Renal Physiology and Pharmacology Lecture PDF

Lecture #15: Renal Phys & Pharm I 02-14-25 Presented by Austin Fairman, OMS-II Slides adapted from Julia Hum, PhD Office Hours: Contact via email [email protected]  Summary Renal Tubular Reabsorption and Secretion LO1  Reabsorpt...

Lecture #15: Renal Phys & Pharm I 02-14-25 Presented by Austin Fairman, OMS-II Slides adapted from Julia Hum, PhD Office Hours: Contact via email [email protected]  Summary Renal Tubular Reabsorption and Secretion LO1  Reabsorption: Support of Peritubular Capillary Network Supplies tubules with oxygen and nutrients Clears recovered fluid from interstitium before it can accumulate and reduce the gradients favoring reabsorption Main force favoring fluid reabsorption is plasma colloid osmotic pressure (∏PC) Main force opposing reabsorption (or favoring filtration) is capillary hydrostatic pressure (PPC) LO4  Forces Controlling Fluid Reabsorption by Peritubular Capillaries ∏PC form of osmotic pressure exerted by proteins (albumin) – tend to pull fluid into the capillaries PPC – declines over the length of the capillary These are also known as Starling Forces LO4  Reabsorption and Secretion Ultrafiltrate in the PT is very similar in composition to plasma Major inorganic ions: Na+, K+, Mg2+, Ca2+, Cl-, HCO3-, H+ and phosphate Sugars, amino acids, peptides, creatinine, urea Renal tubules goal: recover >99% of water and solutes before they reach the bladder Most of that recovery takes place in the PT Paracellularly by osmosis Leaky walls of PT PT has the greatest role in recovering larger solutes (sugars, peptides, amino acids, etc.) PT secretes organic compounds into the tubule lumen for urinary excretion LO2  Tubular Reabsorption Transfer of water and solutes from the tubule lumen to the interstitium After interstitium free to enter peritubular capillary network by diffusion Two main pathways to cross epithelia 1. Paracellular Reabsorption (Diffusion) 2. Transcellular Reabsorption (Active Transport or Passive Diffusion) Powered by ATP Most energy consumed during reabsorption used support Na+/K+ ATPase activity 5 steps…. LO3  PT: Reabsorption Mechanisms….5 Steps Transepithelial transport powered by ATP Nearly all energy goes to 3 intracellular Na+ for 2 extracellular K+ support Na+/K+ ATPase activity Even though it’s a small voltage difference, enough to create significant driving force for ion movement Movement of Na+ creates osmotic gradient which drives water movement LO3  Sodium, Chloride, and Water Major electrolytes of the extracellular fluid On a molar basis, Na+ and Cl- are the most abundantly filtered solutes Plasma Na+ concentration primary way of controlling how water distributes between intracellular, interstitial, and plasma compartments Majority of Na+ recovered by PT Cl- “follows” Na+ because its driven inward by Na+’s positive charge LO5  Sodium, Chloride, and Water Resorption of Na+ and Cl- creates a strong osmotic potential that drive water from lumen towards interstitium Na+ reabsorption is under hormonal control in the kidney Net Na+ and Cl- movement are necessary for setting up the interstitial gradient necessary for urine concentration Na+ and Cl- are reabsorbed in each segment Transporters responsible are different in each segment LO5 Principle Sites of Solute and Water Recovery and Secretion  Proximal Convoluted Tubule: Sodium, Chloride, and Water Primary force in establishing Na+ gradient PT cells designed to recover useful organic solutes and HCO3- in association with Na+ Leads to transcellular Na+ reabsorption Some Na+ leaks backwards paracellularly via voltage gradient LO2  Proximal Convoluted Tubule: Glucose Vast majority of glucose is reabsorbed in the early PT Occurs transcellularly and mediated by transporters “High-capacity, low affinity Na+-glucose cotransporter” SGLT2 – recovers the bulk of glucose PST – very little glucose left to be reabsorbed “High-affinity, low capacity 2Na+ -glucose cotransporter” SGLT1 – last of the glucose prior to the loop LO2,5  Differences in proximal and distal tubules 1. Transport Capacity Proximal = bulk reabsorption of fluid and solute Distal = small capacity – move against steep gradients 2. Electrical characteristics Proximal = leaky Distal = high resistance 3. Control of transport Proximal = controlled by gradients and presence of transporters Distal = hormonally controlled LO2 Switching gears to pharmacology… Therapeutic strategies in HF Chronic HF is typically managed by: Fluid limitations (less than 1.5 to 2 L daily) Low dietary intake of sodium (less than 2000 mg/d) Use of diuretics, inhibitors of the RAAS, and inhibitors of the sympathetic nervous system  Goals of pharmacologic intervention in HF Goals of treatment are to alleviate symptoms, slow disease progression, and improve survival Seven classes of drugs have been shown to be effective 1. Angiotensin-converting enzyme inhibitors 2. Angiotensin-receptor blockers 3. Aldosterone antagonists * 4. β-blockers 5. Diuretics 6. Direct vaso- and venodilators 7. Inotropic agents  Diuretics Drugs that increase the volume of urine excreted Most diuretics are inhibitors of renal ion transporters Decrease the reabsorption of Na+ at different sites in the nephron The diuretic effect of the different classes varies considerably The increase in Na+ secretion varying from less than 2% to over 20% for the potent loop diuretics  PCT Pharmacological Targets: Carbonic Anhydrase Inhibitor Inhibits the reabsorption of HCO3- in the PCT Mechanism of action: Ace-taz-ol-a-mide inhibits CA of the PCT Decreased ability to exchange Na+ in the results in a mild diuresis HCO3− is retained in the lumen with marked elevation in urinary pH Note that while it can be used as a diuretic, this is not it’s typical use in many patients as other parts of the nephron can make up the difference LO2,3,4  PCT Pharmacological Targets: Carbonic Anhydrase Inhibitor – Acetazolamide Inhibits the reabsorption of HCO3- in the PCT Clinical Uses: Glaucoma: decreases the production of aqueous humor in the ciliary body of the eye and reduces intraocular pressure Mountain sickness: prophylaxis use to prevent weakness, breathlessness, dizziness, nausea, and cerebral as well as pulmonary edema LO4  PCT Pharmacological Targets: Carbonic Anhydrase Inhibitor – Acetazolamide Inhibits the reabsorption of HCO3- in the PCT Adverse Effects: Metabolic acidosis (mild) Potassium depletion Renal stone formation LO5  Question #1: A patient presents to your office with complaints of polyuria and polydipsia (frequent urination and extreme thirst). After various tests, you diagnose them with Fanconi syndrome, a defect in function of the PCT. This disease will likely have the greatest impact on reabsorption of which of the following solutes? A. Na+ B. Glucose C. Ca2+ D. Phosphate E. Mg2+ 21  Loop of Henle Similar to plasma https ://upload.wik ime dia.org/wik ipedia /comm ons/d/d6/Blause n_0592_ Kidne yA na tomy_ 01. png Thin Limbs – Function Conveys fluid down through the medulla Exposes fluid to corticopapillary osmotic gradient Fluid movement through kidney promoted by osmotic pressure gradients Responsible for recovering almost all water filtered from the vasculature LO6  Loop of Henle 3 Main Sections: 1. Descending Thin Limb (DTL) Mostly impermeable to urea and Na+ Express aquaporins for water passage Site of ~27L of water reabsorption per day LO6  Loop of Henle 3 Main Sections: 1. Descending Thin Limb (DTL) 2. Ascending Thin Limb (ATL) Transition site at the turn of the loop going from water permeable to water impermanent No aquaporins 3. Thick Ascending Limb (TAL) LO6  Loop of Henle 3 Main Sections: 1. Descending Thin Limb (DTL) 2. Ascending Thin Limb (ATL) 3. Thick Ascending Limb (TAL) Responsible for recovery of large amounts of: Na+, Cl-, K+, Ca2+, Mg2+ LO5,6  Loop of Henle: Thick Ascending Limb “Diluting Segment” Reabsorbs ~25% of Na+ and Cl-, 10% of K+ Transcellular and Paracellular routes Results in hyposmotic contents compared to plasma Despite the fact that there is little water movement here 4 Main Steps of Ion Reabsorption in TAL LO6  Loop of Henle: Thick Ascending Limb Ca2+ and Mg2+ Calcium: reabsorbs ~25% of filtered Ca2+ Magnesium: reabsorbs ~65-70% Paracellular movement, driven by voltage difference LO5,6  Loop of Henle: Thick Ascending Limb Bicarbonate As fluid leaves the PT bicarbonate still present TAL responsible for most of it’s resorption Four Step Process LO5,6  Proximal Tubule Loop of Henle: Thick TAL Ascending Limb Acid PT: generates NH3 to excrete H+ (as NH4+) TAL: site of reabsorption of NH 4+ Na-K-CL cotransporter NH4+ helps facilitate corticopapillary osmotic gradient LO5,6  TAL Pharmacological Targets: The cells are unique in being impermeable to water Active reabsorption of Na+, K+, and Cl− is mediated by a Na+/K+/2Cl− cotransporter Both Mg2+ and Ca2+ enter the interstitial fluid via the paracellular pathway due to the electrical gradient generated TAL of loop of Henle is a major site for salt reabsorption Drugs affecting this site have the greatest diuretic effect LO1  TAL Pharmacological Targets: Loop Diuretics Inhibit the Na+/K+/Cl- cotransporter causing retention of Na+, Cl-, and water These drugs have the highest efficacy in mobilizing Na+ and Cl− from the body They produce copious amounts of urine Fur-o-se-mide is the most commonly used of these drugs Bu-met-an-ide and Tor-se-mide LO2,3,4  TAL Pharmacological Targets: Loop Diuretics Clinical Uses: Reducing acute pulmonary edema and acute/chronic peripheral edema caused from HF Because of their rapid onset of action useful in emergency situations Treating hypercalcemia - stimulate tubular Ca2+ excretion Treatment of hyperkalemia LO4  TAL Pharmacological Targets: Loop Diuretics Adverse effects: Ototoxicity: Reversible or permanent hearing loss may occur with loop diuretics Change in ionic gradient in endolymph within cochlear duct Vertigo Acute hypovolemia Hypokalemia and Hypocalcemia LO5  Question #2: Loss/dysfunction of the ROMK channel on the apical side of the thick ascending limb, would likely lead to which of the following? A. Hypernatremia B. Hypermagnesia C. Ototoxicity D. Hyperkalemia E. Volume Depletion 34 Draw it Out: 1st Half of Nephron PCT and Loop of Henle Summary  Survey Please fill out the survey with the specific topic or idea that is most confusing to you at this time. I will go over the most nebulous topics briefly at the start of the next lecture to hopefully clear up any confusion! https://s.surveyplanet.com/921hdwnk