Renal Physiology Notes 2017 PDF

Physiology Notes 2017 Dr. Ahmad.S. Alarabi Renal Physiology 1  Physiology Notes 2017 Dr. Ahmad.S. Alarabi The renal system is composed of: [2 kidneys / 2 Renal pelvis...

Physiology Notes 2017 Dr. Ahmad.S. Alarabi Renal Physiology 1  Physiology Notes 2017 Dr. Ahmad.S. Alarabi The renal system is composed of: [2 kidneys / 2 Renal pelvises / 2 Ureters / Urinary Bladder / Urethra] The kidney is the main functioning organ in the urinary system. It is composed of:  Outer cortex.  Inner Medulla: made up of a number of medullary pyramids (cone shaped masses). The Nephron It is the functional unit of the kidney. Each human kidney contains about 1 million nephrons. The nephron is composed of: A- Renal Corpuscle (Glomerulus): It is formed of: 1- Glomerular capillaries. 2- Bowman’s capsule: It's the expanded proximal end of renal tubules forming a double walled cup [inner wall (covering glomerular capillaries) and outer wall] 2  Physiology Notes 2017 Dr. Ahmad.S. Alarabi B- Renal Tubules: They are formed of: 1- Proximal Convoluted Tubule (PCT): It is lined by single layer of cuboidal cells (about 15 mm long) resting on a basement membrane. These cells show brush luminal border due to presence of microvilli that increase the surface area of laminal exposure 20 folds (times). Near the basal border of these cells there are numerous mitochondria that provide the energy for active transport. Between the lateral borders of the cells there are spaces called lateral intercellular spaces 2- Loop of Henle: It is composed of descending & ascending limbs. The ascending limb composes of: a- Thin segment: it is the lower part of the ascending limb. It is made up of flattened cells [like the descending limb], and varies from 2 – 14 mm in length. b- Thick segment: it is the upper part of the ascending limb of loop of Henle. It is made up of cuboidal cells [like other parts of the nephron]. 3- Distal Convoluted Tubules (DCT): It is about 5 mm length. Its epithelium is lower than that of proximal tubules, and has fewer microvilli. Functionally, it is divided into: a- First half: it is similar in structure & function to the thick part of ascending limb of loop of Henle, and it is called the diluting segment of DCT. b- Second (late) half. 4- Collecting Ducts (CD): Each group of DCTs coalesce together to form collecting duct that are about 20 mm long, and pass through the renal cortex and medulla to empty the formed urine at the apices of medullary pyramids into the renal pelvis. Functionally, the CD are divided into (Cortical & Medullary) collecting ducts. The nephrons are of 2 types [Cortical & Juxtamedullary] 3 Physiology Notes 2017 Dr. Ahmad.S. Alarabi Cortical Juxtamedullary % of whole nephrons 85% 15% Site of glomerulus In the outer cortex In the deep cortex (juxtamedullary region) Short [penetrates Long (long thin segment) that penetrate deeply Loop of Henle only short distance in the medulla, and many of them reach the in the medulla]. tips of medullary pyramids]. Vasa Recta Absent Present Juxtaglomerular Present Absent Apparatus Renal circulation (Blood supply) In the renal circulation, there are 2 capillary beds: 1- Glomerular capillaries: They are high pressure capillaries [60 mmHg], because blood comes to it through wide arteriole (afferent) and leaves it through narrow arteriole (efferent). It shows continuous filtration of fluid into Bowman's capsule [i.e. function as arterial end of usual tissue capillaries]. 4  Physiology Notes 2017 Dr. Ahmad.S. Alarabi 2- Peritubular capillaries: They are low pressure capillaries [13 mmHg], because it receives blood from narrow efferent arteriole. It shows continuous reabsorption of fluid from tubular lumen [i.e. function as venous end of the usual tissue capillaries.. Note: The blood supply to medulla is derived from the Vasa Recta (a straight capillary loop arise from eff. arterioles of JM nephrons), which are supplied by vasoconstrictor sympathetic fibers decreasing blood flow to medulla. So, blood flow to medulla is slow with little amount [only 1-2 % of total renal blood flow] compared with that of cortex. Renal Blood Flow The Renal Blood Flow = 1200 ml blood/minute [650 ml plasma/min]. The renal fraction is the fraction of cardiac output that passes through kidneys which is: = = 20 – 25 %. ♦ Nerve supply:- The kidneys are richly innervated by sympathetic nerves which originate from 4th Thoracic to 3rd Lumbar spinal segments supplying 1aff. & eff. arterioles (more to aff.), 2PCT, 3JG cells, 4Thick asc. Limb of L.H and 5CD. Its stimulation leads to:  Vasoconstriction of renal blood vessels (the main action).  Stimulation of Rennin secretion.  Stimulation of Na+ and H2O reabsorption from all segments of renal tubules. 5 Physiology Notes 2017 Dr. Ahmad.S. Alarabi Juxtaglomerular Apparatus The juxtaglomerular apparatus is a structure lies at area of contact between DCT and the [afferent & efferent] arterioles of the same nephron of cortical type only. [See the figure below]. The JG apparatus is composed of: 1- Macula densa cells: [ Na Cl Load Sensors ] They are cells lining DCT at this area which are denser than other tubular cells. Their function is responding to (detecting) changes in NaCl concentration (Load) in tubular fluid. 2- Juxtaglomerular (JG) cells: [ Modified Secretory Cells ] They are swollen modified smooth muscles in the media layer of afferent arterioles. Their function is formation, storage and secretion of renin into the blood to regulate Arterial Blood Pressure & Na+ balance. 6 Physiology Notes 2017 Dr. Ahmad.S. Alarabi General function of the kidney 1- Homeostatic function: Kidney plays a major role in the maintenance of homeostasis through formation of urine [the most important function]. It regulates 1volume (ECF), composition of ions (Electrolytes) and H+ concentration (PH) of plasma. 2- Secretory [endocrine] function: The kidney produces (secretes): a- Renin: It is secreted from the JG cells. Renin has an important role in regulating arterial blood pressure. Its secretion increases in response to: i- ↓ NaCl concentration in tubular fluid → stimulates macula densa cells → stimulating JG cells to secrete Renin. ii- ↓ Blood pressure in afferent arterioles → stimulation of JG cells to secrete renin [the JG cells acts as intra-renal baroreceptors]. iii- Sympathetic stimulation → direct stimulation of JG cells. b- Erythropoietin: a hormone stimulating erythropoiesis. c- Active form of vitamin D: It ↑ Ca++ absorption from GIT, and enhances its deposition in bone. 7  Physiology Notes 2017 Dr. Ahmad.S. Alarabi ♦ Mechanism of urine formation: The urine is formed by 3 main processes: 1- Glomerular filtration: It is the filtration of fluid (plasma) from glomerular capillary into Bowman's capsule through glomerular membrane. It's a non selective process [i.e. involves both useful and unneeded waste products]. Usually 1/5 of the plasma flowing in glomeruli is filtered [i.e. 125 ml out of 650 ml of plasma entering both kidneys per minute]. Note: Glomerular filtrate = Plasma – Plasma Proteins. 2- Tubular reabsorption: It's the transport of substances from tubular lumen to blood (peritubular capillary). 99% of glomerular filtrate (which include wanted substances "especially almost all of the water" and many of the electrolytes) are reabsorbed and returns back into systemic circulation. Only 1% of glomerular filtrate is excreted in the form of urine. 3- Tubular excretion: It's the transport of substances from blood (peritubular capillaries) into tubular lumen. 8  Physiology Notes 2017 Dr. Ahmad.S. Alarabi Glomerular filtration Definition: it is the filtration of fluid from the blood in glomerular capillaries to the cavity of Bowman’s capsule due to pressure gradient difference. Glomerular Filtration Rate It is the "volume of fluid filtered in all nephrons of both kidneys each minute". In average sized normal man, GFR = 125 ml/min [180 liters/day]. This value is 10% lower in females. Its magnitude correlates fairly well with surface area of the body. ♦ Glomerular Membrane: It is the membrane through which the filtration occurs. It's formed of 3 layers: 1- Capillary endothelial cells.. lining glomerular capillaries. They are perforated by thousands of Slit Pores small holes called fenestrae. Foot 2- Basement membrane: Processes of Podocyte It's composed mainly of a meshwork Fenestra of fine collagen & protogylacn fibrils that have large spaces through which fluid can filter. 3- Epithelial cells (Podocytes) negatively charged that line the outer surface consist mainly of finger-like projections (Pseudopodia) that cover the basement membrane. These fingers form slits called Slit pores through which fluid can filter. The glomerular membrane (especially fenestrae) is characterized by its high permeability (100 – 500 times that of usual tissue capillary like that of sk. muscles). It also has a high degree of selectivity for passing of molecules as follows: 9  Physiology Notes 2017 Dr. Ahmad.S. Alarabi 1- Molecules with MW 10,000 or less pass freely through membrane (as easily as water). 2- Molecules with MW > 10,000, their permeability are inversely proportional to their MW. 3- Molecules with MW < 80,000 cannot pass through membrane. Example MW Filtration ratio Permeability Urea 60 1.0 100% Glucose 180 1.0 100% Inulin 5,000 1.0 100% Myoglobin 17,000 0.75 75% Small proteins 30,000 0.5 50% Hemoglobin 65,000 0.05 5% Albumin 69,000 0.005 0.5% Globulins 80,000 0.000 0% Note: The strong –ve charge of proteins lining the pores repels negatively charged substances. The –ve charge of albumin explain its poor permeability through glomerular membrane in relation to its MW. Glomerular filtrate is composed of Plasma minus Plasma Proteins [despite it contains trace (minute) amount of albumin (0.03 gm %), i.e. 0.5% that of plasma]. Filtration Fraction It is the fraction of renal plasma flow that becomes glomerular filtrate. Filtration fraction = = = OR 20%. Filtration Forces Forces helping (driving) filtration: 1- Glomerular capillary pressure (GCP) [= 60 mmHg]. 2- Osmotic pressure of proteins in Bowman’s capsule [normally = zero]. 10  Physiology Notes 2017 Dr. Ahmad.S. Alarabi Forces opposing filtration: 1- Osmotic pressure of plasma proteins in glomerular capillary (COP) [= 32 mmHg]. 2- Pressure in Bowman’s capsule (CP) [18 mmHg]. The Net Filtration Pressure (NFP) = (60 + 0) – (32 + 18) = 60 – 50 = 10 mmHg. Filtration Coefficient (Kf ) It is the fluid filtered by all nephrons in both kidneys per minute if the filtration pressure is only 1 mmHg. Normally, Kf = 12.5 ml/min/mmHg. GFR = Kf X filtration pressure = 12.5 X 10 = 125 ml/min. Factors affecting GFR 1- Glomerular Capillary Pressure: The ↑ in glomerular capillary pressure → ↑ GFR and vice versa. This pressure could be affected by the following: a- Renal Blood Flow: ↑RBF → ↑glom. blood flow → ↑glom. cap. Pr. → ↑GFR and vice versa. b- Diameter of Afferent arteriole: Dilatation → ↑ glom. blood flow → ↑ glom. cap. Pr. → ↑ GFR. Constriction has a reverse effect. c- Diameter of Efferent arteriole: Dilatation → ↓ gl. cap. Pr → ↓ GFR. Mild constriction → ↑ glom. cap. Pr. → slight ↑ in GFR. Moderate & sever constriction → ↓ GFR due to marked ↓ in glom. blood flow. d- Sympathetic stimulation: → constriction of afferent arteriole → ↓glo.cap.pr → ↓ GFR. e- Arterial Blood Pressure (ABP) : Change in ABP within physiological range (80 – 180 mmHg) has a little effect on renal blood flow or GFR due to autoregulation mechanism [mechanism by which RBF & GFR are maintained at a nearly constant rate inspite of changes in ABP within physiological range]. 11  Physiology Notes 2017 Dr. Ahmad.S. Alarabi Autoregulation allows glomeruli to filtrate plasma at an appropriate rate for tubular function. The too little GFR → slow tubular flow → reabsorption of unwanted substances, while too high GFR → rapid tubular flow → loss of wanted substances. Autoregulation involves 2 mechanisms: 1- Tubulo-glomerular feedback mechanism: ↓GFR → overabsorption of NaCl in ascending limb of loopof henle → ↓ NaCl load at Macula Densa leading to: a- Dilatation of afferent by signals from Mac. Dens. b- Constriction of efferent by Renin secretion from JG cells. Both effects → ↑ GFR. 2- Myogenic mechanism: e.g. stretching of smooth muscles of afferent arteriole wall → reflex constriction → 2- Osmotic Pressure of Proteins in Bowman’s Capsule: When ↑ → ↑ GFR and vice versa. 3- Osmotic Pressure of Plasma Proteins: ↓ Plasma Osmotic Pressure (as in Hypoproteinemia) → ↑ GFR and vice versa. 4- Hydrostatic pressure in Bowman's Capsule: ↑ Intra-capsular Pressure as seen in obstructed ureter (e.g. due to stone) → ↓ GFR. 5- Filtration Coefficient: It depends on: - glomerular membrane surface area. - glomerular membrane permeability. The ↓ Kf (due to ↓ permeability or surface area) → ↓ GFR, and vice versa. Measurement of GFR GFR is measured by using Plasma Clearance concept. The plasma clearance of any substance means "the volume of plasma cleared from this substance per minute". 12 Physiology Notes 2017 Dr. Ahmad.S. Alarabi For Example: clearance of substance (X) = 50 ml/min, that is mean, meaning that kidneys clear 50 ml of plasma from substance (X) each minute. The clearance of any substance is calculated from the following equation: C= Clearance = The GFR is measured by the clearance of an exogenous substance (normally not present in the body) called Inulin. This is because inulin is: 1- Freely filtered through the glomerular membrane [its MW = 5000]. 2- Neither reabsorbed nor secreted by the renal tubules. Clinically, the clearance of another endogenous substance (normally present inside the body) is used in measurement of GFR, this substance is Creatinine. Creatinine is 1freely filtered, 2not reabsorbed, but 3secreted by 10 – 20 % in PCT. Inspite of that, creatinine clearance is considered an accurate measure for GFR, the methods measuring creatinine clearance giving a value 10 – 20 % > exact plasma creatinine. So, error of estimation cancels error of partial secretion. Measurement of Renal Plasma Flow It's measured by Para-Amino Hippuric acid (PAH) clearance. This is because PAH acid: 1- Freely filtered. 2- Not reabsorbed. 3- Most of remaining PAH in plasma in peritubular capillaries (escaping filtration) is secreted [only 10% of PAH that enters the kidney remains in renal venous plasma]. 13 Physiology Notes 2017 Dr. Ahmad.S. Alarabi The PAH clearance is about 10% less than Total Renal Plasma Flow, but equals the Effective Renal Plasma Flow (ERPF) = 585 ml/min. Extraction of PAH: It is the percentage of PAH removed by kidney from plasma entering the kidney. It is equal to: = Normally = 90% Total Renal Plasma Flow = = = 650 ml/min. Renal Blood Flow can also be calculated from RPF if we know the hematocrite as the following: RBF = RPF X Note: About 10% of TRPF supplies non functioning portions of kidney such as Peripelvic fat (this is a Non Effective Renal Plasma Flow) and this is the cause for lower PAH clearance than TRPF inspite it is completely secreted. 14  Physiology Notes 2017 Dr. Ahmad.S. Alarabi Tubular Reabsorption I- Reabsorption of organic substances Glucose Reabsorption Glucose is completely reabsorbed in PCT (i.e. Normally, glucose clearance = zero) At Luminal Border: Glucose is transported by secondary active transport [co-transport with Na+ / Na+ dependant]. At Basal Border: It is transported passively by facilitated diffusion. Tubular Load  It's the "amount of substance filtered per minute (with GFR)".  Tubular (Filtered) Load TL (mg/min) = GFR (ml/min) X P (mg/ml).  If the GFR = 125 ml/min, and Plasma glucose = 100 mg% (1 mg/ml): Tubular load of glucose = GFR X glucose in each ml of GFR = 125 X 1 = 125 mg/min. That means, kidneys filtrate 125 ml of glucose per minute.  Tubular Transport maximum (Tm):  It's "the maximum amount of a given solute transported (reabsorbed or secreted) by renal tubules per minute".  The Tm for glucose averages 320 mg/min for adult humans [which correspond to blood glucose level of about 255 mg% (125 X 2.55)]. If the Tubular load increased above this amount, the excess glucose is not reabsorbed → pass in urine.  Renal Threshold:  It is the plasma concentration at which a solute starts to appear in urine. Renal threshold for glucose level = 180 mg/dl ,, corresponding to a Tubular load = 220 mg/min. 15  Physiology Notes 2017 Dr. Ahmad.S. Alarabi  Glucosuria: it's presence of glucose in urine. It usually occurs when the blood glucose level exceeds the renal threshold (180 mg %) [As in case of diabetes mellitus]. Note: Renal Glucosuria occurs when renal threshold for glucose is lower than normal. Amino Acids Reabsorption The amino acids (like glucose) are completely reabsorbed at PCT by: Co-transport with Na+ (at luminal border) [Na+ dependant]. Passively by facilitated diffusion (at basal border). Amino aciduria: it is the presence of amino acids in urine. Protein Reabsorption Normally a trace amount of albumin is filtered (30 gm/day) which is completely reabsorbed actively by pinocytosis (mainly at PCT). Proteinuria means presence of more than 150 mg of proteins per 24 hrs urine. Uric Acid Reabsorption 90% of filtered uric acid is reabsorbed actively at PCT, only 10% is excreted in urine. Active transport system for uric acid can be inhibited by some drugs [e.g. Phenylputazone], which is a fact of practical importance in the treatment of Gout [↑ Plasma Uric Acid]. Urea Reabsorption About 50% of filtered Urea is reabsorbed at PCT (passively); the other 50% is excreted. Urea reabsorption takes place also passively at Medullary Collecting Ducts (by solvent drag) after water reabsorption, and goes back to tubules at thin part of ascending limb of L.H [this part of reabsorption is indirectly under the effect of ADH, and is not actually reabsorbed (doesn't go back to circulation). All other segments of renal tubules are impermeable to Urea. 16  Physiology Notes 2017 Dr. Ahmad.S. Alarabi The rate of urea excretion is affected by many factors:  ↑ Plasma urea and/or GFR → ↑ rate Urea excretion.  ↑ rate of water reabsorption → ↓ rate Urea excretion. Urea Cycle  The urea reabsorbed in medullary collecting ducts (50% of filtered urea) pass through medullary (papillary) interstitium to be secreted at lower parts of thin segment of loop of Henle.  This secreted amount of urea will be added at lower parts of thin segment of loop of Henle to the 50% of filtered urea that escaped reabsorption at PCT.  Then, this mixture of urea [50% escaped & 50% secreted] will pass through the [thick segment of loop of Henle, DCT, and cortical collecting ducts] without reabsorption [because these parts are impermeable to urea] until reach back to medullary collecting ducts where most of urea is reabsorbed again to pass through the same cycle [urea recirculates through the same terminal portions of tubular system several times before it is excreted].  The urea cycle keeps urea at high concentration in the renal medulla [450 m.osm./L. i.e. 100 times that of plasma]; thus it shares in Medullary Hyperosmolarity]. 17 Physiology Notes 2017 Dr. Ahmad.S. Alarabi II- Reabsorption of inorganic substances Sodium Reabsorption Normally, 99% of filtered Na+ is reabsorbed actively. At Luminal Border: it is transported passively by facilitated diffusion mainly through carrier proteins which play a very important role in secondary active transport of different substances. At Basal Border: it is transported actively by Na+ – K+ pump. Note: Active Na+ reabsorption accounts for most of energy requirements by kidney. Secondary effects of Na+ reabsorption 1- At PCT: 65% of filtered Na+ is reabsorbed actively at PCT [Fixed value]. Secondary to its reabsorption at this area: a- Glucose, amino acids, K+ and Ca++ are reabsorbed by Co-transport. b- Cl– and HCO3– are reabsorbed passively due to electrical gradient. c- H2O is reabsorbed passively by Osmosis [due to osmotic effect of reabsorbed Na+]. d- H+ is secreted by Counter transport. 18  Physiology Notes 2017 Dr. Ahmad.S. Alarabi 2- At Loop of Henle: 27% of filtered Na+ is reabsorbed at this area. a- The descending limb is impermeable to Na+ (no Na+ reabsorption). b- At thin part of ascending limb, the Na+ is reabsorbed passively after Cl– reabsorption. c- At thick part of ascending limb the Na+ is reabsorbed actively (primary activetransport) in co-transport with K+ & Cl– [1Na+ / 1K+ / 2 Cl– Pump]. 3- At Second ½ of DCT & CD: About 8% of the filtered Na+ reaches this area. Variable amount of filtered Na+ is reabsorbed actively at this area according to the body needs under the control of Aldosterone hormone. Secondary to its Na+ reabsorption at this area: a- Cl– & HCO3– are reabsorbed passively due to electrical gradient. b- K+ is secreted coupled with Na+ [Na+ – K+ exchange site]. Factors affecting Na+ excretion 1- Sympathetic activity: Sympathetic stimulation → ↑ rate of Na+ reabsorption by all segments of renal tubules → ↓ rate of Na+ excretion. 2- Effect of hormones: a- Aldosterone [the most important hormone] leads to ↑ Na+ reabsorption and K+ secretion mainly at DCT & CD.→ ↓ rate of Na+ excretion. b- Angiotensin II → ↑ Na+ reabsorption either by 1direct effect on renal tubules (especially PCT) or 2indirectly through stimulation of aldosterone secretion, and 3causing selective efferent arteriolar vasoconstriction → ↑ GFR → ↑ Na+ filtration. c- Circulating Epinephrine during sympathetic stimulation → ↑ Na+ reabsorption by direct effect on renal tubules. 19  Physiology Notes 2017 Dr. Ahmad.S. Alarabi d- Glucocorticoids (cortisol) when present in high level in blood → ↑ Na+ reabsorption. e- Estrogen [which ↑ during pregnancy] → ↑ Tubular Na+ reabsorption. f- Atrial Natriuretic Hormone: a polypeptide secreted from Atria of the heart (mainly Rt atrium). It is secreted in response to atrial stretch [e.g. by ↑ Venous return or ↑ blood volume]. Thus, it ↑ Na+ excretion (and water) by 1↑GFR, 2inhibiting aldosterone hormones either directly or by inhibiting renin → ↓ body fluids. 3- H+ secretion: ↑ H+ secretion (as in acidosis) → ↑ Na+ reabsorption and ↓ its excretion. This is explained by: a- Direct coupling of H+ to the counter transport of Na+. b- Indirect coupled by electrical forces created by secreted H+. The opposite occurs during ↓ H+ (alkalosis) → ↓ Na+ reabsorption & ↑ its excretion. 4- K+ secretion: ↑ K+ secretion [as in Hyperkalemia] → ↑ Na+ reabsorption & ↓ Na+ excretion, and vice versa. 5- Diuretics: most of diuretics ↓ Na+ reabsorption and ↑ its excretion. Note: The change in GFR leads to minimal change in Na+ excretion due to glomerular balance mechanism, the exact mechanism is unknown. Potassium Reabsorption Nearly all filtered K+ is actively reabsorbed completely at PCT (65% along with Na+), thick part of asc. limb of L.H (27% by 1Na+ / 1K+ / 2 Cl– co-transport at luminal border). Late DCT and Cortical Collecting Ducts either reabsorb or secrete K+ (coupled with Na+ reabsorption) depending on dietary K+ level. 20  Physiology Notes 2017 Dr. Ahmad.S. Alarabi K+ secretion is a function of special cells (principal cells) which are special type of cells (very permeable to K+ at their luminal border in contrast to epithelial cells elsewhere in renal tubules) make up about 90% of cells in Late DCT and Cortical CD, so these are the only sites for K+ secretion. Factors affecting K+ excretion 1- Plasma K+ level: ↑ Plasma K+ (Hyperkalemia) directly ↑ rate of K+ secretion in late DCT & cortical CD. 2- Aldosterone → ↑ K+ secretion as a result of ↑ Na+ – K+ pump, and permeability of luminal border. 3- H+ secretion (acid base change): there is a reciprocal relation between K+ & H+ secretion while their plasma concentration parallel each other For example: when there is ↑ H+ secretion [as in acidosis], there is ↓K+ secretion → Hyperkalemia. The opposite occurs during alkalosis. 4- Increased secretion of anions (e.g. Cl–) → ↑ K+ secretion & excretion. 5- Some diuretics: All diuretics that inhibit Na+ reabsorption in PCT and loop of Henle [e.g. Frusemide & Thiazides] → ↑ Na+ delivered to late DCT and CDs (Na+–K+ exchange sites) → ↑ K+ secretion & excretion (in exchange with Na+ reabsorption). Calcium Reabsorption Calcium is present in plasma in 2 forms:  50% bound to plasma proteins  50% free ionized calcium. Most of filtered Ca++ is reabsorbed actively at:  PCT by co-transport with Na (65%).  Thick part of asc. Limb of L.H by primary active transport (27%).  Late DCT under control of parathormone (variable amount). Note: Only ionized (free) is filtered across glomerular membrane. 21 Physiology Notes 2017 Dr. Ahmad.S. Alarabi Chloride Reabsorption More than 99% of the filtered Cl– is reabsorbed [mainly passively]. 1- At PCT: Cl– passively reabsorbed secondary to Na+ reabsorption. 2- At loop of Henle: a- Descending part: not permeable to Cl– [no reabsorption]. b- Ascending part: i- Thin part: passively [like Na+]. ii- Thick part: actively [1 Na+, 1 K+, 2 Cl– co-transport]. 3- Late DCT & CD: passively secondary to Na+ reabsorption [electrical gradient]. Bicarbonate Reabsorption – More than 99% of filtered HCO3 is reabsorbed mainly at PCT in coupling with H+ secretion by aid of carbonic anhydrase. – But if the filtered HCO3 was more than – available secreted H+, then excess HCO3 will be excreted in the urine. 22 Physiology Notes 2017 Dr. Ahmad.S. Alarabi Note: there is an inverse relation between Cl– reabsorption & HCO3– reabsorption – [i.e. ↑Cl– reabsorption → ↓HCO3 reabsorption, to keep the total anion concentration constant]. Phosphate Reabsorption About 90% of filtered phosphate is reabsorbed actively mainly at PCT by sodium- phosphate co-transport and acts as urinary buffer of H+ (10 % is excreted). The parathormone ↓ phosphate reabsorption → ↑ its excretion and ↓ its plasma level. Water Reabsorption Normally, more than 99% of filtered water is reabsorbed by osmosis in 2 main parts: A- PCT: in the PCT, the water reabsorption has the following characteristics: 1- Fixed fraction is reabsorbed (65%) regardless of body needs [obligatory water reabsorption]. 2- Reabsorbed by osmosis secondary to Na+ reabsorption. 3- The water is reabsorbed with an equivalent amount of Na+, so it has the same osmolarity as plasma (iso-osmotic). [i.e. it does not affect plasma or tubular osmolarity and has no relation to excretion of diluted or concentrated urine]. B- Descending Limb of L.H: 15% of water is reabsorbed without solutes, So the osmolarity of tubular fluid increases too much by the end of this segment. 23 Physiology Notes 2017 Dr. Ahmad.S. Alarabi C- Late DCT & CD: the reabsorption of water at these sites is characterized by: 1- Variable amount is reabsorbed according to body needs [facultative water reabsorption]. 2- It is independent on Na+ reabsorption but depends on: a. Anti Diuretic Hormone (ADH): it increases the permeability of DCT & CD to water by opening the door for its reabsorption [ DCT & CD are not permeable to water except under the effect of ADH]. b. Medullary Hyperosmolarity: it is the power that pulls the water. 3- Pure water is reabsorbed without accompanied Na+ [hypo-osmotic fluid] which will ↓ plasma osmolarity & ↑ tubular fluid osmolarity [this area determine the secretion of diluted or concentrated urine]. Medullary Hyperosmolarity In the medulla, there is a longitudinal hyperosmotic gradient. The superficial layers of medulla are iso-osmolar [300 m.osmol/L] and the osmolarity increase gradually until reach its maximum at the tip of medullary pyramids [1200 m.osmol/L (4 times that of plasma)]. The medullary hyperosmolarity is created by: A- Urea cycle [discussed before]. B- Counter current mechanism. Counter Current Mechanism It is done by: 1- Counter current multiplier [by long loop of Henle of juxtamedullary nephrons]. 2- Counter current exchanger [by vasa recta]. 24  Physiology Notes 2017 Dr. Ahmad.S. Alarabi  Counter current multiplier The long loop of Henle of juxtamedullary nephrons creates a medullary hyperosmotic gradient longitudinally along the different layers of medulla. This is done as the following: 1- The fluid in PCT is iso-osmolar (300 m.osmol/L), because water is reabsorbed with equivalent amount of Na+ (solute). 2- The descending limb of L.H is freely permeable to water and impermeable to Na+ & Cl–]. So, as fluid descends down in descending limb, it loose more and more water → tubular fluid will becomes hyper-osmotic more and more while we descend until reach a maximum osmolarity at the end of loop (about 1200 m.osmol/L). 3- While hyper-osmotic fluid passing in ascending limb of L.H (which is impermeable to water), it will lose theses solutes (Na Cl) that pass passively in the thin part, and actively in the thick part of ascending limb. 4- The transport of solutes (Na Cl) only from tubules into medullary interstitium without accompanied transport of water will make the tubular fluid hypo-osmotic as it passes up in ascending limb till reaches its lowest osmolarity in nephron at the tip of ascending limb of L.H (100 m.osmol/L). 5- All mentioned mechanisms will make small difference transversely [200 m.osmol/L] and a big longitudinal difference [about 900 m.osmol/L]. 25  Physiology Notes 2017 Dr. Ahmad.S. Alarabi 6- Interstitial fluid of medulla will equilibrate osmotically with the fluid in descending limb. So, osmolarity in superficial layers of medullary interstituim is about [300 m.osmol/L] and of the deep layers is [1200 m.osmol/L].  Counter Current Exchanger The vasa recta keeps (maintains) hyperosmolarity created by loop of Henle by the following mechanisms: 1- Low blood flow in medulla (2% of TRBF) → trapping solutes [Na+ / Cl– / Urea] in renal medulla and decreasing their removal by circulation. 2- In descending limb of Vasa recta: a- Na+ & Cl– pass from medullary inerstitium into blood. b- Water passes from blood into medullary interstitium. 3- In ascending limb of Vasa recta, the opposite occurs: a- Na+ & Cl– passe from blood into medullary interstitium. b- Water passes from interstitium into blood → circulation. 26 Physiology Notes 2017 Dr. Ahmad.S. Alarabi Osmolarity in different segments of Nephron 1- Under normal plasma ADH (vasopressin): 2- Under very low plasma ADH level: 3- Under high plasma ADH level: 27 Physiology Notes 2017 Dr. Ahmad.S. Alarabi Osmolar Clearance & Free water clearance Clearance of osmolar substances (solutes) is calculated as clearance of a single substance. Osmolar Clearance = Free water is the excess water that is excreted than osmolar substances, and the plasma volume cleared from this excess water each minute is called Free water clearance. Free water clearance = Urine volume per minute – Osmolar clearance. Free water clearance can either be: 1- Positive: when excess H2O is removed from plasma (diluted urine). 2- Negative: excess solutes are removed (Normal or concentrated urine). 3- Zero: osmolarity of urine equals osmolarity of plasma i.e. solutes removal = water removal. Note: +ve free water clearance occurs when ADH level is low (Urine osmolarity is < 100 m.osm/L), or very low (Urine osmolarity < 70 m.osm/L). Normal ADH High ADH Low ADH Very low ADH Less than More than More than Urine Volume 1.5 L/24 h 500 ml/24 h 1.5 L/24 h 3 L/24 h Urine Osmolarity 900 1200 Below 100 Below 70 Free Water – ve – ve + ve + ve Clearance 28  Physiology Notes 2017 Dr. Ahmad.S. Alarabi Tubular Secretion H+ Tubular Secretion The H+ is secreted actively by all nephron segments (Except descending limb of L.H) by 2 different mechanisms: 1- Secondary active transport: it is the function of Normal tubular cells. More than 95% of the H+ is secreted at PCT, Thick part of ascending Limb & Early Distal Tubule by counter transport with Na+. 2- Primary active transport: it's the function of special dark cells called intercalated cells that constitute 10% of cells in late DCT & CD. Note: H+ active secretion occurs against concentration gradient (3 – 4 folds in PCT, and 10 – 15 folds in DCT). 29 Physiology Notes 2017 Dr. Ahmad.S. Alarabi Reactions of Secreted H+ – – Nearly most of the secreted H+ react with filtered HCO3 [HCO3 reabsorption], this occurs mainly in the PCT. The secreted H+ may react also with ammonia (NH3) to form ammonium ion (NH4+), and with dibasic phosphate to form monobasic phosphate [production of Titrable acids (mainly in DCT & CD)]. – Note: Acid base balance is the balance between H+ secretion and HCO3 reabsorption by removing one of them from ECF and passing it in urine. Factors affecting H+ Secretion 1- ↑ Plasma CO2 [PCO2] as in respiratory acidosis → ↑ H+ secretion. 2- ↑ K+ secretion → ↓ H+ secretion, and vice versa. 3- Carbonic Anhydrase Inhibitors → ↓ H+ secretion. 4- Aldosterone hormone → ↑ H+ secretion. 5- Marked ↑ in Na+ reabsorption by renal tubules → ↑ H+ secretion → Alkalosis. – – 6- ↑ Cl reabsorption → ↓ HCO3 reabsorption → ↓ H+ secretion → Acidosis. Diuretics Diuretic: it is a substance that promotes water loss in urine, i.e. increases rate of urine output (cause diuresis). Diuretic Therapy reduces blood volume, blood pressure and ECF volume; So it's used in treating edema & hypertension. Types of Diuretics The diuretics are classified according to their mechanism of action into: 30 Physiology Notes 2017 Dr. Ahmad.S. Alarabi 1- Water: Drinking large amount of water in short time → ↓ Plasma osmolarity → ↓ ADH secretion → ↓ water reabsorption at distal part of nephron → Diuresis (starts after 15 min, and reaches its maximum after 40 min). 2- Osmotic diuretics: Injecting the body with substances that are filtered but poorly reabsorbed [e.g. Mannitol and related Polysaccharides] leads to: a- ↓ H2O reabsorption mainly in PCT & due to their osmotic effect. b- ↓ H2O reabsorption → dilution of Na+ in tubular fluid at PCT & L.H → ↓ Na+ reabsorption → more water remains in tubules. c- ↓ Solutes reabsorption in L.H → ↓ Medullary Hyperosmolarity; this will ↓ H2O reabsorption in distal part of nephron (especially inner CDs) despite presence of ADH. 3- Loop diuretics: They are the most powerful diuretics [e.g. Furosemide (Lasix) & Ethacrynic acid (Edecrin)], which cause as much as 25% of GFR to pass in urine. – They inhibit active Na+, K+, Cl co-transport (reabsorption) in Thick part of ascending limb of L.H → 1 ↑solute delivery to distal nephron act as osmotic agents , and 2↓ Medullary Hyperosmolarity (both of these effects → ↓ H2O reabsorption). 4- Thiazides: Thiazides (e.g. Chlorothiazide, Hydrochlorothiazide) inhibit active reabsorption – of Na+, K+, Cl in Early DCT → ↑ their excretion ( 8% of GFR pass in urine). 5- Aldosterone Antagonists: They act by competitive inhibition of aldosterone (e.g. Spironolactone / Aldactone) → ↓ Na+ reabsorption & ↓ K+ secretion in distal nephron [K+ retaining (sparing)]. 31  Physiology Notes 2017 Dr. Ahmad.S. Alarabi 6- Carbonic Anhydrase inhibitors: CA inhibitors [e.g. acetazolamide (Diamox)] act on PCT → ↓ HCO3– & H+ secretion → ↑ Na+ & K+ excretion. 7- ADH receptors antagonists: They inhibit the action of ADH (vasopressin) on V2 vasopressin receptors in renal tubules at Collecting Ducts. Note:  When the plasma glucose concentration increases many times, excess filtered amount is excreted in urine and acts as osmotic diuretic.  Osmotic diuresis is due to excess unreabsorbed solutes [e.g. Osmotic diuretics (Mannitol), Loop diuretics, Thiazides, Aldosterone antagonists and CA inhibitors]. On the other hand, Water diuresis is caused by excess water intake or vasopressin (V2) receptors antagonists.  In case of water diuresis, the urine is hypo-osmotic (+Ve H2O clearance); while in osmotic diuresis, the urine is either iso-osmotic (Zero H2O clearance) or hyper-osmotic ( -Ve H2O clearance).  Osmotic diuresis produces a very large urine flow rate, while water diuresis produces relatively lower urine flow rate. 32  Physiology Notes 2017 Dr. Ahmad.S. Alarabi Renal Function Test I- Chemical and physical analysis of urine: ♦ Specific gravity: Normally it ranges between 1005 – 1025. Diluting ability of kidney: It's tested by Water Loading Test. It's done by drinking large amount of water (20 ml /Kg) in short time → 80% is excreted within 4 hours. The urine is diluted with osmolarity < 100 m.osmol /L, and specific gravity ↓ to less than 1005. Concentrating ability of kidney: It is tested by Water Deprivation Test, where patient goes without water for 12 hours or more. By the end of this period, urine should be concentrated with osmolarity exceeds 900 m.osmol /L, and specific gravity exceeds 1025. ♦ Volume per 24 hrs: Normally 1.5 – 2 liters.  In acute renal failure may fall to zero (Anuria).  It is diminished in chronic renal failure (Oliguria). ♦ PH: Normally about 6 [ranging “between” 4.5 – 8]. ♦ Proteinuria: It's excretion of more than 150 mg of protein in urine / day. It's due to ↑ glomerular wall permeability (e.g. glomerulonephritis, nephrotic syndrome). II- Estimation of substances in blood that are normally excreted by kidney: ♦ Serum Creatinine: Normal plasma level is 0.5 – 1.5 mg /dl. ♦ Serum Urea: Normal plasma level is 20 – 40 mg /dl. 33  Physiology Notes 2017 Dr. Ahmad.S. Alarabi Both ↑ in:  Renal failure (10 folds).  Tissue breakdown (e.g. trauma or corticosteroid use).  ↑ Protein diet. III- Clearance tests: They are important in: – Determining GFR (Inulin). – Determining ERPF (PAH). – Study of renal tubular functions (reabsorbed or secreted):  If clearance is 125 ml /min, substance neither reabsorbed nor secreted (e.g. inulin).  If clearance is 0 ml /min, substance is completely reabsorbed (e.g. glucose).  If clearance is 0 – 125 ml /min, substance is partially reabsorbed (e.g. urea).  If clearance is 650 ml /min, substance is completely secreted.  If clearance is 125 – 650 ml /min, substance is partially secreted. Advantages Disadvantages  Specific for renal diseases  Gives the net effect, but not the  Indicate early renal diseases. details of renal function  Indicates the degree of renal diseases Renal Diseases  Acute Renal Failure: It's a sudden deterioration of kidney function. It can be caused by: 1- Acute glomerular damage [Acute glomerulonephritis (autoimmune disease)]. 2- Acute tubular damage [Acute tubular necrosis] by renal poisons or acute renal ischemia. 3- Acute obstruction of renal tubules [e.g. Incompatible blood transfusion → precipitation of hemoglobin in renal tubules]. 34  Physiology Notes 2017 Dr. Ahmad.S. Alarabi ♦ Effects: In moderate cases: rapid development of edema & hypertension. In sever cases: edema, hypertension, azotemia, and acidosis; the patient may die within few days.  Chronic Renal Failure: It is a gradual deterioration of kidney function. It is caused by: 1- Chronic glomerulonephritis. 2- Inflammation of renal pelvis & parenchyma ( Pyelonephritis ). 3- Destruction of nephrons [e.g. by vascular diseases]. 4- Urinary tract obstruction by renal stones or stricture of ureters. 5- Congenital polycystic kidney. ♦ Effects: 1- Water retention and edema. 2- Azotemia [↑ non protein nitrogen in blood (mainly creatinine, urea, & uric acid)]. 3- Metabolic acidosis [due to failure of H+ secretion]. 4- Hyperkalemia. 5- Anemia. 6- Osteomalacia [weakness of bone due to ↓ serum Ca++]. 7- Hypertension [due to Na+ & water retention and ↑ rennin production]. 8- Uremic coma [due to acidosis, Hyperkalemia, & azotemia]. 9- Low fixed specific gravity of urine.  Nephrotic Syndrome: This disorder is characterized by loss of large amount of plasma proteins into urine [sever proteinuria] due to increased permeability of the glomerular membrane.  Diabetes Insipidus: It is a disease characterized by ( Polyurea / Polydepsia / ↑ BMR ). It is caused either by deficiency of ADH (Neurogenic diabetes insipidus) or due to failure of the kidney to respond to normal ADH (Nephrogenic diabetes insipidus). 35  Physiology Notes 2017 Dr. Ahmad.S. Alarabi  Specific Tubular Disorders:  Renal glucosuria (Discussed before).  Aminoaciduria (cystinuria, glycinuria).  Nephrogenic diabetes insipidus.  Renal tubular acidosis (tubules can’t secrete H+). Urination / Micturition The urinary bladder is the site that stores the urine at in rate of 1 ml/min, until it can be evacuated. It can accommodate urine with only slight increase in the intravesical pressure (200 cc of urine produce about 5 ccH2O pressure) until the bladder is nearly full. This is due to the plasticity of its smooth muscles. Urine volume (ml) Intravesical pressure (ccH2O) Zero.…………………………….. Zero Zero – 200 ……………………… Zero – 5 200 – 400 ……………………….. 5 400 – 600 ……………………….. 5 – 25 Sensations from urinary bladder at different urine volumes are: 1- At urine volume 150 – 300 ml → sense to micturate]. 2- 300 – 400 ml → sense of fullness of bladder]. 3- 400 – 600 ml → sense of discomfort]. 4- 600 – 700 ml → pain sensation]. 5- After 700 ml [break point (can’t suppress micturition)]. 36  Physiology Notes 2017 Dr. Ahmad.S. Alarabi  Micturition Reflex: It's an automatic spinal reflex that can be inhibited or facilitated by brainstem or cerebral cortex.  Stimulus: ↑ Pressure in bladder due to urine collection [in adult 300 ml of urine can initiates the micturition reflex].  Receptor: Stretch receptors in the wall of bladder.  Afferent: Afferent fibers in Pelvic Nerve.  Center: 2, 3 and 4 Sacral Segments in spinal cord.  Efferent: Efferent parasympathetic fibers in Pelvic Nerve.  Response: Contraction of the wall of urinary bladder and relaxation of internal urethral sphincter → micturition. ♦ Voluntary Control of Micturition: In an adult person, cerebral cortex can control voluntarily the micturition by descending pathways that may: Delay micturition by: 1- Inhibition of Spinal Micturition Center. 2- Contraction of external urethral sphincter. Initiate micturition by: 1- Contraction of abdominal wall muscles → ↑ intravasical pressure. 2- Relaxation of external urethral sphincter. 3- Stimulation of Spinal Micturition Center. With my Best Wishes Dr. Ahmad Alarabi 2016 - 2017 37