5.7 Renal Regulation of K Ca P Mg(1)1.pptx

Renal Regulation of Potassium, Calcium, Phosphate and Magnesium; Integration of Renal Mechanisms for Control of Blood Volume and Extracellular Fluid Volume Lecture Outline I. Regulation of extracellular fluid potassium concentration and potassium excretion II. Regulation of renal calcium excretion a...

Renal Regulation of Potassium, Calcium, Phosphate and Magnesium; Integration of Renal Mechanisms for Control of Blood Volume and Extracellular Fluid Volume Lecture Outline I. Regulation of extracellular fluid potassium concentration and potassium excretion II. Regulation of renal calcium excretion and extracellular calcium ion concentration III. Regulation of renal magnesium excretion and extracellular magnesium ion concentration IV. Renal regulation of BP 1 Renal Regulation of Potassium, Calcium, Phosphate and Magnesium; Integration of Renal Mechanisms for Control of Blood Volume and Extracellular Fluid Volume Lecture Objectives 1. Identify the unregulated and regulated reabsorption of K+ 2. Identify how K+ is affected by aldosterone, insulin, epinephrine, exercise, alkalosis, and acidosis 3. List the causes and treatments for acute hyperkalemia 4. Identify the functions and forms of diffusible ECF calcium and response to decreased plasma calcium 5. Discuss magnesium homeostasis 6. Identify the major components of renal control of BP and their integration 2 References Assigned reading from your text: Hall Chapter 30 3 Regulation of K+, Calcium, Magnesium 4 Another reference slideThis summarizes much of what’s in your notes. Use it if it helps. From Big Picture: Medical Biochemistry by Lange 5 Potassium Balance  Control of ECF K is essential to prevent membrane potential disruption • K+ determines the resting membrane potential (RMP) • Internal K+ homeostasis maintains a balance between ICF and ECF K+ • 98% K+ is intracellular • ECF K+ is controlled within the range of 3.5-5.5 mEq/L • External K+ homeostasis= K+ ingestion and excretion • Hyperkalemia results from increased ingestion • Or decreased excretion (renal insufficiency or failure) Renal Tubular Sites of Potassium Reabsorption and Secretion  Normal urinary K+ excretion varies with dietary K+ intake • FEK is typically 10-20% • To achieve the excretion of excess K+ from a normal diet • Segmental K+ handling = external K+ homeostasis  Not physiologically regulated: • 70% reabsorbed in the PT • 25% reabsorbed in TAL  Physiologically regulated • Secretion of K+ from the principal cells in the late DT and cortical collecting duct are the most important determinants of urinary K+ output Physiologically Controlled Potassium Reabsorption and Secretion  Secretion • Aldosterone simultaneously stimulates principal cells to secrete K+ & reabsorb Na+ • Increased Na+ (volume) delivery to the cortical collecting duct increases K+ secretion • Na+ influx via ENaC causes depolarization& increases the driving force for K+ secretion  Reabsorption of K+ • Is possible in the collecting duct in states of K+ depletion  Acid–base status: - Acidosis: decreases K+ secretion - Alkalosis: increases K+ secretion Internal K+ Homeostasis  Factors that affect internal K+ homeostasis- the K+ distribution between ECF and ICF • • Aldosterone is the central hormone controlling K+ balance- both internal and external homeostasis K+ balance primarily regulated in the distal collecting duct by negative feedback/aldosterone • Insulin stimulates K+ movement from ECF to ICF • A single meal can contain as much K+ as the entire ECF • Insulin stimulates K+ uptake by liver and skeletal muscle • Infusions can control hyperkalemia • Epinephrine stimulates K+ movement from the ECF to the ICF • An acute K+ load is delivered to the ECF by exercising muscle • Secretion of epi during exercise stimulates K+ reuptake into skeletal muscle cells via β2 receptors • Disturbances in acid-base balance affect internal K+ distribution • Acidosis increases plasma K+ • some H+ is buffered by the ICF and is associated with K+ efflux from the cells • Alkalosis reduces plasma K+ • H+ exits cells in exchange for K+ Potassium Disturbances • Hypokalemia is plasma K+ < 3.5 mEq/L • From intestinal losses (diarrhea, vomiting, or gastric suctioning) • or Renal loss- from a diuretic • Hyperkalemia is plasma K+> 5.5. mEq/L • ECF shifting (eg acidosis) • Cellular release of K+ (hemolysis) Treatment for Acute Hyperkalemia  Acute hyperkalemia can be rapidly fatal- Medical treatment includes: • Calcium gluconate infusion • Increased plasma Ca+ stabilizes cardiac membrane potential • Decreases immediate risk of arrhythmia • Insulin and glucose infusion • Insulin drives K+ into the ICF, concomitant glucose infusion prevents hypoglycemia • Kayexalate • Intestinal K+ chelator reduces K+ absorption and increases fecal K+ elimination • β2 agonists (eg albuterol and epinephrine) • Provide a short-acting mechanism to temporarily drive K+ into ICF Increased Serum K+ Stimulates Aldosterone Secretion Effects of Diuretics to Cause Potassium Depletion  Thiazide and loop diuretics • Inhibit Na+ reabsorption upstream of cortical collecting duct • Causes high Na+ delivery to cortical collecting duct • Drives further K+ secretion Diuretics that Na + reabsorption Water reabsorption Volume delivery to cort. collect. tub. Cell : Lumen gradient for K+ diffusion K+ secretion K+ depletion K+ reabsorption Calcium- Compensatory Responses to Decreased Plasma Ionized  Calcium exists in three forms Calcium  Two diffusible forms of Ca++: • 45% as free ionized Ca++ is diffusible and tightly regulated in normal plasma range • Free Ca++ is a vital second messenger for: • Blood coagulation • Muscle contraction- IV Ca++ may produce a transient increase in SVR • Nerve function • Hypocalcemia has an excitatory effect on nerve and muscle cells • Hypocalcemic tetany – laryngospasm can be fatal • Can occur before clotting compromised • 10% complexed with LMW anions- HCO3-, citrate and oxalate • Most common urinary calculi- calcium oxalate • TZDs increase distal tubular Ca++ reabsorption to decrease urinary Ca++ load  Nondiffusible (protein-bound) • 45% is bound to anionic sites on plasma proteins • Is not filtered into ISF or glomerulus • Plasma proteins more ionized when pH high (alkalotic)- bind more Ca++ Calcium- Compensatory Responses to Decreased Plasma Calcium  PTH regulates plasma calcium Ionized (and phosphate)  Compensatory responses to decreased plasma ionized calcium • PTH, Vit D3 activation, and thiazide diuretics all stimulate Ca++ reabsorption from the DT • In response to low plasma Ca++- Parathyroid hormone secretion: • • At the kidney- two mechanisms increase calcium reabsorption • Increases calcium reabsorption from the DT • Increases Vitamin D3 activation which increases Ca++ reabsorption From bone- PTH increases release of Ca++ into plasma Proximal Tubular Calcium Reabsorption  Ca+ homeostasis involves variable Ca++ input/output/exchange • Input from GI system • Exchanges between ECF and bone matrix • Variable output by renal system • FECa 1-2%- Pattern of reabsorption similar to Na+ • Cells of TAL have an ECF Ca++ sensing receptor that detect decreased plasma Ca++ and increase uptake due to a larger transepithelial electrical difference • Distal tubular reabsorption depends on a transient receptor potential channel (TRP) whose expression is regulated by PTH Magnesium Homeostasis  Mg2+ is an essential cofactor in enzymatic reactions and stabilizes phosphate groups • Plasma Mg2+ is homeostatically regulated by balance between: • Intestinal uptake • Dietary Mg2+ absorbed in ileum • Urinary excretion • Half of daily intake must be excreted to maintain balance • Segmental handling: • Reabsorption regulated in TAL (65% reabsorption) and DT • Loop diuretics cause urinary loss of divalent cations- including Ca 2+ and Mg2+ • Mg2+ compartments • ~1% total body Mg2+ is in ECF • Remainder in bone matrix and ICF • Plasma Mg2+ present in three forms: • ~50% free ionized magnesium • ~35% bound to plasma proteins • ~15% complexed to anions such as phosphate Renal Regulation of BP 18 Renal Responses to Low Effective Circulating Volume  4 main renal responses to counteract a low effective circulating volume: 1. Activation of the renin-angiotensin-aldosterone axis 2. Stimulation of the sympathetic nervous system via the baroreceptor reflex 3. Increased ADH secretion 4. Increased renal fluid retention 19 Renal Responses to Low Effective Circulating Volume  Low effective circulating volume may not correspond to a low total body volume • Involves renin, angiotensin, aldosterone, ADH, and sympathetic nerves • Edema of varying etiologies (of different Starling forces)- Examples: • • • Congestive heart failure- increased hydrostatic pressure related to cardiac congestion Nephrotic syndrome- decreased oncotic pressure is due to loss of proteins in urine Cirrhosis- combines two forces that favor filtration out of vascular system • Decreased oncotic pressure from decreased plasma protein production • Increased hydrostatic pressure from hepatic congestion  With normal circulating volumes: • Activity of renin, angiotensin, aldosterone, and sympathetic nerves is generally low • High circulating volume is poorly addressed by the same mechanisms • Secretion of ANP promotes loss of Na+ and water in urine • ADH secretion is decreased 20 Renal Regulation of Blood Pressure Regulation  Kidney regulate BP by its effect on Na+ and H2O balance- major determinants of BP • Na+ concentration is measured at the macula densa • Intrarenal baroreceptors of the juxtaglomerular granular cells assess perfusion pressure  Tubuloglomerular feedback stimulates renin release • Macula densa – The cells of the macula densa have Na+ and Cl- channels that transport Na+ into the cell – and a limited number of NaK-ATPase pumps that become overwhelmed if the Na+ concentration rises (high tubular flow) • Granular (juxtaglomerular) cells are located in the afferent arteriole – Function as intrarenal baroreceptors and produce the protease renin • Release renin in response to low flow/low perfusion pressure • Decrease renin release in response to high flow/high perfusion pressure 21 Renal Regulation of Blood Pressure Regulation- Details  High tubular flow is sensed at the macula densa – – – Once these pumps are overwhelmed- the Na+ concentration inside the cell increases and osmotic gradient brings water molecules into the macula densa cells Cells “swollen” with H2O contain a “stretch-activated” channel that allows ATP to escape followed by conversion to adenosine- Adenosine (and/or ATP) signals decreased renin release, afferent arteriolar constriction, efferent arteriolar dilation Sources agree these transporters are in the tubular segment cells located between the end of the TAL and DT that lies adjacent to the afferent and efferent arterioles  Low flow through arterioles of renal corpuscle activates: – – – Nitric oxide synthase to produce Nitric Oxide (NO) which activates Gs proteins: cGMP activates protein kinase G inactivates myosin molecules via phosphorylation of regulatory light chain • Inactivated myosin molecules in vessel walls produces relaxation/dilation cAMP leads to increased release of renin  Renin secretion is coupled to the renal baroreceptor – – • Increasing perfusion pressure depolarizes the afferent arteriolar smooth muscle/JG cells • Ca++ influx inhibits renin secretion Decreased renal perfusion produces vasodilation and permits cAMP formation • cAMP formation increases renin secretio n Renin is inhibited by: – – Decreased sympathetic activity Angiotensin II increases intracellular Ca++ which reduces renin release 22 Renin  Renin is released in response to two stimuli : Low perfusion and low Na+ • Release stimulated by three mechanisms: 1. Central baroreceptors of aortic arch, carotid sinus stimulate SNS β-1 receptors on granular cells • Increases MAP • Activation of Autonomic pathways includes fibers that send signals to the hypothalamus to signal ADH release 2. Intrarenal baroreceptors of the JG granular cells • Assess perfusion pressure of blood 3. Macula densa • Senses Na+ concentration as part of the JG apparatus of tubuloglomerular feedback 23 Renal Control of BP  Renin-angiotensin-aldosterone system + ADH • RAS responds to low effective circulating volume • Renin is the protease that cleaves angiotensin • Angiotensin II: • Raises perfusion pressure and • Expands ECF by stimulating aldosterone production from the adrenal cortex • Aldosterone retains H2O while excreting K+ • Isotonic volume control • Water reabsorption with solute • ADH signaled by osmoreceptors and SNS • ADH controls osmolarity at the kidney • Regulates H2O reabsorption without solute • V1 effect is vasoconstriction; V2 is antidiuresis • Vasopressin is an effective treatment for severe hypotension- (vasoplegia - ACEIs) Renin-Angiotensin System & Stimulation of Aldosterone Angiotensin II – increases renal perfusion pressure and ECF volume • Affects kidneys, adrenal glands, heart and blood vessels, SNS, hypothalamus • Preferentially vasoconstricts efferent arteriole- decreases RBF, Maintains GFR • Decreases Kf (mesangial cells contract) • Stimulates thirst • Supplements the stimulus from low pressure baroreceptors to increase ADH secretion Aldosterone causes H2O retention and K+ excretion • Stimulates aldosterone secretion • A mineralcorticoid synthesized in the zona glomerulosa of adrenal cortex • Function- Na+ reabsorption (H2O retention) and K+ secretion • Cl- and H2O follow Na+ reabsorption- effect is to increase plasma volume • Causes of aldosterone secretion: • Activation of the RAS with production of Angiotensin II (most important) • Increased K+ plasma directly affects zona glomerulosa of adrenal cortex • Aldosterone is the primary regulator of ECF K+ 25 26