GENESIS Exclusive Renal systerr 9th Editio For Complete Preparation; Correlation with class is very much essential BANGLAMED| GENESIS Exclusive Renal System 9t Edition For Complete Preparation; Correlation with class is very much essential | Suitable For: > Residency > M. Phil / Diploma > FCPS P-1FA PM SS Renal System Suitable For: Residency, M. Phil / Diploma & FCPS P-1 @2012, Genesis 9% Edition: December 2020 Edited by: GENESIS (Post Graduation Medical Orientation Centre) Publisher:Banglamed Publication Address: 234/C (1+ Floor), Sonargoan Road, North Site Of Katabon Mor, Dhaka. Contact: 01404-432518. Available at Bayanno Medical Book Shop 234/C (1s Floor), Sonargoan Road, North Site Of Katabon More, Dhaka. Contact: 01404-432517, 01404-432537. 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ISBN: 978-984-95056-3-1 Price: 100.00/=Renal System Renal System Contents S/N Topics Page 1__| Suggestion 7 2 _ | Functions of The Kidneys z 3 _| Endocrine Hormones Acting on Kidneys 4 4 | Structures OF The Kidneys 3 5__| Regulation of Renal Blood Flow ui 6 | Renin B 7_| Angiotensin TL 3 8__| Glomerular Filtration 16 9 _| Tubular Reabsorption & Secretion 19) 10_| Formation Of Urine ee 11_| Medullary Interstitial Hyperosmolarity 27 12_| Acidification OF Urine 29 13_| Regulation Of Acid Base Balance By Kidney 31 14_| Diuresis 32 15_ | The Kidney/Renal Function Tests 35 16 | Renal Clearance / Plasma Clearance 41 17_| Micturation 44 18 | Aetiology ae 19 | Devidson’s Nephrology a 30_| Previous Residency MD, MS & Diploma, M. Phil Questions a Di | Previous FCPS P-1 Questions 69.Renal System tructure of nephron Fu + Juxtaglomerular apparatus (IGA) > Types of cell & their functions. *+ Glomerular membrane * Agents causing contraction or relaxation of messengial cells 2. Renal blood flow/ plasma flow + Peculiarities with its importance + Autoregulation 3. GFR: * Characteristics of glomerular filtrate * Difference between glomerular filtrate & urine * Factor affecting GFR 4. Tubular Reabsorption: *+ Hormone that rugulate tubular reabsorption + Substances that are completely reabsorbed ‘*Mechamism of tubular reabsorption of: HCOs HO Glucose Na’ 5. Tubular secretion: ‘+ Mechanisms of tubular secretion of: H x NE 6. Formation of Urine: + Mechanism of urine formation / Basic steps of urine formation + Formation of Dilute Urine ‘+ Formation of concentrate urine 7. Mechanism of acidification of Urine ~ What are the acidic substances present in urine ? - Limiting PH of urine - Renal buffer system 8. Regulation of acid-base balance by kidney 9. Dieresis: * Types * Difference between water dieresis & osmotic dieresis 10. Renal funetion tes 11. Hormone acting on kidney & Hormones secreted from kidney 12. Micturation reflex: + Nerve supply of urinary bladder +Abnormalities of micturation: ~ Atonic bladder - Hypertonic bladder - Overflow incontinence - Automatic bladder 13. Causes of: a) Polyuria ) Proteinuria ©) Haematuria Painless - Painful 4) Glycosuria ) Anuria UTI 14, Function of kidney: * Endocrine function '* Metabolic function 15, Renal clearance / Osmolar clearance / Free water clearance a Pre GENESISRenal System Fe FUNCTIONS OF THE KIDNEY | functions of kidne 4, Formation of urine: By this way it helps to maintain 1, Water balance 2, Electrolyte balance 3, Body fluid osmolarity 4, Acid-base balance B. Excretory function: a, Non-protein nitrogenous substances: * Urea (from the metabolism of amino + Uric acid (from the catabolism of purines) * Creatinine (from muscle creatine) b. Metabolites of hormones. c. End products of hemoglobin breakdown (eg, bilirubin) Excretes toxic substances & foreign bodies that are either produced in the body or ingested, eg, pesticides, drugs & pigments and food additives Eliminates excess of certain nutrients after over cone. (eg, sugar, amino acids) Minerals: Na*, K’, Ca*, Mg*, CL, HCO™, SO?- ete Water. . Endocrine functions: 1. Formation of Erythropoietin is response to hypoxia. 2. Itseeretes renin, which converts angiotensinogen to angiotensin-1. Angiotensinogen Renin _,Angiotensin-1 4 5. 3. Formation of active form of vitamin D: 1,25 dihydroxycholecalciferol [ 1,25 (OH)sDs] under the influence of parathyroid hormone. 4. It also produces Prostaglandin (PG): PGs, PGE: synthesized by messangial cells of glomeruli & interstitial cells of medulla, PG causes vasodilation & increases renal blood flow. 5. EDRF or NO. D. Metabolic function: |. Transamination & deamination of amino acids occur in kidney. 2. Ithelps to maintain blood glucose level during prolonged fasting by gluconeogenesis. E. Regulation of blood pressure: The kidneys play the dominant role in the long-term regulation of blood pressure by- 1. Renal body fluid mechanism 2. Renin-angiotensin-aldosterone mechanism F. Conservation of nutrients: When blood comes into the kidney through vessels, kidney first selects the nutrients and also waste products. Kidney than makes the nutrients to return into the blood and excrete the waste products. Thus, kidney conserves the nutrients such as glucose, amino acid. G. Other functions: : 1. Itmaintains blood glucose level during prolonged fasting condition by gluconeogenesis. 2. Ihit's the important site for degradation of several polypeptide hormones i.. insulin, glucagon & Parathyroid hormone. (Ref: ABC Biochemistry/7 /P-267;Guyton-13" 323,324)1. Aldosterone: It stimulates Na-K pump & proton pump * Increase NaCI and H:0 reabsorption in DCT and CD by increasing Na‘ channel * Increases K* excretion in CD = _ Increases proton excretion in CD by stimulating proton pump 2. ADH (antidi hormone) ci + Increases water reabsorption from DCT and CD by making them permeable to H20 * Vasoconstriction ( in high concentration) 3. ANP: Produced by atrium in volume overload. It act via CGMP & Decreases NaCI and water reabsorption from CD * Causes vasodilation & raises GFR by antagonizing sympathetic narvous system (SNS) * Readuces renin & aldosterone by antagonizing reninangiotensin-aldosterone system (RAAS) * Increases GFR by dilatation of afferent arteriole & Inhibits ADH release + Net effect is salt and water excretion by natriuresis& diuresis to protect against ECF volume expansion, 4. Angiotensin II: A powerful Nat retaining hormone, it is an octopeptide * Increases NaCl, water & HCO3 reabsorption mainly from PCT ‘+ Increases aldosterone secretion from adrenal cortex to increase NaCI and water reabsorption from DCT and * Causes constriction of efferent arteriole at physiological concentation to increase GFR, but at high concentration it causes constriction of both afferent & efferent arterioles to reduce RBF & GFR * Enhances ADH release and stimulates thirst center * Generalized vasoconstriction + Itis an octopeptide * Much of the conversion from ANG-I to ANG-II occurs as the blood passes thorough the although conver also may occur in many others parts if the body + Itis one of the most vasoconstrictor = It decrease the sensitivity of brain baro-reflex. 5. Dopamine = Increases RBF and decreases NaCI reabsorption from PCT. * Causes natriuresis and diuresis 6. Parathyroid hormone (PTH) ‘+ Increases calcium reabsorption from DCT * Decreases phosphate reabsorption from PCT 7. Prostaglandin e.g. PG Ex = _ Regulates renal hemodynamics and maintains RBF and GFR * Antagonizes SNS activity, ADH and angiotensin II = Net effect is renal vasodilatation, natriuresis and diuresis 8. Catecholamine * Renal vasoconstriction & decreases GFR = Stimulation of RAAS and increases renin secretion = NaCl reabsorption from PCT & ALH (Ref: ABC Biochemistry/7* /p. 286-287; Guyton-13"/Renal System structural and functional unit of kidney. Each human kidney comprises about 1 million nephrons. ‘wo types (85%): The glomeruli of these nephrons are loc: Joop of Henle. 2, Juxtamedullary nephrons (15%): ‘The glomeruli of these nephrons are ated in the outer cortex just under the capsule. They have short located deep to the cortex near the medulla, They have long loop of Henle. pifference between cortical and juxta medullary nephron: a Number Situation of glomerulus Juxta medullary nephron 15-20% of total Inner cortex near medulla Loop of Henle (LH) Tae, Extension of LH Deep into medulla ‘Vase recta Present Involvement with counter current mechanism | Not involved Involved r (Ref: ABC Biochemisiry/™/P-267) Parts: A nephron consists of two parts- 1. Renal corpuscle: * Glomerulus: It is a tuft of capillaries arising from the afferent arteriole and again converging to efferent arteriole. It remains enclosed within the Bowman’s capsule. a ‘© Bowman’s capsule: Itis the cup-shaped dilated and invaginated proximal end of renal tubule. 2 Renal tubule: ‘Proximal convoluted tubule (PCT) ‘© Descending limb of loop of Henle * Ascending limb of loop of Henle * Distal convoluted tubule (DCT) * Collecting tubule (CT) Functions of nephron: Formation of urine by- 1. Glomerular filtration 2. Tubular reabsorption of wanted substances 3. Tubular secretion 4. Excretion of unwanted substances. (Ref: Ganong -26" P-661) Notes:Renal System™ Cortical nephron Efferent arteriole Afferent arteriole. Juxtamedullary nephron CORTEX MEDULLA Inner zone Duct of Bellini Figure: Schematic of relations between blood vessels and tubular structures and differences between cortical sai juxtamedullary nephrons. (Ref: Guyton/13"/p-327, Fig. 265) Class Notes: GENESISRenal System A % Z. Red bicod calls Glomorular basal lamina Mesangial / cell +s Bowman's space Granuiar cols Pododyto ocecoos 2 Nerve fibre ian Basal Efferenty“z : arteriole SS Atos famina Smooth muscle Mesangial cell ‘Cyfoplasm of FIGURE 37-2 Structural details of glomerulus. A) Section through vascular pole, showing capillary loops, 'B) Relation of mesangial cells and podocytes to glomerular capillaries, C) Detail of the way podocytes form filtration slits on the basal lamina, and the relation of the lamina to the capillary endothelium. D) Enlargement of the rectangle in C to show the podocyte processes. The fuzzy material on their surfaces is glomerular polyanion. (Ref: Ganong -26" , P-663/Fig-37.2)Renal System JUXTAGLOMERULAR APPARATUS , jd cells are located i The renin is produced by the juxtaglomerular cells (IG cells). These epitheloid eel venules (a the afferent arterioles as they enter the glomeruli, The membrane-lined secreto®y EM. tm have i shown to contain renin. Renin is also found in agranularlacis cells that are located in the junction dete afferent and efferent arterioles, but its significance in this location is unknown. At the point where the afferent arteriole enters the glomerulus and the efferent nephron touches the arterioles ofthe glomerulus from which it arose. At this location, which Ee the stat of distal convolution, there is a modified region of tubular epithelium called the macula aad © macula deny in close proximity to the JG cells, The lacis cells, the JG cells, and the macta Tie cesatie p Juxtaglomerular apparatus. Refi Catt ees, 2 arteriole leaves i, the tubule Types of cells [Eecation 1. IG cells ‘Afferent arteriole (in tunica I media) 2. Macula densa (Specialized | Distal tubule 5 epithelial cell) 3. Lacis cells (extraglomerular | At the junetion between | Mesangial cells) afferent & efferent arteriole This apparatus occurs near the site of contract between the thick ascending limb and the afferent arteriole, contains three components: the macula densa, juxtaglomerular cells, and extraglomerular mesangial cells. 1) Macula densa: + The epithelial cells of the distal tubule that come in contact with the efferent arterioles and particulaty afferent arterioles are more dense than the other tubular cells and are collectively called the macula densa + The macula densa cells appear to secrete some substances toward the arterioles * They function as chemoreceptors and are stiulated by decreased Na+ load 2) Juxtaglomerular cells (JG): * The smooth muscle cells of both the afferent & efferent arterioles are swollen and contain dark granules where thy come in contact with macula densa. These cells are called juxtaglomerular cells( JG) and the granules are composed mainly of inactive rennin, + These epitheliold cells are located in the tunica medila of the afferent arterioles as they enter the glomerili ‘Juxta-glomerular cells secretes renin. 3) Lacis cells / Extraglomerular Mesangial cell: + They are also known as polkissen or pole cashions. + These cells are in contract with both JG cells and macula densa cells, Funetion: 1. When blood pressure is decreased, JG cells release Renin which initiates renin-angiotensin mecbanis® ® increases blood pressure. 2. The decrease in sodium chloride concentration initiates a signal from the macula densa that bes effects: (i) It decreases resistance to blood flow in the afferent arterioles, which raises gl hydrostatic pressure and helps return GFR toward normal, and (ii) it increases renin release from juxtaglomerular cells of the afferent and efferent arterioles, which are the major storage sites for rei-Renal System Agent causing Contraction or Relaxation of Mesangial cell ‘Contraction [Conte [ Relaxation Endothelins Plateletactivating factor ‘ANP Angiotensin IL Platelet-derived growth factor Dopamine Vasopressin ‘Thromboxane As Norepinephrine PGF: Histamine Leukotrienes Cyand Ds ; i inong/26"/P-668) Erythropoietin Structure & Function A circulating glycoprotein that contains 165 amino acid residues and four oligosaccharide chains that are necessary for its activity in vivo. Its blood level is markedly increased in anemia. When an individual bleeds or becomes hypoxic, hemoglobin synthesis is enhanced, and production and release of red blood cells from the bone marrow (erythropoiesis) are increased. Erythropoietin increases the number of erythropoietin-sensitive committed stem cells in the bone marrow that are converted to red blood cell precursors and subsequently to mature erythrocytes. Sources In adults, about 85% of the erythropoietin comes from the kidneys and 15% from the liver. Both these organs contain the mRNA for erythropoietin. Erythropoietin is produced by interstitial cells in the peritubular capillary bed of the kidneys and by perivenous hepatocytes in the liver. Fibroblast-like cells that lie in the interstitium of the renal cortex are responsible for productionof erythropoietin, which in turn is required for production of red blood cells. Regulation Of Secretion Erythropoietin synthesis is regulated by oxygen tension; anaemia and hypoxia increase production, whereas polycythaemia and hyperoxia inhibit it. Failure of erythropoietin production plays an important role in the pathogenesis of anaemia in CKD. (Ref: Ganong -26°/P-696, Davidson/23rd/P-385) Class Notes:Renal System GLOM “RULAR MEMBRAN| Definition: It is a semi permeable membrane through which filtration of plasma occurs from glomerular capillary to the Bowman’s capsule. Structure of glomerular membrane: It has 3 layers. Together these layers make up the filtration barrier, 1, The endothelium of the capillary: The capillary endothelium is perforated by thousands of small holes called fenestrae that are 70-90 nm in diameter. Although the fenestrations are relatively large, endothetia| cells are endowed with fixed negative charges that hinder the passage of plasma proteins. 2, Basement membrane: It consists of meshwork of collagen & proteoglycan that have large spaces that allow filtration of large amount of water & small molecules. The strong negative charges in the proteoglycan prevent the filtration of plasma proteins. 3. Bowman's capsule (a layer of epithelial cells (podocytes) surrounding the outer surface of capillary basement membrane): The cells of the epithelium of Bowman’s capsule are called Podocytes. The podocytes have numerous pseudopodia that interdigitate to form filtration slits along the capillary wal The slits are 25 nm wide and allow filtration. Negative charges of the epithelial cells restrict filtration of plasma proteins, Function: 1, The glomerular membrane permits the free passage of neutral substances up to 4 nm in diameter and almost totally excludes those with diameters greater than 8nm. However, the charges on the molecules as well as their diameters affect their passage into Bowman’s capsule. 2. All layers of the glomerular membrane provide a barrier to filtration of plasma proteins. (Ref: Guyton-13"/335, Ganong-26"/P-663) Class Notes:Renal System BLOOD FLOW Efferent Renal cortex arteriole glomeruli Interlobular vein Peritubular capillary bed Arcuate — prcuate FIGURE:Renal circulation. Interlobar arteries divide into arcuate arteries, which give off interlobular arteries in the cortex. The interlobular arteries provide an afferent arteriole to each glomerulus. The efferent arteriole from each glomerulus breaks up into capillaries that supply blood to the renal tubules. Venous blood enters interlobular ‘veins, which in turn flow via arcuate veins to the interlobar veins. (Modified with permission from Boron WF, Boulpaep EL: Medical Physiology. Saunders, 2009.) (Ref: Ganong/26"/p-664, Fig. 37.3)Renal System Renal blood flow It is the total volume of blood passing through both blood flow through both kidneys is about 1100 ml/’min or about min or just under 25% of the cardiac output dneys per minute. ERPF is about, Renal plasma flow: It is the total volume of plasma passing through both kidneys P* ps mL/min.(Ref: Guyton-13"7340, Ganong-25"/674,675) cc kidneys per mim 22% of the cardiac out} ut or 1.2-1.3L of Bl Z Mody Pecul es of RBF with their importance 1. _ It is a portal system containing two sets of * Glomerular capillary- It is designed for filtration of plasma. , ORES ier nis dexigued fr the secon reabeorpta ef desirable exbaims ay filtrate 2. Kidney has a high-Pressure capillary bed. Renal artery isa direct branch of abdominal aorta, which is a high pressure artery. Hydrostatic pressure in the glomerular capillary (60 mm of Hg). On the other hand, ing Classic microcirculation, hydrostatic pressure atthe arterial end of capillary is only 35 mmHg. 3. Rate of blood flow to kidney is very high (4ml/gm of kidney tissue/min): RBF is four times of the blood fy to liver and eight times of the blood flow to heart 4, Blood flow is selective, not uniform. 98-99% of ren: Maximum, about 100% glomerular capillary lies in cortex. So blood flow in cortex is very high: Auto regulation of RBF by kidney itself: It is the intrinsic capacity of kidney to maintain renal blood flow and GFR relatively constant so long 4 the mean systemic blood pressure remains within the range of 80-180 mmHg. + At blood pressure below 80 mmHg, autoregulation fails and GFR gradually decreases with ceca blood pressure to cause oliguria or anuria. + At blood pressure above 180 mmHg, autoregulation fails and GFR gradually increases with increasiq blood pressure to cause polyuria (Pressure dieresis) 5 6. Renal blood flow is not altered in denervated or innervated kidney. a 7. Presence of vasa recta: In the vasa recta, velocity of blood flow is very slow and direction of blood flowi® c pillaries. ‘al blood flow goes to cortex and 1-2% to medully antiparallel. Importance: This helps to create & preserve medullary hyperosmolarity. Both the kidneys receive about 1,300 ml of blood per minute, ie. about 26% of cardiac output. Kidneys at the second organs to receive maximum blood flow, the first organ being the liver which receives 1,500 ml pa” minute, ie. about 30% of cardiac output. Renal circulation has a portal system, ie, a double network of capillaries. The afferent arteriole enters ti Bowman's capsule forming glomerular capillary tuft. And, he glomerular capillaries unite to form the efferl arteriole, which leaves the Bowman's capsule, The efferent arteriole gives rise to the renal portal system. ie it forms a second capillary network called peritubular capillaries, which surrounds the tubular portions of ft nephrons. Both the capillary systems are functionally important. 10. The peritubular capillaries form a low pressure bed with a pressure of & to 10 mmHg. This low pressure hell tubular reabsorption. i, (Ref: ABC Biochemistry/*/P-246/ Guyton-13"4 , Class Notes: F 1Renal System EEE ee PSH Renin, an acid protease(aspartyl protease)secreted by the kidneys into the bloodst am. This enzyme acts in gag] Soneer_with angiotensin-converting enzyme (ACE) to form angiotensin Il It is @ glycoprotein, Human '5| preprorenincontains 406 amino acid residues. Active renin contains 340 amino acid residues. Some prorenin is converted to renin in the kidneys, and some is secreted. Prorenin is also s ovaries. Active renin has a half-li reted by other organs, including the in the circulation of 80 min or less. Its only known function is to cleave the decapeptideangiotensin I from the amino terminal end of angiotensinogen (ret substrate). (Ref: Ganong/26"/P-690) a [ ‘actors that affect rennin secretion = Stimulatory “7 Increased sympathetic activity via renal nerves Increased circulating catecholamines [Tahibitory Increased Na+ and Cl- reabsorption across macula densa é | Tneresod afc ail resus sa N Angiotensin II Preferentially Constricts Efferent Arterioles in Most Physiological Conditions. A powerfulrenal vasoconstrictor, angiotensin I, can be considered circulating hormone and a locally producedautacoid because it is formed in the kidneys and in thesystemic circulation. Receptors for angiotensin II arepresent in virtually all blood vessels of the kidneys. This protection is due to release of vasodilators,especially nitric oxide and prostaglandins, which counteractthe vasoconstrictor effects of angiotensin II in theseblood vessels. Sa ‘The efferent arterioles, however, are highly sensitive toangiotensin II. Because angiotensin II preferentially constricts efferent arterioles in most physiological conditions,increased angiotensin II levels raise glomerular hydrostatiepressure while reducing renal blood flow. It shouldbe kept in mind that increased angiotensin I formationusually occurs in circumstances associated with decreasedarterial pressure or volume depletion, which tend todecrease GFR. In these circumstances, the increased levelof angiotensin II, by constricting efferent arterioles, helpsprevent decreases in glomerular hydrostatic pressure andGFR; Thus, increased angiotensin II levels that occur with alow-sodium diet or volume depletion help maintain GFRand normal excretion of metabolic waste products suchas urea and creatinine that depend on glomerular filtrationfor their excretion; at the same time, the angiotensinII-induced constriction of efferent arterioles increasestubular reabsorption of sodium and water, which helpsrestore blood volume and blood pressure. ANGIOTENSINOGEN Circulating angiotensinogen is found in the a2-globulin fraction of the plasma. It contains about 13% carbohydrate | and is made up of 453 amino acid residues. It is synthesized in the liver with a 32-amino-acid signal sequence that is removed in the endoplasmic reticulum. Its circulating level is increased by glucocorticoids, thyroid hormones, ‘estrogens, several cytokines, and angiotensin II.Renal SystemRenal System AUTO REGULATION OF RENAL BLOOD FLOW & GFR Auto regulation works so long as the mean systemic blood pressure remains within the range of 80-180 mmHg. ‘* At blood pressure below 80 mmHg, auto regulation fails and GFR gradually decreases with decreases blood pressure to cause oliguria or anuria * At blood pressure above 180 mmHg, auto regulation fails and GFR gradually increases with increasing blood pressure to cause polyuria ( pressure dieresis) Role of tubuloglomerular feedback in auto regulation of renal blood flow & GFR: The tubuloglomerular feedback mechanism has two components that act together to control GFR. 1. Afferent arteriolar feedback mechanism: Y Arterial pressure >W Glomerular hYdrostatic pressure 2W GFR Proximal NaCI reabsorption >Macula densa NaCI> Afferent arteriolar dilatation > Glomerular hydrostatic pressure > GER toward normal Efferent arteriolar feedback mechanism: Y Arterial pressure WY Glomerular hydrostatic pressure >¥ Angiotensin II > Efferent arteriolar constriction >4. Glomerular hydrostatic pressure 34 GFR toward normal. Myogenic autoregulation of renal blood flow & GFR Mechanism: When arterial pressure rises, it stretches the wall of the arteriole. Stretching of the arteriole causes contraction of the vascular smooth muscle. This contraction prevents excessive stretch of the vessel and at the same time, by raising vascular resistance, helps prevent excessive increases in renal blood flow and GFR when arterial pressure Macula densa feedback mechanism for autoregulation of glomerular hydrostatic pressure and glomerular filtration rate(GFR) during decreased renal arterial pressure. (Ref: Guyton-13"/P-342)Renal System ey The filtration that occurs through the glomerular membrane is called glomerular filtration. iitration (mm Forces Favorit Glomerular hydrostatic pressure | Bowman’s capsule colloid osmotic pressure [F iitration (mm F Net filtration pressure: ‘ Definition: the net filtration pressure is the net pressure forcing the filtration of fluid into the Bowman’s capsule through the glomerular membrane. Amount: The normal effective filtration pressure is 10 mm Hg. Glomerular filtrate:It is the fluid that filtrates through glomerular membrane into Bowman's capsule. ‘Composition: Same as plasma with some exceptions 1. Itis isotonic to plasma Osmotie pressure is 280-300 mosm/L. Devoid of cellular element including RBC Specific gravity : 1.009-1,010 PH 7g Albumin conc is only 0.2% of its plasma cone Cone. of anions is 5% greater than in plasma Cone. of cation is 5% lesser than in plasma Ca and fatty acid cone. are less than in plasma,(Ref:Guyton-13"/P-335) GLOMERULAR FILTRATION RATE (GFR) Definition: The quantity of glomerular filtrate formed per minute by all the functioning nephrons of both kidneys is called glomerular filtration rate (GFR). The glomerular filtration rate (GFR) is the rate at which ‘fluid passes into nephrons after filtration and is a measure of renal function. It is proportionate to body size and the reference range is usually expressed after correction for body surface area as 120+25mL/min/1.73 m2. The GFR may be measured directly by injecting and measuring the clearance of compounds such as inulin or radiolabeled ethylenediaminetetraacetic acid, which are completely filtered at the glomerulus and are not secreted or reabsorbed by the renal tubules, yeas Normal value: = 125 ml/min or 180 L/day in an average-sized normal man, = In woman, GFR is 10% less than that in male after correction for surface area.(Ref: Guyton-13th, P-335) Factors affecting GFR 1, Glomerular capillary hydrostatic pressure (Po): It is normally 60 mm Hg, It increases GER. 2. Glomerular capillary colloidal osmotic pressure (Ro): It is 32 mm Hg. It decreases GFR. 3. Bowman’s capsule hydrostatic pressure (Pp): It is 18mm Hg. It decreases GFR. 4. Bowman's capsule colloidal osmotic pressure (Rx) : It increases GFR 5, Glomerular capillary filtration coefficient (Kd : Ke Permeability X Surface area of glomerular capillary. Size of the capillary bed: WSize of capillary bed >VKf> GER. = Permeability of glomerular capillary : @ Permeability >4Kf>4 GER 16 GENESISRenal System 6. Renal blood flow: 4 Renal blood flow > GFR 7, Arterial pressure: Increase or decrease in arterial pressure > Autoregulation of renal blood flow > GFR remains relatively constant. 8, Sympathetic nervous system (SNS) = Stimulation of SNS: Decreases GFR by renal vasoconstriction, + Inhibition of SNS: Increases GFR by renal vasodilation. 9, Constriction of afferent arteriole: It decreases glomerular hydrostatic pressure 2Y GFR, 10. Constriction of efferent arteriole: = Moderate constriction ->4 resistance to out flow of blood from glomerular capillary > glomerular hydrostatic pressure > GER slightly. = Severe constriction > accumulation of blood in the glomerulus for a long time > protein cone. in glomerular capillary >\ glomerular capillary colloidal osmotic pressure > GFR. 11.Ureteral obstruction. 12.Edema of kidney inside tight renal capsule 13.Changes in concentration of plasma proteins: dehydration, hypoproteinemia, etc (minor factors) (Ref: Guyton-139/P-335-338) 14. Hormones &autocoids that influence GFR Hormones or Autocoids | Effects on GFR Epinephrine v ‘Nor epinephrine v | Endothelin Vv ‘Angiotensin-IT © (Prevenis V) Endothelial —derived NO ay Prostaglandin * Bradykinin ae (Ref: Guyton-13"/Table-27.4/P-339) Differences between glomerular filtrate and urine: Glomerular filtrate Urine 1. Slightly alkaline (PH=7.4) 1. Slightly acidic (PH=4.5-8) 2. Itis isotonic to plasma (300 mosm/L) 2. It is hypertonic to plasma (1200-1400 mosm/L) 3. 180 liters/day 3. 15 liters/day 4, Rate of glomerular filtrate formation = 125 mi/mm | 4. Rate of urine formation = 1 ml/min 5. Its composition is same as plasma (except 5. Not same as plasma significant amount of protein) MEASUREMENT OF GFR Glomerular filtration rate (GFR) is the amount of plasma ultrafiltrate formed each minute and can be measured in intact experimental animals and humans by measuring the plasma level of a substance and the amount of that substance that is excreted. A substance to be used to measure GFR must be freely filtered through the glomeruli ‘and must be neither secreted nor reabsorbed by the tubules. In addition to the requirement that it be freely filtered and neither reabsorbed nor secreted in the tubules, a substance suitable for measuring the GFR should be nontoxic and not metabolized by the body. Inulin, a polymer of fructose with a molecular weight of 5200, meets these criteria in humans and most animals and can be used to measure GFR, (Ganong-26"/P-666, 667) ESS v7Renal System ESTIMATED GFR: eGFR c = Creatinine clearance as in index of GFR is commonly measured by using 24 brs ae eee +, but this is hig I susceptible to error because of the incomplete & inaccurate urine collection. An altemative and more conveient method to use formulae devised to calculate the ereatinine clearance & GFR by using serum creatinine level, age, sex and bo, ‘weight of the patient. An example is the Cockeroft- Gault formula: Characteristics of Inulin (Inulin is chosen for measuring GFR) 1, Freely filtered (i.e. not bound to protein in plasma or sieve ‘Substances used to measure GFR. z the Tnulin Creatinine process of ultra filtration) Mannitol 2, Not reabsorbed or secreted by renal tubules and passes through Radioiodine leveled hypac glomerular membrane as freely as crystalloid. EDTA 3. Non toxic. 4, Not stored in kidneys. 5. No effect on filtration rate. | 6. Preferably easy to measure in plasma and urine. 7. Not metabolized in the body. How to estimate glomerular filtration rate (GFR) Measuring GFR + Direct measurement using labelled EDTA or inulin + Creatinine clearance (CrCl) Minor tubular secretion of creatinine causes CrCl to exaggerate GFR when renal function is poor, and can be affected by drugs (e.g. trimethoprim, cimetidine) Needs 24-hr urine collection (inconvenient and often unreliable) | urine ceatineconceaton uno. vote.) ‘asa creatine concen umole iy (mL/min): Estimating GFR with equations + Cockcroft and Gault equation Reasonably accurate at normal to moderately impaired renal function Estimates CrCl, not GFR Requires patient weight GER is not valid in assessing acute kidney injury GFR is not valid in under-18s or during pregnancy (Ref: Davidson 22" /Table-17.1,17.2/P-467,468) Limitations of estimated glomerular filtration rate (eGFR) + Itis only an estimate, with wide confidence intervals (90% of patients will have eGFR within 30% of their measured] GER, and 98% within 50%). Z + Itis based on serum creatinine, and so may over-estimate actual GFR in patients with low muscle mass (e.g, those | Fl with cachexia, amputees) and under-estimate actual GFR in individuals taking creatine supplements (creatinine iv | $© ‘metabolite of creatine) or trimethoprim (inhibits secretion of creatinine), m + Creatinine level must be stable over days; eGFR is not valid in assessing acute kidney injury. H *Ittends to under-estimate normal or near-normal funetion, so slightly low values should not be over-interpreted. Ty + Inthe elderly, who constitute the majority of those with low eGFR, there is controversy about categorising people | 2" having chronic kidney disease (Box 15.3) on the basis of eGER alone, particularly at stage 3A, since ther is ile | © evidence of adverse outcomes when eGER is >45 mL/min/1.73 m? unless there is also proteranie, of + eGER is not valid in under-18s or during pregnancy proteinuria, e + Ethnicity is not taken into account in routine laboratory reporting: the im ‘multiplied by 1.21 for black people. 1; the laboratory GFR. value should therefore be + Few patients will understand ¢GFR in terms of mL/min/1.73 m?; it ma : i "2 E y therefore be hel aGFRof 100 mL/ min/1.73 mis approximately normal and to discuss eGFR values in terme sina fo sssume that» GFR 3 25 mL/min/1.73 m?= 25% of normal kidney function, of a percentage of normal, (Ref: Davidson’s 237 P-387, Box-157) 48, GENESIS _Renal System Ca Ma: Figure 2773 Transport activities of the major nephron segments. Representative cells from five major tubular segments are illustrated with the lumen side (apical membrane) facing left and interstitial side (basolateral membrane) facing right. A. Proximal tubular cells. B. Typical cell in the thick ascending limb of the loop of Henle. C. Distal convoluted tubular cell. D. Overview of entire nephron. E. Cortical collecting duct cells. F. ‘Typical cell in the inner medullary collecting duct. The major membrane transporters, channels, and pumps are drawn with arrows indicating the direction of solute or water movement. For some events, the stoichiometry of transport is indicated by numerals preceding the solute. Targets for major diuretic agents are labeled. The actions ‘of hormones are illustrated by arrows with plus signs for stimulatory effects and lines with perpendicular ends for inhibitory events, Dotted lines indicate free diffusion across cell membranes. The dashed line indicates water impermeability of cell membranes in the thick ascending limb and distal convoluted tubule. (Ref:Harrison’s /18"/ P-2282.) GENESIS 19Renal System Functions of PCT: 1. Reabsorption of water (60-70%) 2. Secretion of H+ (90% of the total H+ secreted by whole nephron) 3. Complete reabsorption of nutrients (e.g. glucose, amino acid, vitamins ete) 4, Ammoniagenesis from glutamine and its secretion as NH’ 5, Secretion of organic acid/ base or organic cation i, Na“=X symporter (here “X” represents glucose or amino acid or phosphate) ii, N° - H® antiporter iii, Cl'driven Na* reabsorption ( via paracellular route) iv. Na’ - K* pump Functions of LH: 1, Water reabsorption (10-20%) from descending loop of Henle (DLH) 2. NaCl reabsorption (20-30%) from ascending loop of Henle (ALH) Magnesium reabsorption (50-60%) from ALH Calcium reabsorption (20%) from ALH Potassium reabsorption (20-30%) from ALH Reabsorption of HCO3- that escapses proximal reabsorption. 7. Reabsorption of NH4+ ( generated and secreted by PCT cells in filtrate), its conversion to NH3 and deposition into medullary interstitial space & Acts as countercurrent multiplier to generate medullary interstitial hyperosmolarity which is needed to form hypertonic ( concentrated) urine. * Like PCT every substance reabsorbed actively from ALH is energized by Na’-K” pump present on basolateral membrane of cell. aaa Funetions of DCT: 1, The early distal tubule reabsorbs Nat, C1, Ca2+, ‘Mg2+ but is virtually impermeable to water and urea. 2. The late distal tubule is composed of two distinct cell types, the principal cells and the intercalated cells. + The principal cells reabsorbs Na* from the Jumen and secretes K+ into the lumen. This exchange is regulated by the aldosterone secretion of supra-renal cortex. + The intercalated cells reabsorbs K+ & HCO3- from the lumen and secrets 1-1+ into the lumen. 3 gerne CUI 2 i 4 all ou : ae ei eee, 23 1 [> eetoniocarsne : Proximal tubular cells. a 4 ng ' la cs a oY es ; t ti} —+ntt' ont eh ‘Transport systems operating in ALH B. Typical cell in the thick ascending limb of the loop of Henle. = | te Pk om Lune Distal convoluted tubular cell.a Renal System 4, 1tallows active absorption of the H20 of the filtrate. The increased permeability of tubular epithelium to water js regulated by the antidiuretic hormones (ADH) of the neuro-hypophysis. Distal tubule absorbs about 15% ‘water of the filtrate by a process which is known as facultative reabsorption. ‘4, The entry of hydrogen ions in the lumen of distal tubule helps acidification of urine, (Ref: Ganong-25th, P-684-685) 5, Water reabsorption (5%) by ADH 6, NaCl reabsorption (5%) by aldosterone 7, Calcium reabsorption (5-10%) by PTH and calcitriol (Re BC Biochemistry/7/P-281-286) Functions of CD: 1 Actas fine tuner for final qualitative changes in aKa" urinary excretion 2. Reabsorption of water by ADH and concentrated urine formation M4 3, Reabsorption of NaCl (1-8%) & secretion of yg" oe potassium by aldosterone 4, Secretion of H” by aldosterone and acidification Hee ase nl of urine LUMEN CELL BLOOD 5, Potassium reabsorption in hypokalemia & HCOs excretion in alkalosis a apes — (Ref: Ganong/26th/P-682-674) Mechanism of solute reabsorption! & —— secretion from CD: ‘* Collecting duct consists of principal cells and intercalated cells ‘* Principal cell concerns with sodium and water reabsorption with secretion of K*/H", whereas type a fo aoe ees ancora) ‘and bicarbonate generation with its addition to Hyde seatica isod blood. it is also concerned with K* reabsorption in ‘4 hypokalemic state invexchange of H” secretion ‘© Na’ reabsorption in principal cell is powered by asolateral Na'-K* pump which keeps the intracellular Na* concentration low to allow Na’ reabsorption from lumen via Na* channel down the concentration gradient. In contrast 10 the electroneutral NaCl reabsorption in PCT, ALH and DCT, here Na’ is reabsorbed alone, so it makes the Jjumen potential negative that promotes: — The secretion of K* or H’ from cello lumen Wegbeopllictecste > The reabsorption of Clrpracellularly ) Sin type A intercalated cell H’ and HCQs- are coy} -Ncor-——— gos ‘generated within the cell from H:COs. H” is eeakied fib medi bHO-ATPase (proton pump), ME SEL (woh ale PEeRe, Bicarbonate goes to blood by Na’-HCOs ‘* Type B intercalated cells have the polarity “Tamport systems operating in pe intercalated cel of CD opposite to type A intercalated cell because of “Which in alkalosis they can absorb H’ to blood with excretion of HCOs from the body. i (Ref: ABC Biochemistry//P-286+Ganong/26"/P-672-674) PP: Proton pump moon r0P, ‘ype A intercalated cell of CD q GENESIS aRenal System Renal tubular transport system | Exchangers (antiporters) | NaH | f H-K* ATPase H’-ATPase Ca"*-ATPase a | Cotransporters pale Na’-Glucose Na*-amino acid Na’-HPO+ | Na’-HCOy Na‘-2CI--K* Kl ” a) PROCESSES OF REABSORPTION OF SOLUTES e The hormones that regulate tubular reabsorption: : ‘Hormones Site of action y Effects i Aldosterone CT& CD ANAC, H20 reabsorption, K+ secretion, A H+ secretion ‘Angiotensin-II PCT, thick AL of loop of Henle/ DCT, CT. | 4.NaCl, H2O reabsorption 4 H+ secretion Antidiuretic hormone (ADH) | DCT/CT & CD ALO reabsorption Atrial natriuretic peptide DCT/ICT & CD WNaCl reabsorption __ Parathyroid hormone PCT, thick AL of loop of Henle, DCT V PO. reabsorption, 4 Ca reabsorption N (Ref: Guyton-13", Table 28-3,P-38) of ne A. From tubular lumen to the interstitial fluid: tu a. Active transport Er 1. Primary active transport It * Na’ K* pump © HY-pump + HK’ Pump © Ca®* pump 2. Secondary active transport Na’- Glucose cotransport , Passive transport “cl = Urea B, From interstitial fluid to the blood: 4 Ultra filtration (bulk flow) (Ref: Guyton- 134/238) 22 GENESIS= Db del 5) Renal System Must to know: “Completely Reabsorbed: Glucose, Proteins, Aminoacid, Acetoacetate, Vitamins Passively Reabsorbed: H30,Cr | p=Proximal Convoluted Tubule, L=Loop Of Henley, D= Distal Convoluted Tubule, C=Collecting Duct Glucose, Uric Acid HCOs [se PLDC= | Na’, rest of all. Mechanism of reabsorption Na:(site: PLDC) From tubular (0 tubular epithelial ce Na’ is transported from tubular lumen into tubular epithelial cell by passive diffusion or by secondary active co- transport (eg, Na‘- glucose co-transport) or by secondary active counter transport (eg, Na’-H" counter transport) along its cone, and electrical gradient produced by Na'+K* ATPase pump. Na+ reabsorption from theck segment of loop of Henle oceurs by Na*- 2CI4-K’ co-transporter. Site of reabsorption | Mechanism Proximal tubule ‘Active transport ALLA (thick) Co-transport (Na*-K"-2Cl) ‘ALLH (thin) Passive transport Distal tubule and ‘Aldosterone induced Collecting ducts Counter transport rom tubular epithelial cell into intersitium: ‘Na+ is transported from tubular epithelial cell into interstitium by Na‘-KT ATPase. Three Na+ are transported out of the cell in exchange of two K+. Intracellular Na+ cone. becomes low and electrical potential becomes very negative (-70 mV) which provides energy for the secondary active transport of Na+ from tubular lumen into tubular epithelial cell. From interstitium into blood; Tt occurs by ultra filtration, a passive process. (Ref: Ganong-26"/P-669 to 670, Guyton-13"/P-350) GENESIS AnRenal System FIGURE 37-7 Mechanism of Na+ reabsorption in the proximal tubule, Lateral intorcoltular space Interstitial 4 Na+ moves out of the tubular lamen by cotransport and exchange mechanism through the apical membrane of the tubule (dashed line). The Na* is then actively transported into the interstitial fluid by Na, K ATPase in the basolateral membrane (solid lines). K+ centers the interstitial fluid via K+ channels. A small amount of Na+, other solutes, and H2O reenter the tubular lumen by passive ‘transport through the tight junctions (dotted lines). (Ref: Ganong-26°/P-670Fig-37.9) Hydrogen ions Urea, uric acid Ammonia Creatinine Potassium Urobilinogen | Hormones Histamine | 1,25 dihydroxycholecalciferol Acetylcholine, epinephrine and nerepinephrine Erythropoietin Steroid glucoronides Prostaglandin Foreign substances | Enzymes Paraaminohippuric acid (PAH) ay Penicillin (actively secreted in the PCT) a-hydroxylase Diodine | S 24 GENESISRenal System Machanism of urine forma: Prine formation takes place by the following three | Erereat | mechanisms eh oe 7 alsarlat Histon, > Late, B._ Reabsorption of substances from the renal tubules into | eptares — seoie| the blood, and C. Secretion of substances from the blood into the renal aaa | tubules apa | ‘A. Formation of glomerular filtrate: | ‘Due to the effective filtration pressure (about 10 mmilig), glomerular filtrate is formed through the ronal ay glomerular membrane. Normally glomerular f capillaries filtration rate is 125 ml/min or 180 liter/day. B. Tubular reabsorption: 1. In the proximal tubule: = 60 to 70% of the glomerular filtrate is reabsorbed. i. en = Glucose, amino acids, vitamins are ei taeh See ecraersbcn's Becraton reabsorbed completely. Sib saa + The filtrate remains isotonic to plasma. 2. In the descending limb of loop of Henle: = Reabsorption of water and Na* takes place ‘= _ Filtrate remains isotonic to plasma = 20% of glomerular filtrate rem: 3. In the ascending limb of loop of Henle: = Only Na* reabsorption takes place = The filtrate becomes hypotonic to plasma 4. In the distal tubule: = 5% water reabsorption occurs under the influence of ADH. = Na’& CI are also reabsorbed = The filtrate becomes isotonic. 5. In the collecting tubule: + Reabsorption of Na+ and water (due to ADH) takes place. «The filtrate becomes hypertonic. C. Tubular secretion : 1. In PCT; H+K+ & NHB. Bile salt, oxalate, urate, catecholamine, PAH are secreted. 2. In AL of loop of Henle: Urea & H’ are secreted by passive diffusion. 3, In DCT: NH is secreted by diffusion, K* and H” are secreted by exchange pump. 4, In CT: Aldosterone causes secretion of K’ and NH; y exchange pump. ‘After these reabsorption and secretion, a fluid remains in the collecting duct and is passed as urine. Renal | = (Ref: Guyton-13"/330) Difference between filtrate and urine : Feature Filtrate Urine Volume. 125 mbmin or 180 Liday 1 ml/min or 1.5 Lida pH TA 45 06.0 ‘Osmolarity 300 mosm/L (isotonic) {600 - 900 mosm/L (hypertonic) Glucose, amino acid, Present Absent HCO, Vitamin, ketone body (Ref: ABC Biochemistry/™/p-271)] —e | Renal Systm MECHANISM OF CONCENTRATED AND DILUTE URINE FORMATION + Filtrate formed at the level of Bowman’s capsule is isotonic to plasma with osmolarity (OP) 300 osm/L. Figg, E PCT. 60-70 % water is reabsorbed isoosmotically maintaining the isotonic status of filtrate at the entry of _j From DLH, 10-20 % water is reabsorbed without solutes raising the osmolarity of filtrate to the point o R ‘maximum (1200-1400 mosnv/L) at the tip of LH» From ALH solutes are reabsorbed without water. This cause, Th lowering of the osmolarity of filtrate to 100-150 mosm/L at the entry of PCT. pe + Water reabsorption from PCT and DLH continues irrespective of plasma ADH status and about 20% hypotonie fe filtrate goes to the distal nephron (DCT, CD). Thence onward further water reabsorption and the final volume 2 and osmolarity of urine depends on: i > Plasma ADH concentration it > Responsiveness of distal nephrons to ADH ci > Creation and maintenance of medullary interstitial hyperosmolarity ‘+ In normal condition, to make concentrated urine; the CD functions as concentrating segment because here iy presence of ADH and medullary interstitial hyperosmolarity relatively more water in comparison to solutes is, reabsorbed. As a consequence, the hypotonic filtrate presented to distal nephron gradually shows increasing osmolarity with isotonicity at corticomedullary junction of CD and finally hypertonic (concentrated) urine is produced at the exit of CD with osmolarity 600-900 mosm/L. So, to make concentrated urine there must be > Adequate solute (NaCI) delivery to the loop of Henle. 4 > Normal function of the loop of Henle. > Presence of ADH & collecting duct responsiveness to ADH * To make dilute urine, ALH functions as diluting segment of nephron because the hypertonic filtrate that get entry at the ALH with osmolarity 1200-1400 mosm/L becomes gradually hypotonic due to the unilateral solu ¢ (NaCl) reabsorption without water as the filtrate moves along the ALH and finally'at the entry of DCT the @ osmolarity of filtrate decreases to 100-150 mosm/L. In absence of ADH or in absence of medullary interstitial hyperosmolarity; from this hypotonic filtrate very small amount of water is reabsorbed in DCT and CD, but solute reabsorption continues. This makes the filtrate further hypotonic and finally hypotonic (dilute) urine is produced at the exit of CD with osmolarity decreased to 30-50 mosm/L. So to make dilute urine there must be > Adequate solute (NaCl) delivery to the loop of Henle & distal tubule, > Normal function of the loop of Henle & distal tubule. ) > Absence of ADH activity (Ref: ABC Biochemsitry 7"/p-296-29) Obligatory urine volume: Excretable solute load 600 mOsm/day Obligatory urine volume = Concentration of urine 1200 mOsm.Renal System TITIAL HYP! ‘rom LH. of _ Requirements For Excreting A Concentrated Urine—High ADH Levels And Hyperosmotic Renal Medulla seg The basic requirements for forming a concentrated urine are (1) a high level of ADH, which increases the permeability of the distal tubules and collecting ducts to water, thereby allowing these tubular segments to avidly onig _reabsorb water, and (2) a high osmolarity of the renal medullary interstitial fluid, which provides the osmotic amg, _ gradient necessary for water reabsorption to occur inthe presence of high levels of ADH, Medullary interstitial Hyperosmolarity 1.At the corticomedullary junction of kidney, interstitial fluid has osmolarity same as that of plasma which is 300mosmw/L 2 Medullary interstitial fluid osmolarity increases progressively with increasing depth into medulla and attains the value of about 1200mosnvL at the papilla ( deepest medulla). This makes the vertical corticomedullary interstitial osmotic re in gradient from 300 mosm/L to 1200 mosm/L- S is 3 This medullary interstitial hyperosmolarity is created by deposition of NaCI and urea into the interstitial space Sing 4NaCI is deposited by countercurrent multiplication function of LH and urea is deposited by urea trapping ( urea ne is recycling) mechanism, LH as counter current multiplier Solutes (NaCI are actively reabsorbed from the ascending limb of L and then deeper medulla due to the counter ‘current flow of filtrate along the descending and ascending limbs of loop of Henle. "Urea trapping (recycling) mechanism ‘A) 40-60 % of filtered urea is passively reabsorbed from PCT since PCT is freely permeable to urea. Descending LH shows limited degree of urea permeability, but ascending LH, DCT and CD are virtually impermeable to urea, B) Consequently urea gets increasingly concentrated in the tubule as water is reabsorbed from LH, DCT and CD. Medullary CD becomes permeable to urea in presence to ADH, So when filtrate with high urea concentration reaches the medullary CD, urea diffuses out into the medullary interstitium to make thesrea again diffuses into the tubular uid through descending LH sing in is more than that in descending LH. This diffused urea again a ‘ium from medullary CD and the process is repeated again and again " fof urea (exit from CD and entry into descending LH) hetps iy PP0% stitial space ty Na ©) From medullary interstitium the u concentration of urea in interstit of the tubular fluid into the interstt D) The consequence of this recycling trapping and accumulation of urea into the medullary inte ‘ ity created by countercurrent multiplication of LH and urea recycing s e not removed) by two mechanisms: process is preserved (NaCI and Urea 1) Slugaish blood flow to medulla ba a, the rate of blood flow to m too slow to wash out deposited sohys = ters ince only 5% of RBF goes to medull i e from medullary interstitium, I 2). The countercurrent exchange function of vasa recta (VR) c Blood enters into the medulla via descending limb of VR and by U-turn blood exit medulla via ascengy limb of VR. As blood passes down descending limb, it loses water and gain solutes (NaCl, urea), but wg blood exits medulla through ascending limb, it loses solutes and gain water. As a result water is remo, from medullary interstitium with persistence of solutes which make the interstitium hyperosmolar. (Ref: ABC Biochemistry/7" /P-291 - 293; Guyton-13"/P-37. Class Notes: Tech roxin techa This HC asc Ati con abo For * Coa ee ee Renal System ses involved in the secretion of H+ into the renal tubules Proteere Serle Intersil Renal tubule cell e counter transport: About 85% of H” is secreted in the PCT, fuid | 10% in the ascending limb of loop of Henle, both by Na‘-H’ counter transport. 2, H'-ATPase pump: 5% in the DCT &CT by H’-ATPase pump. Mechanism of H+ secretion: secretion occurs in proximal and distal tubules. In the Proximal tubule: * CO» binds with H20 to form H2CO) catalyzed by carbonic g anhydrase. n * —HyCOs dissociates into HCO’; and H* d * Hi’ is secreted into tubular lumen by Na*-H* counter transport the | energy of which is derived from Na’ -K” pump. ) In the distal tubule: | = In the intercalated cells, CO;& H.0 binds to form H:CO: which dissociates into H"& HCO; ‘+ His secreted into tubular lumen by a primary active transport called H’-ATPase. Tubular bomen (Ref ABC Biochemistry/7"/P-302) ‘Mechanism of ammonia secretion NH,! => NH + HY The principal reaction producing NH4* in cells is conversion of glutamine to glutamate. This reaction is catalyzed by the pH = pk’ + log NHS) enzyme glutaminase, which is abundant in renal tubular (nie cells. Glutamic dehydrogenase catalyzes the conversion of, cars| glutamate to a-ketoglutarate, with the production of more Glutamine Glutamate + NH” NH4+. Subsequent metabolism of a-ketoglutarate utilizes amare 2H4, freeing 2HCO3 dehydrogenase Glutamate -Ketoglutarate + NH.” (Ref: ABC Biochemistry/7/P-302-303; Ganong/26"/P-702 Mechanism of acidification of urine: Proximal acidification (HCOs’) reabsorption mechanism: ‘+ Its concemed with the complete reabsorption of filtered HCOy mainly from PCT (80-90%) and partly from ascending limb of Henle (ALH) (10-20%) ‘+ Atnormal GFR (180L/day) and normal plasma HCO; concentration (25 mmol/L), the tubular load of HCOs is | about 4500 mmol/day (180X25). | * For reabsorption of very HCO; from filtrate, one H* is to be secreted from tubular cell into lumen. Therefore, PCT 4 and ALH together secrete about 4500 mmol H™ daily to reabsorb filtered HCOs" completely. * Compete reabsorption of HCOs causes reduction of the P" of filtrate from 7.4 to 6.8. (Ref: ABC Biochemistry/7*/P-306-310) GENESIS 29