Title MOD11-5-Tubular Function 2 (Renal 4).pdf ✅

PHYSIO ● PHYSIOLOGY Tubular Function 2 (Renal 4) TRANS 5 V MODULE 11 ictor Mendoza, MD, MSC, FPCP, FPCC, FPSP March 3, 2023 LECTURE OUTLINE I Recap of Tubular Function 1 II Peritubular Fluid III Loop of Henle A. Thin Descending Limb B. Ascending Limb a. Thin Ascending Limb b. Thick Ascending Limb C. Other Functions D. Summary of Events in the Loop of Henle IV Distal Convoluted Tubule and Connecting Tubule A. Collecting Ducts B. Other Functions of the Distal Convoluted Tubule C. Maintenance of Intracellular Volume D. Factors Affecting the Concentrating and Diluting Mechanisms E. Factors Affecting the Maximum Osmolality of Gradient V Urine Flow VI Control of K+ Balance A. Major Causes of Increased K+ Secretion in Distal Nephron VII Renal Regulation of pH A. Regulation of Plasma HCO3- B. Secretion of Bicarbonate C. Control of H2CO3- Derived H+ Secretion LECTURE OBJECTIVES I. At the end of the sessions, the student should be able to – Discuss the function of the tubules: 1. Proximal Tubule 2. Loop of Henle a. Thin descending b. Thin ascending c. Thick ascending 3. Distal Convoluted Tubule & Connecting tubule 4. Collecting ducts a. Cortical collecting duct b. Medullary collecting duct c. Papillary collecting duct I. RECAP OF TUBULAR FUNCTION 1 ● The 3 main processes that lead to urine excretion: Filtration Occurs in the glomerulus Reabsorption Accomplished by the renal tubules Secretion ● Proximal Tubule ○ Initial segment of the tubular segment of the nephron ○ Responsible for: ■ Initial processing of the tubular fluid ■ Reabsorption of approx. 2⁄3 (~67%) of the filtered sodium and water ■ Reabsorption of all glucose and amino acids that have been filtered at the level of the glomerulus II. PERITUBULAR FLUID Table 1. Peritubular Osmolality (from outermost to innermost) Cortex Outer zone of medulla Inner zone of medulla mOsm/kg of H2O is similar to plasma increases progressively increases until it passes the hairpin loop of Henle (highest) 300 mOsm/kg water (similar to plasma) 600 mOsm/kg water 900 up to 1200 mOsm/kg water 1200 mOsm/kg is where loop of Henle is found Mostly attributed to high concentration NaCl 1⁄3: concentration of urea 2⁄3: concentration of NaCl 1⁄2: concentration of urea (when osmolarity reaches 1200) Source: Dr. Vic Mendoza’s Tubular Function 2 Video NOTE: Thus, an osmolality gradient exists in the medulla with the progressive increase in the osmolality moving inward from the corticomedullary region towards the tip of the papilla. Figure 1. Flow of the Peritubular Fluid Source: Dr. Vic Mendoza’s Tubular Function 2 Video III. LOOP OF HENLE ● Reabsorption of sodium (Na+ ), chloride (Cl- ), and water (H2O) occurs at the loop of Henle ● Reabsorption of Na+ and water is markedly dependent on the loop length due to the differences in the ascending limb structure and function. Group 4A, 5A, 6A | Tubular Function 2 (Renal 4) 1
LONG NEPHRONS THIN descending limb THIN ascending limb THICK ascending limb starts near the outer zone and ends at the hairpin turn starts at the hairpin turn starts at the junction between the inner and outer medulla SHORT LOOP NEPHRONS THIN descending limb NO THIN ASCENDING LIMB THICK ascending limb starts near the outer zone and ends at the hairpin turn starts near the hairpin turn, above the junction of the inner and outer medulla Figure 2. Loop of Henle Source: Dr. Vic Mendoza’s Tubular Function 2 Video Figure 3. Permeability and Transport Characteristics of Loop of Henle and Distal Nephron Source: Dr. Vic Mendoza’s Tubular Function 2 Video A. Thin Descending Limb Water permeability High Urea permeability Not permeable Na+ and Cl- permeability Not permeable Reabsorption No active reabsorption NOTE: “The descending part of thin segment is HIGHLY permeable to water and MODERATELY permeable to most solutes, including urea and sodium” Guyton and Hall (14th ed), Solute and Water Transport in Loops of Henle, p.350 ● Lacks mechanism for active solute transfer ● As the tubular fluid entering the thin descending limb flows downwards through regions of increasingly hypertonic peritubular fluid, there is an increasing peritubular tonicity or osmolality ● Since the thin descending limb is very permeable to water, water is actively reabsorbed ○ Approximately, 3⁄4 of the water entering the thin descending limb of long loop nephrons is reabsorbed ○ Approximately 1⁄2 of the water entering the shortloop nephrons is reabsorbed ● As the tubular fluid in the thin descending limb flows towards the hairpin turn, its osmolality increases equalizing with that of the peritubular fluid Table 2. Important differences in composition between Tubular fluid and Peritubular fluid Tubular osmolality Peritubular osmolality Majority of the long loop nephrons Contributed by NaCl (sodium chloride) 1⁄2: contributed by urea 1⁄2: contributed by NaCl Source: Dr. Vic Mendoza’s Tubular Function 2 Video ● The tubular fluid in the thin descending limb of the long loop nephrons are concentrated approximately 4-fold because water is actively moving out and the solutes remain in the tubules ● The tubular fluid in the thin descending limb of the short loop nephrons are concentrated 2-fold ● In both long and short loop nephrons, the predominant solutes are sodium and chloride but a substantial fraction of solute in the surrounding peritubular fluid is urea B. Ascending Limb ● After passing the hairpin turn, the tubular fluid enters the ascending limb: 1. Thin Ascending Limb Thin ascending limb Long loop nephrons Short loop nephrons Location Begins at the hairpin turn Absent Water permeability Negligible Urea permeability Moderate Na+ and Cl- permeability High Reabsorption No active solute transport ● Due to greater concentration of NaCl and urea in the tubular system compared to the peritubular fluid, Na+ and Cl– diffuse passively from lumen to peritubular space, while urea diffuses passively from peritubular space into the lumen. ○ Because the thin ascending limb is much more permeable to Na+ and Cl– than to urea, the number of moles of Na+ and Cl– leaving exceeds the number Group 4A, 5A, 6A | Tubular Function 2 (Renal 4) 2
of moles of urea that enters the lumen. ● The volume of water does not change because of the low water permeability. ○ Thus, with the net solute exit and the no appreciable volume change, the osmolality of the tubular fluid in the thin ascending limb falls slightly below that of the surrounding peritubular fluid. 2. Thick Ascending Limb Thick ascending limb Long loop nephrons Short loop nephrons Location Begins at the junction of the inner and outer medulla Begins at the hairpin turn located at the junction of the inner and outer medulla Water permeability Negligible Urea permeability Low Reabsorption Actively transports Na + and Cl – from the tubular lumen into the peritubular space ● Na+ and Cl– are now taken into the peritubular capillaries; hence, called reabsorption ○ Lowers both the osmolality of the tubular fluid and the concentration of Na+ and Cl– in the tubular fluid to levels below those of the surrounding peritubular fluid. ● Hence, the combination of low water and urea permeability means that the urea concentration is not altered by the thick ascending limb. Figure 4. Active reabsorption of Na and Cl Source: Dr. Vic Mendoza’s Tubular Function 2 Video ● The mechanism of the active reabsorption of Na+ and Cl– is characterized by the apical entry of Na+ along its electrochemical gradient, followed by active extrusion of sodium by the Na+ /K+ -ATPase pump. ● The mechanism is distinguished from the other active reabsorption processes by the carriers mediating the apical entry of Na+ ○ Na+ reabsorption is coupled with the entry of K + and 2 Cl– ions termed Na+ -K+ -2Cl– symport. ■ Reabsorption of sodium is load dependent ■ Inhibited by certain prostaglandins and loop diuretics (ex. Furosemide and BBumetanide) ○ Although K + is moved from the tubular lumen into the peritubular space, some of the K + are moved back towards the tubular lumen. ● Water permeability ○ Dependent upon ADH (antidiuretic hormone) ○ Depends on the presence of vasopressin (ADH) ■ Activates/opens up cAMP-dependent aquaporins, thus, less volume of urine is produced (due to water reabsorption) ■ Hence, it is called ADH = prevents diuresis or formation of urine ● Water moves out of the lumen because the peritubular fluid has a very high oncotic pressure. C. OTHER FUNCTIONS Reabsorbs K+ THICK ASCENDING LIMB (Na+ -K+ -2Cl- Symport Mechanism) Secretes K+ THIN ASCENDING LIMB Reabsorption of Ca++ THICK ASCENDING LIMB D. SUMMARY OF EVENTS IN THE LOOP OF HENLE ● The fluid that leaves the proximal tubule (and enters the Loop of Henle) which is rich in Na+Cl- and approximately isotonic, is reduced in volume and transformed into a hypotonic fluid (at the level of the Loop of Henle) in which the major osmotically active solute is urea. ● 25% of filtered Na+ (Na+ /K+ -2Cl- ) and 20% of the filtered water is reabsorbed while a substantial amount of urea is added into the tubular fluid at the level of the Loop of Henle. IV. DISTAL CONVOLUTED TUBULE AND CONNECTING TUBULE ● Similar to the composition of the THICK ASCENDING LIMB, the segmental characteristics of the Distal Convoluted Tubule (DCV) are important to take note: Water permeability Low Urea permeability Low Reabsorption Active Na+ reabsorption lowers osmolality of the tubular fluid and its electrolyte concentration Figure 5. Relative Permeabilities of the Distal Convoluted Tubule and Collecting Tubule. Source: Dr. Vic Mendoza’s Tubular Function 2 Video ● Combination of low H2O and Urea permeability = Urea concentration is unchanged Group 4A, 5A, 6A | Tubular Function 2 (Renal 4) 3
● At the end of the connecting tubule, the tubular fluid is estimated to contain: ○ 50 mmol/L of Urea ○ 50 mmol/L of Non-Urea solutes including electrolytes ○ Total osmolality: 100 mOsm/kg H2O ● Solute concentration and osmolality of surrounding cortical peritubular fluid is similar to plasma ● The hypotonic tubular fluid entering the distal nephron’s osmolality is further reduced in the distal convoluting and connecting tubule ○ Urea concentration remains considerably greater than that of plasma ● Thus, the hypotonic tubular fluid entering the distal nephron has its osmolality further reduced in the distal convoluted tubule and connecting tubule. The urea concentration remains greater than that of plasma. Figure 6. Na + -Cl - Symport Source:Tubular Function Part II Lecture Video ● In these segments, the apical entry of Na+ is coupled to the entry of Cl- . ● The mechanism for active Na+ reabsorption in these segments is the Na+ -Cl- symport ● IMPORTANT CHARACTERISTIC OF Na+ -Cl- symport : An increased amount of Na+ will be reabsorbed by the distal convoluted tubule and connecting tubule if an increased load of Na+ is delivered to these segments. ● Like the proximal tubule and thick ascending limb of the Loop of Henle, the distal convoluted tubule and connecting tubule exhibit load-dependent Na+ reabsorption. ● The Na+ -Cl- symport is inhibited by thiazide diuretics. A. COLLECTING DUCTS ● The collecting ducts (cortical, medullary and papillary segments) are not permeable to Na+ , but are capable of active Na+ reabsorption. (Refer to Figure 5.) ● Unlike other segments of the nephron, the water and urea permeability properties of the collecting duct are regulated by a hormone: antidiuretic hormone (ADH) aka vasopressin. ○ ADH is synthesized in the hypothalamus and stored in the posterior pituitary gland. ○ In the absence of ADH, the collecting duct is relatively impermeable to water and urea. ○ However, in the presence of ADH, the water permeability of the entire collecting duct and the urea permeability of the papillary collecting duct increases significantly. ● The changes in tubular fluid composition and osmolality that occur in the collecting duct will be a function of the ADH level. Figure 7. Conductive Na + Channel Source: Tubular Function Part II Lecture Video ● How Naᐩ is actively reabsorbed at the level of the collecting ducts: ○ Apical entry of Naᐩ is via Conductive Naᐩ channel, since it is not directly coupled to the entry and secretion of other ions/solutes ○ The ability (movement) of Cl– to accompany Naᐩ is limited due to the very tight junctions between epithelial cells ○ Effects of ADH to H2O permeability of the collecting duct → binding of two receptors to the basal lateral surface of epithelial cells, activates adenylate cyclase and generates cAMP ○ Protein containing aggregates in the luminal membrane serves as water movement channels known as, aquaporins ■ Aquaporins: components of tubular vesicles that fuse with luminal membrane in the presence of ADH ○ In maximal ADH, high H2O permeability of the collecting duct → prevents the establishment of osmotic gradient across tubular epithelium RECALL: Osmolality of fluid entering the duct: 100 mOsm; osmolality of surrounding peritubular fluid: approx. 300 (cortex) to 1200 (tip of papilla) – meaning water is reabsorbed as fluid flows thru the collecting duct (due to max ADH). 1. Cortical Collecting Duct ● Over 70% of H2O entering is reabsorbed ● High H2O permeability + low urea permeability = ↑[urea] concentration ○ From 50 to 175 (as seen in Figure 5) ● Reabsorption of Na+ and Cl– = ↑ less markedly ● At the end the duct, osmolality of tubular fluid ≈ 300 mOsm/kg H2O in osmotic equilibrium with peritubular fluid at corticomedullary space/junction 2. Medullary Collecting Duct ● H2O continues to be reabsorbed (along with more Na+ and Cl- ) as tubular fluid goes downwards through regions of increasingly hypertonic peritubular fluid ○ Over 50% of water entering is reabsorbed Similar to cortical collecting duct: ● High H2O permeability + low urea permeability = ↑2x[urea] ● Reabsorption of Na+ and Cl- = ↑ less markedly 3. Papillary Collecting Duct ● Additional water is reabsorbed as the tubular fluid continues to flow downward through the medullary region. ● However, the papillary collecting duct differs from the cortical and medullary collecting ducts in that ADH increases papillary collecting ducts’ permeability to urea and water. Group 4A, 5A, 6A | Tubular Function 2 (Renal 4) 4
NOTE: “The permeability of the medullary collecting duct to water is controlled by the level of ADH. With high levels of ADH, water is avidly reabsorbed into the medullary interstitium, thereby reducing the urine volume and concentrating most of the solutes in the urine.” Guyton and Hall (14th ed), Medullary Collecting Ducts, p.354 ● Since the concentration of urea in the tubular fluid entering the papillary collecting duct exceeds the surrounding peritubular fluid (400 vs 200), urea is reabsorbed by the papillary collecting duct at the junction between the inner and outer medulla. ● Reabsorption of urea has an important role in the generation of the medullary gradient and promotes further reabsorption of water. ● Non-urea solutes concentration increases less markedly. ● Osmolarity at the end of the papillary duct is = 1200 mOsm/kg water in osmotic equilibrium with the peritubular fluid at the tip of the papilla. ● In the presence of maximal ADH, the final urine has an osmolality of 1200 mOsm/kg water ○ 600 mOsm (urea) and 600 mOsm (non-urea solutes) ● Non-urea solutes: sodium (Na+ ), chloride (Cl– ), creatinine, uric acid, ammonium, phosphate, potassium (K+), and magnesium ● In the presence of maximal ADH only 0.5% of filtered H2O is excreted, with 99.5% reabsorbed. ○ If the glomerular filtration rate is 125 mL/min then around 180 L/day is being filtered. ○ The Urine Flow Rate will only be 0.6 mL/min, about 0.9 L/day not even 1 L/day in the presence of maximal ADH. ● In the absence of ADH, the entire collecting duct is relatively impermeable to H2O. ○ Since the thin ascending limb, thick ascending limb, distal convoluted tubule are always relatively impermeable to H2O, this means that in the absence of ADH the nephron is H2O impermeable (from the hairpin turn, at the tip of the loop of Henle all the way to the end of the papillary collecting duct). ○ As a result the volume of the tubular fluid remains virtually unchanged, not only in the ascending limb, distal convoluted tubule, and connecting tubule but in the collecting duct as well. ○ The urea concentration also remains approximately constant since the entire collecting duct has a low permeability to urea in the absence of ADH. ○ However, the reabsorption of Na+ and Cl- continues, thereby reducing the concentration of non-urea solutes. The osmolality of the tubular fluid at the end of the collecting duct is therefore as low as 70 mOsm/Kg H2O in the absence of ADH. ○ In the absence of ADH, nearly 15% of H2O is excreted, and 85% reabsorbed. With a Glomerular Filtration Rate of 125mL/min, meaning 180 L/day of blood is filtered. The Urine Flow Rate will be greater than 15 mL/min (about 26 L/day). ● Because the volume of the tubular fluid remains virtually constant throughout the entire ascending limb and distal nephron in the absence of ADH, this urine flow rate also should represent the flow rate of the tubular fluid at the tip of the loop of Henle. ● However, even in the absence of ADH, the water impermeability of the collecting duct is actually relative, not absolute, so that a small fraction of the water flowing through the collecting duct will be reabsorbed. ● The actual urine flow rate may therefore be slightly less than the flow rate of the tubular fluid at the tip of the loop SUMMARY PRESENCE OF MAXIMAL ADH ABSENCE OF ADH H2O 0.5% excreted 95.5% reabsorbed 15% excreted 85% reabsorbed GFR (125 ml/min) Around 180 L/day filtered 180 L/day of blood is filtered URINE FLOW 0.6 mL/min (≈ 0.9 L/day) Greater than 15 ml/min (≈ 26 L/day) B. OTHER FUNCTIONS OF THE DISTAL NEPHRON/CONVOLUTED TUBULE ● Virtually all regulation of K + excretion occurs in the distal nephron ● It plays an essential role in the regulation of acid-base balance via secretion of H+ and HCO3 - ● Plays a role in the regulation of Ca++ Figure 8. Active Na + Cl - Reabsorption and Passive Water Reabsorption Source: Tubular Function Part II Lecture Video Medullary Gradient ● Plays an important role in the modification of the volume and composition of the tubular fluid as it passes through the different tubular segments of the nephron ● Key factor in the formation of the medullary gradient is the unusual anatomic configuration of the loop of Henle. ● Allows fluid to flow in opposite/countercurrent directions in its two limbs. ● Because of the specific transport and permeability properties of the ascending and descending limbs, countercurrent flow allows a large osmotic gradient to be established in the peritubular fluid between the corticomedullary junction and the tip of the papilla. RECALL: The loop of the short loop nephron consists of a thin descending limb — which is relatively impermeable to solutes but is highly soluble to water, and a thick ascending limb which actively reabsorbs Na + and Cl - but is relatively impermeable to water. Group 4A, 5A, 6A | Tubular Function 2 (Renal 4) 5