Physiology week 16 Renal 2 (volume/buffers)

Transcription

1 Physiology week 16 Renal 2 (volume/buffers) Defense of Tonicity and Volume Defense of tonicity Tonicity = osmolality of a solution relative to plasma Osmolality measures [ ] all particles in solution, where as tonicity measures only those particles capable of exerting osmotic force across cell membrane; therefore the effective osmolality isotonic = same osmolality as plasma hypertonic = greater osmolality than plasma hypotonic = lesser osmolality than plasma Total body osmolality is proportional to total body sodium and potassium and inversely proportional to TBW. Normal mosm/l Mediated by ADH and thirst. If osm then thirst and Vp secretion resulting in urinary loss free water If osm then thirst and Vp secretion resulting in renal reabsorption of free water in CDs/pyramids Osmolality determined by total body sodium and potassium divided by water Any alteration will affect tonicity When osmotic pressure of plasma rises, osmoreceptors in ant pituitary stimulate post pituitary to release ADH High tonicity stimulates vasopressin and vice versa ADH also released in response to decreased circulating volume All solutions initially iso-osmotic with plasma remain isotonic if not for diffusion some solutes into cells or metabolism 0.9% normal saline - remains isotonic 5% glucose - iso-osmolar initially BUT glucose metabolised so hypotonic Tonicity of physiological body fluids estimated as osmolality minus conc urea & glucose (ineffective solutes) Defense of volume Decr renal perfusion releases renin - enzmatically converts angiotensinogen to angiotensin I - converted to angiotensin II by ACE Volume of ECF determined by total amount of osmotically active solute. Sodium and chloride are the most abundant solutes. Changes in Cl occur secondary to changes in Na therefore Na balance is major influence on ECF volume. Low pressure receptors Reduced stretch of low pressure receptors causes afferent arteriolar vasoconstriction Pressure natriuresis Reduced blood pressure results in reduced GFR therefore less sodium is filtered. ADH and thirst ADH (vasopressin) volume control Increases permeability of CDs of kidney, so water enters hypertonic interstitium of renal pyramids Urine becomes concentrated and volume decreases Overall retention water in excess of solute osmotic pressure of body fluid decreases Without it urine hypotonic and volume increased, causing water loss osmolality of body fluids rise Decrease in volume causes increased secretion of ADH Volume stimuli override osmotic stimuli. Mechanism ADH binds to G-receptor V2 activates adenylate cyclase Incr IC camp migration of IC endosomes Water channels (Aquaporin 2) inserted in luminal membrane principal cells Incr water permeability of CD with incr water reabsorption Metabolism Rapidly inactivated mainly in liver and kidneys Biologic half life 18mins Effects on kidney develop rapidly, short duration 1

2 Stimuli affecting ADH secretion Increased secretion Incr plasma osmotic pressure Decr extracellular fluid volume Pain, emotion, stress, exercise Nausea and vomiting, standing Clofibrate, carbamazepine Angiotensin II Decreased secretion Decr effective osmotic pressure of plasma Incr extracellular fluid volume Alcohol Diabetes insipidus vasopressin deficiency or kidneys fail to respond to it SIADH causes dilution hyponatraemia and loss of salt in urine Angiotensin II Stimulates thirst and ADH secretion. Causes vasoconstriction Stimulates aldosterone secretion - incr tubular reabsorption sodium. ANP Causes natriuresis and diuresis ph ph inversely related to H + conc, defined as logarithm to base 10 of reciprocal of [H+] (negative log of H+) [H+] in arterial plasma is meq/l - negative logarithm of this is 7.4 decrease in ph of 1 unit represents tenfold increase [H+] Ka - equilibrium dissociation constant for dissociation of acid (HA) to produce H+ & anion A - pka is negative logarithm to base 10 of this dissociation constant - at ph equal to pka, the acid is 50% dissociated ie equal amount of HA & A Henderson-Hasselbalch equation Buffering capacity of a system greatest when amount of free anion equal to undissociated buffer so A/HA = 1 and log of 1 is 0, so ph = pk As long as ratio between bicarbonate and PCO2 remains at 20 then the ph is maintained Sources of hydrogen ions Amino acid metabolism in liver 50meq/day Amino acid metabolism yields NH4+ and HCO3- NH4+ is incorporated into urea, HCO3- buffers protons Especially sulphur containing amino acids and phosphorylated amino acids which yield H3PO4 Carbon dioxide and carbonic acid 12500meq/day Most CO2 is excreted by lungs. 2

3 Extra acid Lactic acid - Anerobic glycolysis Keto acids - Acetoacetic acid and beta hydroxybutyric acid from DKA Ingestion of acidifying salts - Calcium chloride plus failure of the kidney to excrete acid Buffers A mixture of weak acid & its conjugate base that attenuates change in H+ conc when strong acid or base is added to it. Any substance that can reversibly bind H +. Three main systems regulate H + concentration in body fluids: (1) chemical acid-base buffer systems of body fluids, prevent excessive changes in H + concentration Carbonic acid/bicarbonate system, plasma proteins, Hb (imidazole groups of histidine residues) (2) respiratory center, regulates removal of CO 2 (3) kidneys, regulate extracellular fluid H+ concentration through three mechanisms: (1) secretion H+, (2) reabsorption filtered HCO3-, (3) production new HCO3- Blood buffers Bicarbonate/carbonic acid Carbonic anhydrase required Present intracellulary - Red blood cells, Gastric parietal cells, Renal tubule cells Inhibited by - Cyanide, Azide, Sulphide, Sulphonamides Haemoglobin Six times the buffering capacity of plasma proteins Deoxygenated haemoglobin is a better buffer Imidazole groups of histidine residues Plasma proteins Interstitial fluid buffers Bicarbonate Intracellular fluid buffers Phosphate, Proteins, Hb Effect of adding strong acid to the blood Major buffer reactions are driven to left Blood levels of 3 buffer anions (Hb-, prot- & HCO3-) decreased Anions of added acid filtered into renal tubules (accompanied by cations, esp. sodium) Renal tubules replace sodium with H+ so reabsorb equimolar amounts of sodium & bicarbonate, thus conserving cations, eliminating acid & restoring supply of buffer anions to normal ph derangements Respiratory acidosis Rise in arterial pco2 which reduces HCO3-/PCO2 ratio with fall in ph. Retained CO2 equilibrates with carbonic acid, results in rise plasma H and bicarb Renal response: increased H actively secreted into PT, thick asc loop henle and DT, facilitates reabsorption of HCO3 by forming carbonic acid, which dissociates to CO2 and water extent determined by base excess Causes: reduced ventilation and removal CO2 - COPD, Hypoventilation Respiratory alkalosis Fall in pco2 accompanied by rise in ph Reduced CO2 equilibrates with carbonic acid and results in a fall in plasma hydrogen and bicarb Renal response: renal tubular hydrogen ion secretion decreases - bicarb loss/reduced plasma bicarb extent determined by base deficit Causes: increased ventilation and removal of CO2 - voluntary hyperventilation, altititude 3

4 Metabolic acidosis Fall in ph accompanied by fall in pco2 Ratio falls HCO3- may be lowered by accumulated acids eg DM, hypoxia (buffering) Carbonic acid formed and converted to water and CO2. Resp response: incr ventilation - CO2 removed (stimulated by incr H ion conc on chemoreceptors) extent determined by base deficit or negative base excess Renal response: renal tubular cells excrete excess H in exchange for Na anions that replace HCO3 filtered along with corresponding cations (mainly Na) (Buffering in urine gives greater capacity to this system (otherwise limiting ph 4.5) Causes: Incr anion gap (normochloraemic) DKA, AKA, lactic, CRF, ASA, methanol, ethylene glycol, starve Normal anion gap (hyperchloraemic) diarrhoea, RTA, carbonic anhydrase inhibitors, Addisons Metabolic alkalosis Rise in ph accompanied by rise in pco2. Increase HCO3- and incr ratio Removal acid/addition alkali results in rise in buffer anion levels. Resp response: hypoventilation elevates pco2 and bicarb Extent determined by base excess Causes: Prolonged vomiting; Ingestion of alkali Hydrogen secretion PCT and DCT Hydrogen ions enter luminal fluid via sodium/hydrogen exchanger Hydrogen originates from intracellular dissociation of carbonic acid H2CO3 Carbonic anhydrase catalyses formation of H2CO3, drugs that inhibit this reduce acid secretion in PT DCT and CD Hydrogen secretion independent of tubular sodium. Hydrogen is secreted by ATP driven proton pump. Pump activity incr by aldosterone. I cells (contain carbonic anhydrase and numerous tubulovesicular structures) secrete the acid Number of H+ pumps increased in acidosis Some H+ also secreted by H+ K+ ATPase Max H+ gradient against which transport mechanisms secrete H = urine ph of 4.5 (limiting ph). Normally reached in CD, as urine bufferred to enable more acid to be secreted. Factors that increase H+ secretion and HCO3- reabsorption in renal tubules PCO 2, H +, HCO 3 -, Extracellular fluid volume, Angiotensin II, Aldosterone, Hypokalemia Factors that decrease H+ secretion and HCO3- reabsorption in renal tubules PCO 2, H +, HCO 3 -, Extracellular fluid volume, Angiotensin II, Aldosterone, Hyperkalemia Renal acid secretion also affected by changes in: Carbonic anhydrase level Urine buffers Amount of acid secreted is limited by minimum ph of 4.5. Presence of buffers remove free hydrogen ions permitting more acid to be secreted. 4

5 Bicarbonate pk 6.1 Most secreted hydrogen in tubular fluid reacts with bicarbonate to form carbonic acid. Carbonic anhydrase is present in the brush border of the PCT and facilitates formation water and CO2. CO2 diffuses into the tubular cells, and is rehydrated back to carbonic acid. Carbonic acid dissociates making hydrogen available for the sodium/hydrogen exchanger. This mechanism effectively reabsorbs (though indirectly) filtered bicarbonate as sodium bicarbonate. Phosphate pk 6.8 H+ reaching DCT/CD reacts with dibasic phosphate (HPO42-) - form monobasic phosphate (H2PO4-) Ammonium pk 9.0 Tubular cells produce NH4+ via the formation of glutamate and alpha ketoglutarate. Non-ionic diffusion NH4+ enters PCT lumen and reabsorbed in thick ascending limb of loop of Henle In tubular cells, NH4+ is in equilibrium with NH3 but since pk is 9.0, the ratio of NH3 to NH4+ is 1:100 NH3 is lipid soluble and is able to enter the CD where it combines with hydrogen and is excreted. In chronic acidosis NH4+ secretion is increased ph of urine varies from 4.5 to 8 Definitions Anion gap difference between concs of cations other than Na+ and anions other than Cl- and bicarb in plasma. difference between unmeasured anions and unmeasured cations AG (meq/l) = ( Na+ + K+ ) - (Cl- + HCO3-) Normal - 7 to 17 meq/l Incr if: incr protein, PO42-/SO42-/organic acids; abnormal anion present (drugs); decr Ca/Mg Usually indicates metabolic acidosis - AKA/DKA, lactate, renal failure, salicylates, methanol, ethanol, paraldehyde, ethylene glycol, CO, cyanide, toluene, uraemia, iron/isoniazid, starvation Decr if: decr unmeasured anions (uncommon severe hypoalbuminaemia); incr unmeasured cations - high Ca/Mg, abnormal cations eg IgG (myeloma), lab error Standard bicarbonate not actual bicarb conc but what bicarb conc would be after elimination of any respiratory component Plasma bicarbonate conc in whole blood which has been 37oC with gas mixture with pco2 40 mmhg. A calculated parameter that reflects metabolic acid-base status of plasma if lung function was normal Indicated on Siggaard-Anderson curve nomogram by which CO2 titration line intersects bicarbonate scale on the pco2 = 40mmHg line Measure of alkali reserve of blood, except that it is measured by determining ph rather than total CO2 content of sample after equilibration. Buffer base equal to total number of buffer anions (prot-, HCO3-, Hb-) that can accept hydrogen ions in blood. Shown on Siggaard-Anderson nomogram curve by the point where CO2 calibration line of arterial blood sample intersects upper curved scale. Equal to total number buffer anions (esp prot-, HCO3-, & Hb-) that can accept H+ ions in blood. Normal value 48 meq/l. Base excess amount acid or base that would restore 1 litre blood to normal acid-base composition at pco2 of 40mmHg. Positive in alkalosis, negative in acidosis 5