current Mechanism 53  CHAPTER 4 Mechanism of Na+ & Cl- transport in the distal thick part of the ascending limb of loop of Henle: a) Secondaryactive transport as following: One Na+, one K+ and 2Cl- are co-transportedfrom the tubular lumen into the cells. This transport needs a symportcarrier. b) Primary active transport of Na+ Na+ is actively pumped out from the cells into the medullary interstitium by ATPase in exchange for K+. Then, K+ passivelydiffusesinto the tubular fluid. c) Transport of Cl- from the cellsinto interstitium: One Cl- is co-transportedwith the absorbed K+ into the medullary interstitium. The other Cl- diffusespassivelyintothe interstitium. Fig 4.6: The transport of Na+, K+, Cl in thick ascendinglimb of loop of Henle 54  CHAPTER 4 The vasa recta The main function of vasa recta is to maintain the medullary interstitium hyperosmolarity. This is achieved by operating as a countercurrent osmotic exchanger systemas following: a) It provides a trapping (holding) mechanism for Na+, Cl-& urea in the medullary interstitium. b) It removes excesswaterfrom the medullary interstitium. Such effects occur as following: 1- In the descendinglimb: The solutesdiffuse from the medullary interstitium into the blood (because the concentration of these solutes is higher in medullary interstitium). Water diffuses from the blood to the medullary interstitium (so the blood osmolarity rises). 2- In the ascendinglimb: The solutes diffuse from the blood into the medullary interstitium. Water diffuses from the medullary interstitium to the blood (so the blood osmolarity falls). 55  CHAPTER 4 Fig 4.7: Vasa recta as a countercurrent exchanger system N.B.1: The excesswater comesfrom 2 sources: i) Water that diffuses from the descendinglimbsofboth vasa recta & loop of Henle. ii) Water that is reabsorbed from the collecting ducts (see later). N.B.2: The countercurrent exchanger function of the vasa recta is helped by: 1- They are highly-permeable to both solutes and water. 2- They constitute a low pressure systemof capillaries at which the blood flow is small (about 2% of the renal blood flow) & sluggish. Properties in 1 &2 allow: Maximal diffusion of the solutesfrom the ascendinglimbs of the vasa recta into the medullary interstitium. Diffusion of water in the opposite direction. 56  CHAPTER 4 Renal handling of urea through the different parts of the renal tubules a- In the PCTs: The permeability of the PCTs to urea is high. Urea follows Na+, Cl-& water by passivediffusion. b- In the descendinglimb of loop of Henle: The permeability to urea is low. Thus, the fluid that reaches the tip loop of Henle has high urea. c- In the DCTs & the cortical part of the collectingduct. The tubule is almost impermeableto urea. Thus, urea becomes concentrated in this segment. d- In the medullary part of the collectingducts: The permeability to urea is high. Urea diffuses passivelyfrom the collecting duct into the medullary interstitium. Once urea inters the medullary interstitium it is trapped there by the countercurrent exchange between the ascending & descending limbs of the vasa recta. Causesof medullary interstitium hyperosmolarity 1- Na+ and Cl- transport from the ascending limb of loop of Henle: (the most important cause): Passivelyat their lower thin parts. Actively at their upper thick parts. 2- Small amounts of Na+ & Cl- transported from the medullary collecting ducts: Na+ by primary active transport. Cl- by passivediffusion. 57  CHAPTER 4 3- Urea: The medullary collecting ducts are partially permeableto urea as the PCTs. They become highly permeableto urea in the presence of ADH. Therefore, urea diffusespassivelyfrom the medullary collecting ducts to the medullary interstitium. N.B.: The cortical interstitium is iso-osmotic(have an osmolarity about 300 mOsm/liter). This is due to the much greater blood flow rate in the cortical peritubular capillaries (as compared with that in the vasa recta). So, the peritubular capillaries drain excess solutes from the cortical interstitium. Functions of the distal convoluted tubules (DCTs) The DCTs receive hypotonicfluid from the ascending limbs of the loops of Henle. Functionally, they are divided into 2 parts: a- The initial part: This has the same characteristics as the thick segment of the ascending limbs of loop of Henle. It is almost impermeabletoboth water & solutes (urea, Na+ &Cl-). But, Na+ is reabsorbed by primary active transport & Cl- follows it passively. The tubular fluid becomes more hypotonic(about 100 mOsm/liter). Thus, this part is called the diluting segmentofthe nephron. The initial parts of DCTs secrete H+ mainly by secondary active transport. 58  CHAPTER 4 b- The late part: This part performs the following functions: I- Reabsorption: (1) Na+ reabsorption: This occurs by primary active transport. It is controlled mainly by aldosteronehormone. It is followed by passivereabsorptionof Cl-& water. About only 5% of the filtered water is reabsorbed in the DCTs, as they poorly permeableto water. There is no urea reabsorption, because the DCTs are normally poorly permeableto urea. The fluid delivered from the DCTs into the collecting ducts is hypotonic. (2) Ca++ reabsorption: This also occurs by primary active transport. It is increased by the parathyroid hormone. Figure 4.8: The action of aldosteronein the DCTs 59  CHAPTER 4 II- Secretion: (1)H+ secretion: This occurs mainly by secondaryactivetransportby Na+-H+ antiport carrier. However certain cells called (intercalated, dark or brown cells) start to appear in this segment (and become more abundant in the collecting ducts). These cells secrete H+ independent of Na+ (by primary active transport) against high concentration gradient by specific uniport carrier protein & H+-ATPase. III- Secretion of buffers for excess H+ in the DCTs: The kidney often excrete urine at pH as low as 4.5 in acidosis or as high as 8 in alkalosis. In acidosis,theurine is buffered by the following buffer systems to prevent marked decrease of pH below 4.5. a- Bicarbonate buffer: The HCO3- ions & H+ are normally titrate each other in the tubules mainly in the PCTs. The remaining excess H+ in the tubular fluid is buffered by the phosphate & ammonia buffers. b- Phosphatebuffer: This buffer is a much more powerful in the tubular fluid than in blood (due to its high concentrationin the urine). c- Ammonia buffer (2)K+ secretion: This occurs actively as follows: a) K+ is transported inside the tubular cells by the Na+- K+ pump at their basolateral borders. b) Then, it is secreted by counter-transport mechanism at their 60  CHAPTER 4 luminal borders of the principle cells,(which start to appear in this segment), into the tubular fluid in exchange for Na+ reabsorption (utilizing an antiport carrier). K+ secretion in the DCTs and cortical collecting ducts is increased by: i) IncreaseThe extracellular K+ level. ii) IncreaseAldosterone level. N.B.: K+ & H+ compete for secretion in the DCTs and cortical collecting ducts. So, an increase of any of these ions in the tubular cells favours its secretion. 61  CHAPTER 4 Acidification of urine (H+ secretion) by the renal tubules Urine acidification occurs by secretion of H+ into the tubular lumen. This mostlyoccurs in the PCTs, DCTs & collecting ducts. To lesserextentin the ascending limbs of loop of Henle. It occursas following: 1) H+ is formed inside the renal tubular cells as a result of dissociation of H2CO3. (The later is formed by combination of CO2 and H2O under the influence of C.A enzyme). 2) Then, H+ is secreted by either: a) Secondary active transport: In exchange for Na+ reabsorption (i.e. by counter-transport utilizing an antiport carrier). It occurs in the PCTs, loop of Henle, DCTs & collecting ducts. b) Primary active transport: This occurs against high H+ concentration gradient by the intercalated cells. These cells are abundant in the late parts of the DCTs & the collecting ducts. It occurs only in the late DCTs & collecting tubules. 62  CHAPTER 4 Fig 4.9: Buffering of the hydrogen ion Functions of the collecting ducts (CTs) The collecting ducts receive hypotonicfluidfrom the DCTs Functionally, they are divided into 2 parts: 1) Cortical part. 2) Medullary part. They perform the following functions: I- Reabsorption: 1- Na+ reabsorption: This occurs by primary active transport all over the CDs. It increasesby aldosterone only in the cortical CDs. It is followed by passivediffusionof Cl- & water. It is coupled with K+ secretion. 63  CHAPTER 4 2- Urea reabsorption: This occurs by passive diffusion only in the inner parts of the medullary CDs (because these parts are partially permeable to urea) especially in the presenceofADH. Urea is not reabsorbed in both cortical CDs and outer parts of medullary CDs (because these parts are impermeableto urea). 3- Water reabsorption in the CDs: The CDs are relatively impermeableto water in absenceofADH. However, in the presence of ADH the CDs become highlypermeable to water (due to activation of water channels in that segment which are called aquaporins[AQP2 & AQP3]). Water reabsorption in the CDs and to some extent also in the DCTs is called facultative water reabsorption (because it depends on the blood level of ADH). Water reabsorption in the cortical CDs occursas following: The cortical CDs receive hypotonicfluid from the DCTs. At the normal rate of ADH secretion about 10% of the filtered water is passively reabsorbed into the iso-osmotic cortical interstitiumin excess of Na+ reabsorption. So, the tubular fluid becomes isotonicatthe end of the cortical CDs. Water reabsorption in the medullary CDs occursas following: This isotonic fluid enters the medullary CDs, Then, an additional 4.7% of H2O is reabsorbed by the hyperosmotic medullary interstitium. 64  CHAPTER 4 II- Secretion: 1- K+ secretion: This occurs only in the cortical CDs in exchange for Na+ reabsorption. It is increased by the aldosteronehormone. 2- H+ secretion: It is secreted all over the CDs: In the cortical CDs it occurs by both primary and secondaryactive transport. In the medullary CDs it occurs mainly by primary active transport. 3- Secretionof buffers: As in DCTs. N.B.1: Summary of water reabsorption through the different parts of the renal tubules: Normally, about 99.7% of the filtered water is reabsorbed in the renal tubules as follows: (1)65% in the PCTs. (2)15% in the descending limb loop of Henle. (3)5% in the DCTs. (4)10% in the cortical CDs. (5)4.7% in the medullary CDs. Only, 0.3% of the glomerular filtrations excreted producing about 1.5 liters urine daily with osmolarity about 400 mOsm/liter. 65  CHAPTER 4 Fig 4.10: Intracellular mechanismof action of ADH in the CDs Urine concentration and dilution (1) Mechanism of urine concentration: This occurs in: a) Hypovolemia (e.g. in dehydration & hemorrhage). b) Blood hypertonicity (e.g. due to excessive salt intake). This mechanism depends only on the facultativewater reabsorptionin the CDs which is determined by 2 main factors: 1- Blood level of ADH: When it increasesin (hypovolemia or hypertonicity) increasethe permeability for water reabsorption in the CDs and to the little extent the late part of DCTs. IncreaseADH secretion larger part of the medullary CDs become water-permeable so, more water is reabsorbed result in excretion of concentrated urine. 66  CHAPTER 4 2- The hyperosmolarity of medullary interstitium: It is increasedby countercurrent mechanism which causes passive diffusion of water from the CDs into the medulla. The net effect is excretion of small volume of concentratedurine (0.5 liter daily with an osmolarity about (1400 mOsm/liter). (2) Mechanism of urine dilution: This occurs in: a) Hypervolemia. b) Blood hypotonicity. The following occurs: 1- Inhibition of secretionADH. This decreases the water permeability of the CDs decrease the reabsorption of water. 2- Decreasethe osmolarity of medullary interstitium. The net effect is the excretion of large volume of diluted urine with an osmolality less than 80 mOsm/liter. e.g. in diabetesinsipidus complete absence of ADH so, the urine volume 23.3 liter/day with osmolarity is about 30 mOsm/liter. Diuresis Definitions Diuresismeans increasing the rate of urine output. Types (methods of diuresis: I- Water Diuresis: This is produced by drinking of a large amount of water which increase the urine volume after about 15 minutes. The maximal diuresisoccurs within 40–45 min. While, the ingested amount completely excreted after 2 hours. 67  CHAPTER 4 II- Osmotic diuresis: This is produced by administration of osmoticallyactive substances that are not readily absorbed in the PCTs. e.g. mannitol & sucrose. Difference between water and osmotic diuresis: Water diuresis Osmotic diuresis Facultative water Obligatory & facultative water 1-Water reabsorption reabsorption only reabsorption are 2- ADH secretion Normal 3- Na+ excretion Normal 4-Tonicity of urine Hypotonic Isotonic III- Pressure diuresis: The changes in the ABP within the autoregulation level have a little effect on GFR with parallel changes in urine volume. Marked increasein ABP increaseurine output. Drop in the mean ABP below 50mmHg stop urine formation. 68  CHAPTER 5 Chapter 5 Role of Kidney in Acid BaseBalance Acids and bases: A hydrogen ion is a single free proton released from a hydrogen atom. Acidsare molecules containing hydrogen atoms that can release hydrogen ions in solutions. An example is hydrochloric acid (HCl), which ionizes in water to form hydrogen ions (H+) and chloride ions (Cl-). Likewise, carbonic acid (H2CO3) ionizes in water to form H+ and bicarbonate ions (HCO3–). A baseis an ion or a molecule that can accept an H+ For example, HCO3– is a base because it can combine with H + to form H2CO3. pH The hydrogen Ion concentration [H+] can be expressed in a simpler form by using the pH expression. The pH is the negative logarithm (base 10) of H+ concentration. pH = -log[H+] So, if the (H+) is 10-7gram/ion/liter, the pH will be 7. The pH of acidic solutions ranges from 0 – 7, of neutral solution is 7 and of alkaline solutions ranges from 7 – 14. Precise H+ regulation is essential because the activities of almost all enzyme systems in the body are influenced by it. Therefore, changes in hydrogen concentration alter virtually all cell and body functions. About 50 to 100 millimoles of hydrogen ions are released from cells into extracellular fluid each day. However; the extracellular hydrogen ion concentration ([H+]) is maintained between about 35 and 45 nanomol/L (40 nmol/L = pH 7.40). There are three primary systems that regulate the H+concentration in the body fluids to prevent acidosis or alkalosis: 69  CHAPTER 5 (1) The chemical acid-base buffer systems of the body fluids, which immediately combine with acid or base to prevent excessive changes in H+concentration; (2) The respiratory center, which regulates the removal of CO2 (and, therefore, H2CO3) from the extracellular fluid; (3) The kidneys, which can excrete either acid or alkaline urine, thereby readjusting the extracellular fluid H+ concentration toward normal during acidosis or alkalosis. Fig 5.1: pH value in the body Buffers and buffering system Definition: A buffer is an aqueous solution that resists changes in pH upon adding limited amounts of strong Acids or alkalies.ie. if we add 1 ml of HCl to pure water, pH drops Significantly where as if we add the same amount of HCl to a buffer solution pH will drop slightly. Buffer solution consists of a mixture of a weak acid and its conjugate of strong base or a weak baseand its conjugate acid.. e.g buffer solution consists of acetic acid (weak acid) + sodium acetate (conjugate base). If strong alkali is added to solution it releases (OH-) which combines with acetic acid and so pH doesn’t rise. 70  CHAPTER 5 CH3COOH (aq) + OH-(aq) CH3COO-(aq) + H2O (aq) If a strong Acid is added it releases H+ which combines with CH3COO- to form Weak acid so pH doesn’t drop. CH3COO-(aq) + H+(aq) CH3COOH (aq) Fig 5.2: Body’s buffering of blood pH levels Physiologic buffer systems(in our body) Are important to keep the pH suitable for enzymatic reactions and for keeping the pH of blood within normal range (7.3 – 7.5) since any marked change in pH of blood is fatal. 1. Plasma proteins (amino acids in proteins are amphoteric ie contain basic NH3 group which can receive H+ and acidic COOH group which can lose H+ and become COO-). 2. Bicarbonate buffer system. (H2CO3/NaHCO3). 3. Phosphate buffer system (NaH2PO4/Na2HPO4). 4. Haemoglobin (when it releases Oxygen, H+ binds to NH3 in this protein) 71  CHAPTER 5 Fig5.3: Physiologic buffer systems Respiratory system: Quick way to respond, takes minutes to hours to correct pH Eliminate volatilerespiratory acids such as CO2 Doesn’t affect fixed acids like lactic acid Body pH can be adjusted by changing rate and depthof breathing. Urinary system: - Only the kidneys can rid the body of metabolic acids (phosphoric, uric, and lactic acids and ketones) and prevent metabolic acidosis. - The most important renal mechanisms for regulating acid-base balance are conserving bicarbonate ions and excreting bicarbonate ions. Losing a bicarbonate ion is the same as gaining a hydrogen ion; Conserving a bicarbonate ion is the same as losing a hydrogen ion Conserving of Bicarbonate: At normal, Plasma bicarbonate is freely filtered at the glomerulus. Renal tubular mechanisms are responsible for reabsorbing virtually all this HCO3. HCO3- is not able to cross the luminal membrane of the renal tubular cells. 72  CHAPTER 5 H+ is pumped from the tubular cell into the lumen, in exchange for Na +. The H+ combines with HCO3- to form H2CO3 in the lumen. This dissociates to give water and CO2 , which readily diffuses into the cell In the cell, CO2 recombines with water under the influence of carbonate dehydratase to give H2CO3. This dissociates to H+ and HCO3. The HCO3 then passes across the basal membrane of the cell into the interstitial fluid. This mechanism results in the reabsorption of filtered HCO3, but no net excretion of H+. Fig 5.4: (HCO3- reabsorption) The net excretion of H+ relies on the same renal tubular cell reactions as HCO3 reabsorption, but occurs after luminal HCO3 has been reabsorbed, and depends on the presence of other suitable buffers in the urine The main urinary buffer is phosphate, most of which is present as HPO42- , which can combine with H+ to form H2 PO4- 73  CHAPTER 5 Fig 5.5: (H+ secretion) The term renal tubular acidosis(RTA) is applied to a group of transport defects in the conservation of bicarbonate (HCO3−), the excretion of hydrogen ion (H+), or both. In its responses to alkalosis, the kidneys may excrete more bicarbonate by decreasing hydrogen ion secretion from the tubular epithelial cells. Metabolic acid base disorders I- Metabolic acidosis In metabolic acidosis the primary problem is a reduction in the bicarbonate concentration of the extracellular fluid. It can be caused by increased production of acids as in ketoacidosis, lactic acidosis or loss of HCO3- ( Loss from the GI tract as in severe diarrhea or loss in the urine in ureteroenterostomy, proximal renal tubular acidosis Compensatorymechanism:Thedrop in pH stimulates ventilation 74  CHAPTER 5 \Anion Gap Anion gap is equal to the difference between the plasma concentrations of the major cation (Na+) and the major measured anions (Cl-+HCO3-). Representing unmeasured anions including proteins, phosphate, sulphate and lactate ions. Anion Gap = (Na+) – (Cl- + HCO3-) It ranges between 4 to 12mmol/L Normally; blood is neutral with net charge equals zero, this gap is caused by the presence of serum phosphate and serum albumin that carry negative charges and not measured or considered in this equation. An increased anion gap usually is caused by an increase in unmeasured anions, and that most commonly occurs when there is an increase in unmeasured organic acids, that is, an acidosis. If anion gap > 30 mmol/L then metabolic acidosis invariably present. II- Metabolic alkalosis: The causes of a metabolic alkalosis are: a. Lossof hydrogenion in gastricfluid during vomiting. This is especially seen when there is pyloric stenosis preventing parallel loss of bicarbonate-rich secretions from the duodenum. b. Ingestion of an absorbable alkali such as sodium bicarbonate. Very large doses are required to cause a metabolic alkalosis unless there is renal impairment. Compensatory mechanism: Similar to a metabolic acidosis, the respiratory system is the first-line compensatory mechanism. Ventilation decreases to retain CO2. Respiratory acid–basedisorders I. Respiratory acidosis: This is caused by CO2 retention due to hypoventilation. It may accompany intrinsic lung disease, or defects in the control of ventilation, or diseases affecting the nerve supply or muscles of the chest wall or diaphragm, or disorders affecting the ribcage. 75  CHAPTER 5 In acute respiratory acidosis, the PCO2 in the blood will rise immediately and the [H+] will rise quickly Compensatory mechanisms:Unless the cause of the acute episode is resolved or treated quickly and successfully, renal compensation causes HCO3- retention and H+ excretion, thereby returning plasma H+ towards normal while HCO3- increases. But the kidneys take days to fully compensate. II. Respiratory alkalosis: Respiratory alkalosis is much less common than acidosis but can occur when respiration is stimulated (hyperventilation) as in (fever, encephalitis ,high altitude) giving rise to low PCO2 Compensation:Thekidneys compensate by eliminating HCO3 – and conserving H+, but the kidneys take days to fully compensate. N.B: The concentrations of H+ and HCO3– are very different, H+ being measured in nanomoles per litre while HCO3 – is measured in millimoles per litre. The same rise in each may therefore result in a substantial relative increase in the concentration of H+, but a relatively imperceptible increase in that of HCO3–. Fig 5.6: Acid Basedisturbances 76  CHAPTER 6 Chapter 6 Diuretics Fig 6.1: Classification of diuretics Fig 6.2: Site of action of diuretics 77  CHAPTER 6 Diuretics: drugs that increase urine volume I-Natriuretic: is an agent which increase sodium excretion and hence water excretion. II-Aquaretic: agent that increase solute free water excretion. I-Natriuretic Classification 1.High efficacy diuretics (Inhibitors of Na+- K+-2Cl~ cotransport( Loop diuretics: a. Sulphonamide derivatives (Furosemide, Bumetanide, Torasemide) b. Non-Sulfonamides: Ethacrynic acid, Indacrinone.. N.B: can act even the GFR < 10 ml/min 2.Medium efficacy diuretics (Inhibitors of Na+-Cl~ symport) a. Thiazides:Hydrochlorothiazide,Benzthiazide,Hydroflumethiazide b. Thiazide-like : Chlorthalidone, Metolazone, Indapamide. N.B: can act only if the GFR > 20 ml/min 3. low efficacy diuretics a. Carbonic anhydrase inhibitors (CAI) :Acetazolamide b. Potassium sparing diuretics: 1. Aldosterone antagonist: Spironolactone, Eplerenone 2. Inhibitors of renal epithelial Na+ channel: Triamterene, Amiloride. c. Osmotic diuretics: Mannitol N.B: can act only if the GFR >50 ml/min 1-Loop diuretics I. Pharmacokinetics: Rapidly