Physio Reviewer Renal to Acid Base

RENAL 1 Functions of kidneys: • Excretory, regulatory, endocrine, metabolic Anatomy • Paired extraperitoneal organs that lie posteriorly • Divided into the cortex and medulla Nephron- functional unit of the kidney • Renal corpuscle/glomerulus o Glomerular capillaries- supplied by afferent arterioles; drained by efferent arterioles o Bowman’s capsule- visceral layer formed by podocytes; bowman’s space between the parietal and visceral layers o Mesangium- consists of mesangial cells and mesangial matrix; secrete EC matrix, prostaglandin and cytokines • Renal tubules o Proximal tubules, descending thin limb, loop of Henle (LH), ascending thin limb, ascending thick limb (TALH), distal tubules, collecting ducts (CD) • 2 types: o Cortical nephron  75%; located in the outer cortex  short LH  fxn: reabsorption and secretion  DOES NOT take part of hypertonic medullary interstitium o Juxtamedullary nephron  25%; lie deep in the cortex near the medulla  long LH that enter deep medulla  generates OSMOTIC gradient for reabsorption of water Macula densa • Monitors the composition of the fluid in the tubular lumen at the TALH Juxtaglomerular apparatus • Consists of macula densa, extraglomerular mesangial cells, juxtaglomerular cells • One of the components of tubuloglomerular feedback mechanism involved in autoregulation Capillary beds: • Glomerular capillaries o HIGH pressure where FLUID is filtered • Peritubular capillaries o LOW pressure where SOLUTES & FLUID are absorbed Vascular supply: • Arranged in series; separated by efferent arterioles • Efferent arterioles continue to the outer medulla to become: o Peritubular capillaries  Supply tubules of cortical nephrons o Vasa recta  Specialized peritubular capillaries that supply the LH of the juxtamedullary nephron

NICOLEs’  notes  

Urine Formation 3 processes: • Glomerular filtration o Ultrafiltration of the protein-free plasma o Movement of large volume of fluid: glomerular capillaries → Bowman’s space • Tubular reabsorption o Regulated transport of substance: tubular urine → back to capillary blood • Tubular secretion o Capillary blood → tubular urine 4 mechanisms: • Freely filtered not reabsorbed or secreted o Excretion rate = filtration rate o Creatinine • Freely filtered but partly reabsorbed back to the blood o Excretion < Filtration o Excretion rate = Filtration rate – reabsorption rate o Electrolytes • Freely filtered but all are reabsorbed o Nothing is excreted o Amino acids, glucose • Freely filtered not reabsorbed but secreted from capillary blood to renal tubules o Excretion rate = filtration rate + tubular secretion o Organic acids and bases Properties of Filtratition barrier: 3 major layers (same as glomerular capillaries): • Endothelial cells of the capillaries o Fenestrated  Freely permeable to water, small solutes (Na, urea, glucose)  IMPERMEABLE to RBC, WBC, platelets o Negatively-charged glycoprotein surface o Synthesize vasoactive substances  Dilator- NO  Constrictor- endothelin • Basement membrane o Prevent filtration of plasma protein o CHARGE-SELECTIVE FILTER- porous matrix of NEGATIVELY- charged protein o Gel-like structure of proteoglycans • Foot processes of podocytes o Long finger-like processes that completely encircle the outer surface of the capillaries o Interdigitates to cover the basement membrane o SIZE-SELECTIVE FILTER- separated by filtration slits that keeps proteins & macromolecules from entering the Bowman’s space Filtration of macromolecules • Determined by size and valence or charge

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• • •

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Neutral molecules with smaller radius- filtered freely Size of 20-42 A- depends on charge Positively-charged- easily filtered (remember negatively-charged glycoprotein on surface of BM + negative podocytes) Some low MW substances are bound to plasma protein- NOT freely filtered

Dynamics of Ultrafiltration: Net ultrafiltration pressure: Kf x (PGC – PBS -- πGC ) Determinants: • PGC o hydrostatic glomerular capillary pressure o glomerular capillary → Bowman’s space o primary means for GFR regulation • PBS o hydrostatic Bowman’s space pressure o opposes filtration • πGC o oncotic glomerular capillary pressure o opposes filtration • πBS o oncotic Bowman’s space pressure o nearly 0 because protein-free so no influence on filtration DECREASE GFR Physical Determinants ↓Kf →↓GFR ↑PBS → ↓GFR ↑πGC → ↓GFR ↓PGC → ↓GFR ↓APressure→ ↓GFR ↓REfferent→ ↓GFR ↑ RAfferent→ ↓GFR

Pathophysiologic/physiologic causes Renal disease, DM, HTN Urinary tract obstruction (stones) ↓ RBF, ↑ plasma proteins (look below) Small effect only due to autoreg ↓ angiotensin II (ACE inhibitors) ↑ sympathetic activity, vasoconstrictor hormones (NE, endothelin)

PGC Alterations: • changes to AFFERENT arteriolar resistance o ↓resistance → ↑PGC, ↑GFR o constant afferent: PGC ∝ efferent arteriolar resistance o constant efferent: PGC 1/∝ afferent arteriolar resistance o PGC x afferent = efferent (??) • changes to EFFERENT arteriolar resistance o ↓resistance → ↓PGC, ↓GFR o BIPHASIC EFFECT!! o Moderate vasoconstriction = ↑GFR o Severe vasoconstriction = ↑RBF; ↑filtration fraction; ↑πGC; ↓ net filtration pressure • changes to renal arteriolar pressure o ↑BP = ↑PGC o autoregulation maintains PGC and GFR at relatively constant values (80-180mmHg) o medullary BF • Lower blood flow in medulla by the vasa rectamaintain hyperosmolar environment in concentrated urine formation

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↑rate of Na filtered = ↑ O2 consumption

Autoregulation • RBF and GFR are maintained relatively constant as arterial BP is 80-180 mmHg • Achieved by changes in vascular resistance by afferent arteriole • Myogenic o Pressure-sensitive o Responds to changes in arterial pressure o ↑ arterial pressure → afferent arteriole stretches → smooth muscle contracts → ↑afferent arteriole resistance = offsets pressure increase o ↓ arterial pressure → ↓ stretch → renin release by JG cells → ↑BP • Tubuloglomerular Feedback o NaCl- dependent mechanism o Responds to changes in NaCl concentration o Ensure constant delivery of NaCl to the distal tubule o NaCl is sensed by macula densa of JG app o ↑ GFR → ↑ NaCl entry via Na-K-2Cl symporter → ↑ATP & adenosine → constrict → ↓ GFR o ↓ GFR → ↓ flow rate → ↑ reabsorption → ↓NaCl conc at MD cells → ↓ formation of ATP and adenosine → dilation of afferent Hormones that affect GFR & RBF: Stimulus Effect Vasoconstrictors Sympa ↓ ECFV Constrict afferent arterioles; enhance Na reabs Angiotensin ↓ ECFV Constrict aff and II eff arterioles; (↓BP, more effect on eff; ↓volume) aff protected by NO & prostaglandin Endothelin ↑stretch, Cpmstrict afferemt arterioles epi, A-II, bradykinin; ↓ ECFV Vasodilate PGE ↓ECFV; Dampen constrictor effect ↑shear of sympa & A-II stress , A-II Nitric oxide ↑ shear Counteract const. (EDNO/ by A-II, stress, EDRF) catecholamines bradykinin, Ach, ATP, histamine Bradykinin ↑ PGE; Stim. NO and PGE release ↓ACE Dopamine Inhibits renin sec. Natriuretic ↑ ECFV Dilate afferent peptides Constrict efferent

NICOLEs’  notes  

GFR

RBF

↓

↓

↓

↓

RENAL 2 Urinary Excretion = Glomerular Filtration- Tubular reabsorption + Tubular secretion I. Tubular Reabsorption • Passive o Diffusion o Facilitated diffusion  Channels- Na, K  Uniport- Glucose  Coupled: • Antiport- Na-H • Symport- Na-glucose • Solvent drag • Active o Primary- coupled to Na-K ATPase o Secondary- coupled to indirect energy source such as ion gradient (glucose) o Endocytosis of proteins • Transcellular route- through cellular membrane • Paracellular route- through junctional and intercellular space • Ultrafiltration (bulk flow)- mediated by hydrostatic and oncotic forces Proximal Tubule (PT) • Reabsorbs 2/3 (67%) of fluid filtered by glomeruli • ISOMOTIC volume reabsorption • Reabsorbs solute (glucose, aa) by 2° active transport driven by Na-cotransports • Protons are ACTIVELY SECRETED via Na-H antiport st • 1 half: H, glucose, Na o CO2 + H2O → H + HCO3 o H exits with Na entering via Na-H antiporter o Na back to blood via Na-K ATPase o HCO3 enters blood with Na Na & glucose both enter via 2° active transport o Na to blood via Na-K ATPase o Glucose to blood passive diffusion nd 2 half: Na, Cl o H-anion dissociates to H and anion o Na-H antiporter o Anion brought out and recycled with H o Anion exit coupled with Cl entering the cell o Cl undergoes paracellular transport creating a + lumen so Na will be repelled and reabsorbed paracellularly also o

↓

↓

NC / ↑

↑

↑

↑

↑

↑

↑ ↑

↑ NC

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Loop of Henle (LH) • Thin descending limb of LH (dLH) o Has AQUAPORIN-1 water channels o Very permeable to water, less permeable to solutes (reabsorbs 15% water) • Thin ascending limb of LH o Passively reabsorb NaCl; impermeable to H2O

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Thick ascending limb of LH (TALH) o Reabsorbs 25% filtered Na,Cl,K by Na-K-2Cl co-transporter  Inhibited by FUROSEMIDE (loop) o Impermeable to water o Reabsorb Mg, Ca, K, HCO3- paracellularly o Reabsorb Na and secrete H- Na-H antiporter o Tubular fluid becomes diluted or HYPOSMOTIC o DILUTING SEGMENT

Distal Convoluted Tubule (DCT) • Reabsorbs Na, K, Cl • Impermeable to water and urea → HYPOOSMOTIC • Reabsorbs 5% NaCl via Na-Cl cotransporters o Inhibited by THIAZIDE diuretic Late Distal Tubule & Cortical Collecting Tubule • Reabsorbs 3-18% filtered H2O with ADH control • Impermeable to urea • 2 cell types o Principal cells  Na & H2O reabsorption creating a – lumen so K is secreted (due to channels)  Aldosterone- ↑ Na channel activity  Acted on by AMILORIDE (block Na channels) and SPIRINOLACTONE (aldosterone competitive antagonist) o Intercalated cells  Reabsorb K ions and secrete H using H-ATPase (1° active)  Acid base regulation Medullary Collecting Duct • Reabsorbs BNP natriuresis o Sympathetic

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Constricting renal arterioles → ↓GFR → ↓ Na & H2O excretion  ↑ Na & H2O reabsorption  ↑ renin release and A-II → tubular reabsorption → ↓ Na excretion Urodilantin  Not present in systemic circulation  MORE POTENT than ANP  Inhibit NaCl & H2O reabsorption in CD Dopamine  Opposite NE and Epi  Directly inhibits NaCl & H2O reabsorption in PT Uroguanylin  Produced by neuroendocrine cells in the intestine in response to ORAL ingestion of NaCl  inhibit NaCl & H2O reabsorption Adrenomedullin  Induces a marked diuresis 

o

o

o

o

HORMONE

STIMULUS

Sympathetic nerves A-II

↓ ECV

Aldosterone

↑ A-II, ↑ K

ADH Dopamine ANP Urodilantin Uroguanylin

↑Posm, ECV ↑ ECV ↑ ECV ↑ ECV ORAL ingestion of NaCl HTN, CHF

Adrenomedulin

↑ renin

SITE OF ACTION PT, TALH, DT/CD PT, TALH, DT/CD TALH, DT/CD DT/CD PT CD CD PT, CD

EFFECT ON TRANSPORT ↑ NaCl and H2O reabsorption

↓ NaCl and H2O reabsorption

COUNTERCURRENT MECHANISM • interaction between loop of Henle (multiplier) and vasa recta (exchanger) • goal- maintain hyperosmotic interstitium • dissipation of medullary osmotic gradient is prevented due to vasa recta equilibrating with interstitial fluid • Steps in countercurrent multiplication o Na is pumped out of the TALH with max gradient of 200 mOsm/L – single effect o Water flows out of the descending tubule – osmolality rises to 400 mOsm/L o Osmolality equilibrates between tubule and interstitium o Fluid shifts • As the loop becomes longer, the greater is the longitudinal gradient ADH • • • • •

Autoregulation of RBF and GFR • Keep RBF and GFR constant through 90-180mmHg • Precise control of renal excretion of water & solutes • 2 mechanisms: • Myogenic mechanism o Pressure-sensitive mechanism o Responds to changes in arterial BP (stretch) o Prevents overdistention of vessel o Q= ΔP/R • Tubuloglomerular feedback mechanism o NaCl concentration-dependent o ↑GFR → ↑NaCl conc sensed by macula densa of JG apparatus → afferent arteriole increase resistance → normal RBF and GFR Urine Concentration and Dilution • Countercurrent multipliers o Loops of Henle o Establish interstitial osmotic gradient that increases from cortex to tip of papilla

NICOLEs’  notes  

Countercurrent exchangers o Vasa recta o Maintain the gradient • ADH function o Alter permeability of the late distal tubule and collecting ducts to water o Concentrates urine bec H2O is reabsorbed Obligatory Urine volume • Max concentration- 1200 – 1400 mOsm/L • 600mOsm/day / 1400 mOsm/L= 0.444 L/day obligatory water loss •

Urea • • • • • • • • •

Secreted from the posterior pituitary Conserve water to decrease urine output Binds to receptors in the distal and collecting tubules Stimulates insertion of water channels/ aquaporins to transport solute-free water back to the blood ↓ plasma osmolality and ↑ urine osmolality

from protein breakdown of liver interstitium back to loop of Henle (urea recycling) major osmole in the urine freely filtered in the glomerulus 50% reabsorbed in proximal tubule thin loops of henle- recycled; enters passively TALH- impermeable Cortical collecting ducts- impermeable Medullary collecting ducts- reabsorbed due to ADH

COUNTERCURRENT EXCHANGER • Vasa recta- critical to the maintenance of the osmotic gradient • Specialized hairpin structure- allows blood to reach inner medulla • Highly permeable to water and solutes • Provides nutrients and O2 to the medullary tissues • Maintain medullary interstitial gradients is flow dependent

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Formation of CONCENTRATED urine • At TALH- active reabsorption of NaCl accumulates in the medullary interstitium = ↑ osmolality • Filtrate becomes diluted at DCT and CCT • WITH ADH- ↑H2O reabsorption = ↑tubular osmolality • Interstitial fluid osmolality progressively increases from corticomedullary jxn to papilla • + ADH- ↑urea permeability = ↑ interstitial osmolality • can be as high as 1200 mOsm/kg; 0.5 L/day Formation of DILUTED urine • no ADH secretion making the collecting ducts impermeable to water • no water reabsorption occurs after the active reabsorption of Na in TALH • can be as low as 50 mOsm/kg; 18 L/day Free water clearance • ability of the kidneys to generate solute-free water • diluted urine- solute-free water is excreted • concentrated urine- solute-free water is returned • factors for excretion: o absent ADH o normally functioning tubular segments  TALH- most important o reduced delivery of tubular fluid to ascending thin LH, TALH, DT, CD impairs the ability of kidneys to maximally excrete solute-free water Factors needed to excrete maximally-concentrated urine • maximal ADH • normal NaCl tubular reabsorption o TALH- most important • adequate delivery of tubular fluid • hyperosmotic medullary interstitium maintained by NaCl reabsorption of Henle’s loop and urea accum. Factors that modulate urinary concentration and dilution • Osmotic gradient o Length of LH  Longer loop- more concentrated o Rate of active NaCl reabsorption in TALH  ↑ luminal Na delivery to TALH = ↑ Na reabsorption  High NaK ATP pump - ↑ NaCl reabsorption • Protein content of diet o ↑ protein content = ↑ urea accumulation = ↑concentrating ability • Medullary blood flow o ↓ blood flow = ↑ high interstitial osmolality o ↑ blood flow = ↓ concentrating ability • Osmotic permeability of CT and CD to water o ↑AVP = ↑ H2O permeability = ↑ H2O reabsorption • Luminal flow in LH and CD

NICOLEs’  notes  

↑ flow = ↓ countercurrent multiplier efficiency = ↓interstitium osmolality = ↑ conc Pathophysiology o Diabetic insipidus reduced AVP levels or responsiveness to AVP o

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Micturition • Urinary bladder empties when it is filled • Sympathetic Innervation o T10-L2 o Hypogastric nerves o α-adrenergic receptors in bladder neck o Bladder storage, closure of urethra • Parasympathetic Innervation o S2-S4 o Muscarinic o Sustained bladder contraction • Somatic Innervation o Motor S2-S4 o Pudendal nerves o Controls voluntary muscles of external sphincter Micturition Reflex • Storage Phase o Filling of bladder triggers micturition reflex o (-) parasympathetic o (+) pudendal nerves o relaxation of detrussor muscle o contraction of urethral sphincter • Voiding Phase o Voluntary relaxation of external urethral sphincter o Relaxation of internal urethral sphincter o (+) parasympathetic o (-) pudendal nerves o contraction of detrussor muscle o relaxation of urethral sphincter • Urge to void= 150 mL • Sensation of bladder fullness= 400-500 mL

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FLUID AND ELECTROLYTES • Osmolality = water balance • ECF volume = sodium balance • Osmolarity = solutes per liter • Osmolality = solutes per kg (not affected by temperature) • 0.6 x BW = adult males = total body water o 2/3s intracellular o 1/3s extracellular  ¼ of ECF = plasma volume  ¾ of ECF = interstitial fluid • Major Cations and Anions in ECF o Na+ (145) o Cl- (105) o HCO3- (25) o pH= 7.4 • ICF o K+ (150) o Phosphorus (100) o pH=7.1 • More protein in plasma than interstitial fluid • More water in thin than fat people • Inc Hypertonic solution (10% NaCl) o Inc osmolality o Dec ICF volume o Inc ECF volume o Inc plasma Na+ o Inc urine Na+ • Inc Water (hypotonic) o Dec osmolality o Dec plasma Na+ o Inc ECF and ICF volume o Inc urine Na+ • Inc Isotonic (0.9% NaCl) o No change in osmolality o Inc ECF volume only o Inc urine Na+ • Starling’s forces o Filtration and reabsorption  Filtration = algebraic sum (+) = net force at arterial end  Absorption = (-) = net force at venous end o Edema, nephrotic syndrome, CHF • Maximally concentrated urine = 1200 mOsm/kg H2O ; 500 ml/24 hours • Total osmolality = effective + ineffective osmoles • Effective osmole = cannot cross cell membrane; restricted to ECF only o Sodium, glucose, mannitol o Affects total osmolality and tonicity • Ineffective osmoles o Crosses freely o Found in both compartments o Total osmolality not tonicity o Cannot affect water shifts o Urea, ethanol, methanol o Urea in blood = ineffective osmole

NICOLEs’  notes  

Urea in urine = effective osmole = keeps medullary interstitium hyperosmotic Total osmolality = 2 Na + (Glucose/18) + (BUN /2.8) + (every solute/mol wt) Estimation of osmolality = 2 x (plasma Na) Control of ECF osmolality o Osmoreceptor ADH system  High plasma osmolality  inc ADH  dec UO, perspiration; inc water reabsorption, vasoconstriction, BP  to dec plasma osmolality  Low plasma osmolality  dec ADH o Thirst mechanism  Respond only to effective osmoles  Inc plasma osmolality  thirst center stmulation  inc water intake  Inc plasma osmolality  excretion of hyperosmotic urine   to dec plasma osmolality  Set point = 295 mOsm • Because kidneys cannot concentrate urine greater than 1200 mOsm Threshold o If below 280 mOsm/ kg water = no ADH release o If > 280 = ADH is released o Direct linear relationship o Steep = minute changes can lead to response o Change of 3-5% in setpoint (275-290 mOsm)  ADH release Baroreceptors o Low pressure receptors = pulmonary vasculature = responds to high volume o High pressure = carotid sinus and aorta = responds to high pressure o 5-10% drop in BP = ADH release Actions of ADH: o Inc permeability of CD to water o Inc permeability of medullary portion of CD to urea o ADH stimulates reabsorption of NaCl by TALH, DT and CD Change in plasma osmolality is more potent stimulator of ADH secretion than change in blood volume or pressure (+) water balance = low osmolality = low Na (-) water balance = high osmolality = high sodium (+) na balance = hypervolemia/ volume expansion (-) na balance = hypovolemia = volume depletion Where sodium goes, water follows Effective circulating volume is directly related to: o ECF volume o Arterial BP o CO Volume sensors: o

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Low pressure = responds to fullness/ stretch  ANP, BNP o High pressure – responds to changes in pressure  Carotid sinus, aortic arch, JG apparatus of kidneys in afferent arteriole Signals of ECF volume and renal NaCl excretion o RAAS – JG cells release renin o Sympathetic NS  afferent > efferent vasoconstriction  dec capillary hydrostatic pressure  dec GFR  Dec GFR  Inc renin, nacl reabsorption in PT, TALH, DT and CD o ANP – opposite of RAAS and SNS  Inc GFR  Dec renin, aldosterone, sodium and water reabsorption in CD  Dec ADH effect on CD Euvolemia o CD is main segment where Na reabsorption is adjusted o CD determines amt of sodium that will be excreted in urine o Operates on glomerulotubular mechanism o Normal sodium excretion = 1% Hypovolemia o Inc RAAS and SNS activity o Dec GFR o Inc na reabsorption in PT and CD o Dec renal na excretion = 0% Hypervolemia o Dec RAAS and SNS o Inc ANP, urodilatin from DT o Inhibit ADH o Dec renin dec angiotensin 2 o Inc renal sodium excretion = 6% o

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•

• • • • •

•

•

•

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• Osm Regulation Stimulus

Plasma osmolality

Sensors

Hypothalamic osmoreceptors

Effectors

Response

ADH Thirst Urine osmolality and intake (thirst)

POTASSIUM • Major intracellular cation • Important for repolarization

NICOLEs’  notes  

Volume Regulation Effective circulating volume HIGH and LOW pressure baroreceptors: Carotid sinus Afferent arteriole Atria RAAS SNS ANP ADH Urine Na excretion

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•

•

•

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Dec K = difficult to stimulate Inc K = inactivation of fast sodium channels PT = passive K absorption TALH = recycles K back into lumen DT o Principal cell = K secretion o Intercalated cell = K absorption Physiologic factors: o Epinephrine  Alpha receptors = K release  Beta receptors = K uptake o Insulin – major regulator of plasma K level o Aldosterone - K excretion Pathophysiologic factors: o Acid base balance  Low pH  low K uptake  low intracellular K and displace K for H+  K exits o Inc plasma osmolality  cell shrinks  inc intracellular K  K exits o Cell lysis  inc K in ECF o Exercise  inc K in ECF  Walking = inc by 0.3 mEqs/ L  Vigorous = inc up to 2 mEqs/ L Drugs that induce hyperK o Dietary supplement o Ace inhibitor o K sparing diuretic – spirinolactone o Heparin Acidosis = K efflux Alkalosis = K influx Inc plasma K  inc K secretion Aldosterone  inc NaKATPase in basolateral membrane  K secretion o Inc aldosterone  in NaKATPase  K inside, sodium outside  inc ENaC, inc SGK  inc CAP  K permeability to lumen  K secretion Inc tubular flow rate  inc K secretion o Inc flow  cilia bends  activation of PKD1/ PKD2 and calcium entry  calcium influx activates MAXI-K  K secretion o Inc flow  Na influx Inc glucocorticoids  inc GFR, K secretion ENaC – amiloride sensitive epithelial sodium channel o Sodium goes in/ reabsorbed  lumen becomes negative o K is secreted by ROMK and MAXI-K to make lumen (+) – electrochemical gradient o Amiloride inhibits ENaC ROMK channel o Low conductance o Basal K secretion MAXI-K o High conductance o Calcium activated o Flow stimulated K secretion Acute acidosis  dec K secretion

 

• •

Chronic acidosis  inc K secretion Low ECV  inc aldosterone  inc K excretion o

CALCIUM • Bone formation • Regulators: o PTH  inc plasma Ca = bone resorption o Calcitriol  inc plasma Ca = from kidney : activated form of VitD  Inc calcium absorption in gut o Calcitonin  dec plasma Ca = bone formation • Inc plasma Ca  inc calcitonin • Dec plasma Ca  inc PTH • PT = transcellular (20%) and paracellular (20%) • TALH no paracellular – calcium is not reabsorbed by solvent drag because TALH is impermeable to water o 20% transcellular • DT = active transport Ca reabsorption o Exclusively transcellular o No paracellular in DT and TALH o Ca enters through Ca permeable epithelial channel (TRPV5/6) o Calcium inside binds to calbindin  calbindin-Ca complex  deliver Ca to basolateral membrane o At basolateral membrane  calcium is extruded via Ca-ATPase (PMCa1b) or 3Na1Ca antiporter (NCX1) Phosphate • Inc excretion o inc PTH o Phosphate loading o Volume expansion o Acidosis o Glucocorticoids • Dec excretion o Dec PTH o P depletion o Volume contraction o Alkalosis o GH • Calcitonin o Major stimulus – hypercalcemia  inc bone formation  dec bone resorption  minor effect on kidney and GIT  overall effect: dec calcium • PTH, calcitonin, calcitriol  inhibits Ca excretion • Dec plasma Ca  inc PTH  inc P excretion and dec Ca excretion via kidneys • Inc plasma Ca  inc calcitonin  inc P excretion and dec Ca excretion via kidneys • PT = mainly transcellular o Uptake via Na-P symporter (NPT1, NPT2, NPT3)  NPT1 = 2Na-1P

NICOLEs’  notes  

 NPT 2 and 3 = 3Na – 1P  NPT 2 is most important Inorganic phosphate exits basolateral membrane using inorganic phosphate anion antiporter

ACID-BASE PHYSIOLOGY • Acid – proton donor • Base – proton acceptor • Volatile acids – CO2, ketones o Excreted by lungs • Non-volatile acids/ fixed/ metabolic acid – lactic acid o Excreted by kidney • Normal blood pH = 7.35-7.45 • Low pH = acidosis • High pH = alkalosis • Acidosis o Decrease in pH o Dec base or inc acid = dec pH = inc H+ concentration o Inc pCO2, dec HCO3 • Alkalosis o Inc in pH o Dec pCO2, inc HCO3 • Compensation o There is return to normal blood pH o 20:1 ratio (HCO3/ pCO2) • Acid base balance • Buffer – ability to minimize changes in pH • pH – expression of H+ concentration o varies inversely with H+ concentration o low pH = high H+ Bicarbonate buffer • pKa = 6.1 • most important buffer in ECF because of high concentration • can maintain pCO2 at constant level Phosphate buffer • pKa = 6.8 o not far from 7.4 o better chemical buffer in a closed system than bicarbonate • but with low plasma concentration • important in renal tubular fluids • impt in ICF where phosphate is abundant Protein buffer • most powerful buffer • most plentiful in the body, pK of proteins are not far from 7.4 • with dissociated carboxyl groups on acidic amino acids = multiple negative charges bone buffers • calcium bicarbonate • for prolonged metabolic acid-base disorders

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Ammonia = NH3:H = 1:1 o More important quantitatively o Urinary H+ excretion (2/3 of excreted H+ due to ammonia) o Most acidic region = CD o Ammonium formation in PT o Ammonium reabsorption in TALH to prevent loss of NH4 o Ammonium trapping in CD o Dec pH  inc H+ secretion  inc NH4 production o Inc pCO2  inc H+ secretion  inc NH4 production o Dec K  in renal ammonia production  inc H+ secretion in exchange for K absorption o Aldosterone  H+ secretion and Na absorption Condition Etiology Primary Compensatory biochemica mechanism l alteration Respi Impaired respi Inc pCO2 Intracellular acidosis drive (narcotics, buffers  RBC CNS lesion) generate HCO3 b exchanging Chest wall Na, K ions with disorder (burns, H+ (acute) scoliosis) Increased renal Respi muscle acid excretion weakness  inc synthesis (spinal cord of HCO3 injury, severe (chronic) hypoK) •

TIME TO COMPENSATE • chemical buffers = seconds • respiratory = mins to hours • renal = hours to days Intracellular buffers • organic and inorganic phosphates • hemoglobin o major buffer for H+ produced in RBC  deoxyHgb more powerful than oxyHgb  oxy unloading  inc CO2 carriage (Haldane effect)  chloride shift – chloride goes in RBC, hco3 goes out to plasma o 6x more impt quantitatively than plasma proteins  Concentration is twice as much  Each hgb molecule = 3x more histidine residues than average plasma protein • Imidazole group = can provide buffering capacity at physiologic pH (pK=6.8) Isohydric principle = any condition that causes H+ concentration to change  all buffer systems change at the same time  buffer system buffers each other by shifting H+ from one to another buffer system • Studying the behavior of one buffer system is adequate Renal regulation of acid base balance: • H+ ion secretion  excretion of H+ as titrable acid (H2PO4-); excretion of H+ as NH4+ • Bicarbonate reabsorption • Production of new bicarbonate ions H+ secretion in PT is responsible for 90% of filtered bicarbonate • Na-H linked transport system (Na-H antiporter)  influx of Na  H+ secretion to lumen • Presence of carbonic anhydrase on brush border of PT  reabsorption of HCO3

Airway obstruction (laryngospasm)

Respi alkalosis

Pulmonary disorders (COPD) Hypoxemia  hyperventilation

Dec pCO2

DT • •

No carbonic anhydrase H+ secreted is mostly buffered by phosphate buffer o Occurs in intercalated cells o HATPase pump are responsible for movement of H+ ions into lumen o Maximally acidic urine production

Urine buffers • Phosphate buffers o Depends on phosphate intake o PO4:H ratio = 5:4 o Cannot increase in response to acid load o Little regulation of acid excretion

NICOLEs’  notes  

Metaboli c acidosis

Inc anion gap (ketoacidosis, uremia)

Metaboli c alkalosis

Normal anion gap (GI loss of HCO3, exogenous administration of chloride) Loss of GI secretions (vomiting)

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Dec HCO3

Reduce HCO3 production in RBC Decreased renal acid excretion  decrease plasma HCO3 Increase serum HCO3 levels Hyperventilatio n to dec pCO2 Inc urinary excretion of H+

Inc HCO3

Dec HCO3 levels Hypoventilation

 

Diuretics  bicarbonate rich fluid in ECF  contraction alkalosis

to inc pCO2 Inc excretion of HCO3

Rapid correction of chronic hypercapnea Inc mineralocorticoi d activity Severe hypoK ANION GAP = Na – (Cl + HCO3) • Normal = 12+- 4 mEq/L (8-12) • Law of electroneutrality o Total cation = total anion • UA – UC = anion gap • For differential diagnosis of metabolic acidosis Normal anion gap metabolic acidosis • Dec HCO3  inc Cl to compensate normal AG o Hyperchloremic acidosis o Isotonic solution infusion o Diarrhea = alkaline pH of stool = normal AG o Acetazolamide = carbonic anhydrase inhibitor = low HCO3 absorption = normal AG High anion gap metabolic acidosis • Excess acid • If non-chloride acid is introduced • Dec HCO3  Cl no change  high AG • Hypertonic solution infusion • Methanol, uremia, DKA, paraldehyde, ischemia (lactic acidosis), isoniazid, ethanol, salicylates Parameters pH pCO2 HCO3 pO2

Normal Values 7.35-7.45 35-45 22-26 80-100

PaO2 changes with age • Corrected PaO2 = 80 minus age in years above 60 AaDO2 – difference between alveolar O2 (PAO2) and arterial O2 (PaO2) • Inc AaDO2 = abnormal O2 exchange • Normal = less than 15 mmHg • Value increases normally approximates 3 mmHg per decade of life • Less than 25 mmHg is considered the upper limit of normal AaDO2

NICOLEs’  notes  

UST  FMS  2017