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Renal Physiology (Regulation of EXTRACELLULAR FLUID Volume (Overview of…

- - - - decrease in ECV sensed due to decreased cardiac output, effector signal sent to kidneys -> salt and water retantion
      - Increase in intravascular volume, but retention could go to an extent such that resultant increase in intravascular P may force fluid out of intravascular space
      - Can lead to peripheral edema and life-threatening pulmonary edema
      - In this case, ineffective circulating vol associated with increase in ECF and intravascular vol
    - - Has ascites, ECF therefore increased
      - Due to cirrhotic liver impeding blood flow through portal vein, fluid accumulate in splanchnic venous circulation, intravascular vol therefore increased
      - Cirrhotic patient have multiple arteriovenous fistulas (blood shunt from arterial to venous circulation, bypass capillary beds), and in response, cardiac output is increased
      - Thus has increased ECF, intravascular vol and cardiac output, but despite this, tissues still not adequately perfused
      - fluid pooled in peritoneal cavity and splanchnic circulation does not effectively perfuse tissues, shunted blood too
      - Patient also has marked peripheral vasodilation and low BP, and when body sense decrease ECV, kidneys retain salt and waterm which leads to further increase in ascitic fluid vol.
  - - - low P side of circulatory system, has high capacitance
      - Changes in wall tension in this side determined primarily by changes in blood vol
      - Specialized nerve endings located in atria and large intrathoracic veins, stretching cause increase receptor discharge, which are carried to medullary cardiavascular centres via afferent fibers in vagus nerves
    - - High pressure side, respond primarily to changes in BP
      - located in aortic arch and carotid sinus
      - stretching increase receptor discharge, conducted to medullary cardiovascular centers via vagus and glossopharyngeal nerves
    - - also respond to changes in pressure
      - Located in vascular pole of glomerulus, where the thick ascending limb returns to glomerulus
      - Specialized cells of TAL (macula densa) are in close proximity to afferent and efferent arterioles. Granular cells of afferent and efferent arterioles are modified smooth muscle cells that synthesize and secrete renin
      - decrease in afferent arteriole tension (from decrease BP) stimulate renin secretion by granular cells, increased delivery of NaCl and fluid to macula dense also lead to increased afferent arteriolar resistance (tubuloglomerular feedback)
  - - - impulses from volume sensors integrated in medullary cardiovascular centers
      - when discharge from volume sensors increased (ECFV expansion), renal sympathetic nerve activity decreased
      - This nerve innervate afferent and efferent arterioles
      - In ECFV contraction, renal sympathetic nerve activity enhanced -> increased conc of circulating catecholamines -> three main effects
        
        Activation of a-adrenergic receptors that constricts afferent and efferent arterioles
        
        as vasoconstriction is more pronounced in afferent arteriole, PGC decreases, GFR falls, decrease filtered load of Na
        
        also stimulates NaCl reabsorption by nephron (most prominant in PCT)
        
        Activation of B-adrenergic receptors stimulate renin release from afferent and efferent arterioles
        
        RAAS (three regulators of renin secretion: sympa, afferent arteriole P and delivery of NaCl to macula dense)
        
        during volume contraction, less NaCl delivered to macula densa due to decrease in GFR -> renin secretion stimulated
        
        ANG II: stimulates ADH secretion and thirst, Na reabsorption in PCT by increasing apical Na+/H+ exchange, maintaining ECFV and arterial BP
        
        also stimulate aldosterone secretion by zona glomerulosa of adrenal crotex (renin being most impt regulator despite others such as plasma [Na], [K], ACTH and ANP)
        
        Aldosterone
        
        bind to cytosolic receptor (freely permeable through cell membrane), hormone receptor complex enter nucleus and activate transcription of mRNA that encode for proteins involved in Na reabsorption
        
        Increase Na entry into principal cells through ENaC, and increased exit of Na across basolateral membrane through enhanced Na-K-ATPase activity
        
        As Na is a cation, lumen negative potential created -> K goes down gradient out of cell through ROMK
        
        overall thus stimulate reabsorbtion of NaCl by CD, Na excretion vary inversely with aldosterone levels
        
        Antrial Natriuretic Peptide (ANP)
        
        synthesized and released by atrial myocytes
        
        released in response to atrial distension (in vol expansion)
        
        effects antagonize RAAS and increase excretion of NaCl and water by kidneys
        
        Specific actions: vasodilation of afferent and vasoconstriction of efferent arterioles of kidney, inhibit renin secretion, inhibit aldosterone secretion, inhibit NaCl reabsorption by CD and inhibition of secretion and actions of ADH
  - - - autoregulation
        
        despite this, small perturbations do occur, but must be accompanied by parallel changes in Na reabsorption or dramatic changes in Na excretion will occur
        
        GFR increase, na reabsorption increase -> glomerulotubular balance
      - Loop of henle and DCT ablt to alter reabsorption in response to alterations in Na delivery -> increase Na in these segments will lead to icnrease Na reabsorption
    - - However, in pathological conditions, changes in GFR are more pronounced and play a more impt role in regulation of Na excretion and maintenance of ECFV
        
        regulation of Na excretion during Vol expansion
        
        signals to kidneys
        
        increase ANP
        decrease renal sympathetic nerve activity, ADH and renin secretion
        
        Response by kidneys
        
        increase GFR -> decrease Na reabsorption by PCT (from decrease sympathetic nerve activity) -> increased FLNa -> decrease Na reabsorption at PCT (from decreased sympathetic nerve activity and Ang II) -> increase Na delivery to CD -> decrease Na reabsorption by CD -> increase excretion of water to maintain constant body fluid osmolality
        
        Regulation during volume contraction
        
        signal to kidneys
        
        Decrease ANP
        increase renal sympa nerve activity, renin and ADH secretion
        
        Response by kidneys
        
        decrease GFR -> decreased FLNa -> increased Na reabsorption by PCT -> decreased Na delivery to CD -> increased Na reabsorption by CD (from aldosterone) -> increased water reabsorption by CD
- - - - Oxidation of sulfhydryl groups of cystine and methionine to form H2SO4
      - Hydrolysis of phosphoproteins to form H3PO4
      - Incomplete degradation of carbohydrates, fats and proteins to organic acids ( B-hydroxybutyric acid and lactic acid)
      - Called fixed acid, daily acid load is excreted by kidneys to keep body in zero H+ balance
  - - - Hemoglobin, other proteins, phosphate compounds, bone and bicarb (most impt)
      - Carbonic acid dissociates rapidly to yield H+ and HCO3-, conversion of carbonic acid to water and CO2 is slow unless catalyzed by CA (in erythrocytes and proximal brush border of kidney)
      - Dissolved CO2 is in equilibrium w gaseous CO2 which is excreted via lungs
      - Lungs' ability to remove or retain CO2 by controlling ventilation and kidney to change bicarb conc increases power of carbonic acid system to buffer pH changes
      - Bicarb loss in titration of acids must be regenerated by kidney to maintain normal acid-base balance
        
        note that addition of H+ to the system is same as removal of bicarb
  - - - H+ secretion (linked to Na reabsorption)
        
        w vol depletion, Na reabsorption stimulated, promote H+ secretion and thus bicarb reabsorption
      - Cl- depletion is an accompaniment of vol depletion, when Cl is unavailable for reabsorption w Na, Na:H exchange must substitute
      - Any condition that raise intracellular H+ will stimulate bicarb reabsorption (e.g. acidosis)
      - Hypokalemia: K leaks out of cells and H+ enters in exchange to maintain electrical neutrality, this rise in intracellular H+ augments bicarb reabsorption
      - Hypercapnia -> increased dissociation to H+ and HCO3- inside cell, makes more H+ available to promote HCO3- reclamation
    - - Reformation of lost bicarb in buffering of acid
      - H+ generated within tubular cell via similar cycle to PCT, H+ then excreted into lumen by an energy requiring proton pump or energy requiring H-K exchanger in intercalated cells of CD.
      - In some segments, this is promoted by -ve lumen charge established by Na reabsorption by principal cells, but proton pump is primary essential factor
      - secreted H+
        
        combines with NH3, formed from glutamine in PCT and freely diffusable across cell membranes, to form NH4+, which is charged, trapped in lumen and excreted
        
        Combine with non-ammonia buffers and is excreted. Amt of buffer formed can be measured by titrating urine from its native pH to pH of plasma (7.40), by convention, this subset of secreted H+ is called titratable acid
        
        principle constituent is filtered HPO42- which accepts H+ to form H2PO4-
        
        Combines with remaining HCO3- that has not been reclaimed in PCT to form H2CO3, which proceeds slowly since CA is not present. HCO3- and CO2 are excreted in urine
        
        Small fraction of secreted H+ remains free in lumen, causing urine pH to be acidic (around 4.8 and 6.0)
        
        When an excess of HCO3- is present, net excretion of HCO3- via luminal Cl: HCO3- exchange may occur
      - Every H+ secreted, a bicarb is returned to the body, any bicard lost in urine represents a net gain of H+ in body
        
        majority of H+ secretion goes into reabsorption of filtered bicarb, with some going into acidification of phosphate and ammonia buffer, with a negligible amt in acidic urine pH
    - - Distal proton pump is the primary determinant of H+ secretion, in the cortial CD, H+ is also voltage dependent
      - Proton secretion increase if tubular lumen is made more -ve by augmented Na Reabsorption, which will occur when distal Na delivery is increased by a high salt diet, or proximally acting diuretics or aldosterone stimulate Na reabsorption
      - Blocking Na reabsorption in this segment (K+ sparring diuretics) will impair proton secretion
      - Excess mineralocorticoid effect stimulates while mineralocorticoild lack decreases H+ excretion
      - Acidosis also increase distal acid excretion
  - - - Partly corrected through buffering
        
        Process begins at once, but may take 6 hours to reach completion
        
        When protons are added, immediately titrate NaHCO3 in plasma, gradually, protons are taken up by RBC and buffered by hemoglobin and other intracellular proteins
      - Lungs and kidneys attempt to limit the change by altering pCO2 or [HCO3-] in a direction that will minimize the pH change
        
        Called compensation
        
        Occurs within minutes if compensation is pulmonary, but can take 6-12 hrs to become established and days to become maximal if compensation is for a change in pCO2 and renal generation or loss of HCO3 is required
        
        Returns pH toward normal, but is never complete
        
        If patient has acidosis as sole disturbance, pH will be lower than normal, if alkalosis is present, even after compensation, pH will still be higher than normal (Alkalemia)
        
        But patient can have acidosis w/o acidemia and alkalosis w/o alkalemia -> only in patients with equally severe acidosis and alkalosis that coexist -> offset pH
    - - pH is determined by ratio of HCO3- to pCO2
      - Henderson-hasselbach eqn
      - Thus a disturbance that alters pCO2 will cause a compensatory change in HCO3- in the same direction to return the ratio and pH to normal
      - if primary change is pCO2, its respiratory, if primary change is [HCO3-], its metabolic
      - A simple acid-base disturbance is present when oly one primary process and its expected compensation are present
    - - 2 or more primary disturbances may coexist
      - e.g. cardiorespiratory arrest
        
        lack of perfusion -> tissue anoxia -> reliance on anaerobic metabolism -> increased production of lactic acid -> lactic acidosis
        
        Lack of ventilation leads to CO2 retention and respiratory acidosis
        
        [HCO3-] is depressed, pCO2 elevated -> profound decrease in pH
      - two severe changes can cancel out the changes in pH, but doesnt mean that patient is fine
    - - Acidosis
        
        due to reduction in bicarb
        
        High anion gap
        
        Anion gap = [Na+] - 2 x ([Cl-] + [HCO3-])
        
        Occurs when fall in [HCO3-] is due to addition of lactic acid, salicylate, ketoacids or some other anion not directly measured in the standard electrolytes
        
        [Cl-] is unaffected and remains normal
        
        Hyperchloremic
        
        Non-anion gap
        
        Fall in bicarb is matched by an equal increase in [Cl-]
        
        Could be due to loss of bicarb in stool with diarrhea and inability of ddiseased kidney to excrete daily proton load
        
        Upper limit of anion gap is 12 mEq/L
        
        Hyperventilation is the normal response for compensation
        
        Expected pCO2 is defined by winter's formula
      - Alkalosis
        
        elevated arterial pH and bicarb, with compensatory increase in pCO2
        
        Due to addition of bicarb or loss of acid in body
        
        Most common causes: gastric secretions during vomitting or nasogastric suction
        
        in latter, renal proton excretion is stiumlated due to secondary hyperaldosteronism induced by vol depletion
        
        Hypoventilation to increase pCO2
        
        Formula
    - - Acidosis
        
        due to rise in pCO2 (hypercapnia) due to abnormalities in respiratory function (asthma and chest wall paralysis)
        
        as renal compensation is slow, acute and chronic forms exist
        
        In acute respi acidosis, CO2 enter erythrocytes where it is bound to Hb or converted to H+ and HCO3-, HCO3- is then exchanged across cell membrane for Cl-, plus some intracellular K+ shifts out of cell inexchange for H+
        
        only modest change in [HCO3-]
        
        In chronic, hypercapnia stimulates renal acid excretion with bicarb reabsorption
        
        raises [HCO3-] further and is effective, but takes 2 days for maximum effect
      - Alkalosis
        
        Primary lowering of pCO2 through hyperventilation, leading to elevation of pH
        
        In acute compensation, bicarb will fall slightly as H+ and HCO3- combine to form CO2
        
        Chronic will lead to increased renal excretion of bicarb, which needs several days
- - - - cells in hypothalamus (osmoreceptors) detect changes in bodily fluid osmolality
      - Cells respond only to effective osmoles, and when effective osmolality of plasma rises, ADH secretion is enhanced, while it is inhibited when effective osmolality falls
      - Set point for ADH secretion from 280-290 mOsm/Kg, below this, no ADH secreted, above this, ADH secretion increases dramatically in response to small changes
    - - Peripheral baroreceptors (left atrium, pulmonary vessels, aortic arch and carotid sinus) sense change in blood vol and BP
      - While a rise in plasma osmolality of 1% will affect ADH secretion, a 5-10% decrease in blood vol or BP is necessary to stimulate ADH secretion - plasma osmolality is the main physiologic regulator of ADH
      - However, during life large, life threatening reductions in blood vol or BP, set point of ADH is reset to lower values for plasma osmolality and slope of relationship between ADH and plasma osmolality increases
      - because when faced with circulatory collapse, body conserves water at the expense of lower body fluid osmolality
    - - increase permeability of collecting duct to water
      - ADH bind to vaspressin receptors (V2) on basolateral membranes, which activates adenylate cyclase, increase cAMP, which lead to insertion of preformed water channels (aquaporin-2) into apical membrane of collecting duct cells
        
        increased water reabsorption, produce low vol of conc urine
      - When ADH is removed, water channels are returned to cell interior
      - does not affect solute excretion
  - - - patient excretes large volumes of dilute urine (3-18L)
      - 2 forms
        
        central: no ADH is produced by hypothalamus despite rise in plasma osmolality
        
        can be resolved with exogenous ADH
        
        nephrogenic: ADH is released, but collecting ducts do not respond to ADH
        
        common cause: lithium poisoning
      - As thirst mechanism is intact (and because water is readily available in our society), patients can maintain normal plasma osmolality by drinking large vol of water
      - However, in times where patients are weak and cant access water (e.g. after surgery), life threatening hypernatremia can ensue unless corrected (through IV drip or makin water more accessible)
- - - - there is a diff in conc of ion on both sides of membrane and
      - Membrane is permeable to the ion
    - - Shows that equilibrium potential for a given ion is dependent on charge of ion and size of conc gradient.
      - Membrane potential of cell at any time depend on permeability of ions that have equilibrium potentials (different conc in and out)
    - - RMP becomes less negative, depolarizing excitable tissues, fewer voltage gated Na channels availabel
      - Prolonged P-R interval (broad QRS), high T wave and depressed S-T segment
    - - RMP more negative, more voltage gated Na channels available, more excitble
      - Low T wave, high U wave, low S-T segment
  - - - Insulin
        
        primary regulatory hormone that promote cellular uptake of K
        
        impt means of handling post prandial K+ load
        
        Diabetics thus at high rik for developing hyperkalemia since they have absolute or relative insulin deficiency
      - Epinephrine
        
        Stimulation of B2-receotors augments K+ uptake
        
        Stimulation of a receptor promotes K+ release from cells
        
        When epinephrine is released during exercise or stress, B-effect predominates and K+ taken in by cells
        
        Patients under high stress may have frank hypokalemia due to high epinephrine levels -> contribute to arrhythmias
        
        B blockers may reduce K+ uptake and contribute to hyperkalemia, particularly in patients receiving large doses of K+
      - Acid-base disorders
        
        metabolic alkalosis, H+ shifts out of cells in exchange for K+ -> partial correction of extracellular alkalosis but lowers plasma [K+]
        
        Metabolic acidosis: opp happens
        
        Shift is greater when inorganic acid is responsible, while organic acidoses such as diabetic ketoacidosis and lactic acidosis have a much smaller effect
      - Cellular lysis
        
        cells have very high content of K+, hemolysis can release enough to cause hyper kalemia
        
        Can sometimes cause an artifactual elevation of plasma K+
        
        Rhabdomyolysis -> pathological condition of muscle breakdown, which releases K+ too
        
        when WBC or platelet count extremely high, sufficient K+ may be released from these cells invitro to produce a spurious elevation of [K+]
      - Hyperglycemia
        
        during hyperosmolality, particularly in hyperglycemia, water leaves cells
        
        Sufficient K+ may accompany water due to solute drag, increasing [K+]
        
        more likely to affect diabetic patients, insulin lack is a prerequisite for hyperglycemia and contributes to failure of moving K+ back to cells, and defective aldosterone secretion further impair K+ uptake
  - - - cell to lumen K+ gradient, which depends on both activity of Na-K-ATPase and luminal [K+]
      - Electric charge gradient between lumen and cell (lumen -ve)
      - Permeability of luminal membrane to K+
    - - Plasma [K+]
        
        increase [K+] directly stimulates Na-K-ATPase, which will increase intracellular K+, causing favorable gradient for K+ secretion across luminal membrane
        
        Also, increase [K+] directly stimulates aldosterone release, independent of renin
      - Aldosterone
        
        increase amount of Na-K-ATPase present on basolateral membrane of cells
        
        also increase amt of ENaC, which increase apical permeability to Na
        
        Generate -ve luminal electrochemical gradient, favour K+ secretion into lumen via ROMK
        
        Unregulated exposure to aldosterone thus lead to hypertension, vol expansion and low plasma [K+]
      - Acid-base disorders
        
        Na-K-ATPase and luminal channels for K+ pH dependent
        
        Acute acidosis inhibits Na-K-ATPase activity and reduce luminal K+ permeability, thus decreasingg K+ secretion
        
        also, to buffer metabolic acidosis, H+ moves into cells in exchange for K+, lowering intracellualr K and reduce gradient for K+ secretion in principal cell
        
        Effect of acidosis on K+ excretion can be small and unpredictable, but metabolic alkalosis reliably increases K+ secretion as a direct effect of pH
        
        metabolic alkalosis cause K+ to move into cells for H+ to move out, increase intracellular [K+], which favors secretion
        
        Metabolic alkalosis also associated w other conditions like vol depletion, diuretic use, hyperaldosteronism that may increase K+ secretion, hypokalemia is a cardinal feature in metabolic alkalosis
      - Distal Na+ delivery
        
        as more Na is delivered to principal cell, more Na reabosorption will occur via ENaC, which will increase Na-K-ATPase activiry and generate a -ve lluminal electrochemical potential, overall favoring K to leave via ROMK
      - Tubular fluid flow rate
        
        High flow rate will wash away recently secreted K+ and replace with relatively low K+ fluid -> favor a gradient for continued secretion
        
        Increased flow also bends primary cilium in primary cells, activate Ca channels -> increased intracellular [Ca2+], which stimulates apical K channel activity, leading to enhanced K+ secretion
        
        This is through to occur in order to allow independent regulation of Na and K balance
        
        e,g, vol expanded (excess total body Na), renin and aldosterone supressed and secondary increase Na delivery and high urinary flow rate promote K secretion and prevent hyperkalemia
        
        Vol depleted -> high renin aldosterone levels and low urinary flow rates prevent excessive K loss inurine
        
        However, if process not corrected and GFR declines, hyperkalemia can develop, in which volume expansion will increase distal Na delivery and urine flow allowing K to be appropriately secreted
      - Diuretics
        
        increase urine flow rate
        
        Loop diuretics and thiazide block Na+ reabosorption in loop and DCT, increasing distal Na delivery, which coupled with flow rate will increase K secretion
        
        Diuretics also tend to cause vol depletion and secondary hyperaldosteronism, which also increases K+ secretion
        
        K sparring diuretics: diminish renal K secretion, act of CD
        
        Spironolactone: competitive inhibitor of aldosterone
        
        Amiloride and triamterene block epithelial Na channel (ENaC)
- - - - Ultrafiltrate free of cells and nearly free of protein
      - Filter based on size and charge
      - Conc. of electrolytes and small organic molecules such as glucose and urea are nearly identical in plasma and ultrafiltrate as barrier is freely permeable to them
    - - 3 layers
        
        Fenestrated capillary endothelium
        
        Glomerular basement membrane
        
        Epithelial cells (podocytes)
      - Podocytes have cell extensions (foot processes) which interdigitate w foot processes of neighbouring podocytes
        
        chief function appears to be to lay down and maintain glomerular basement membrane
      - Each layer restricts filtration to some degree
      - Basment membrane composed of glycoproteins (mainly collagen IV, laminin, fibronection) that are negatively charges, believe to be main barrier to filtration of large molecules
      - Capillary endothelium prevents blood cells and platelets from coming into contact with glomerular basement membrane
      - molecules <20A freely filtered
        
        molecules >42A not filtered
        
        20-42A filtered to verying degrees depending on size and charge
      - Due to -ve charge, cationic molecules are more readily filtered than anionic molecules
    - - Equation:
      - Based on starling forces, which produces ultrafiltration and afferent end of glomerular capillary
      - Net ultrafiltration pressure decreases along length of glomerular capillary, as although PGC remains relatively constant along the length, there is progressive rise in oncotic P due to progressive rise in protein conc. along length as more protein free fluid is filtered
      - Renal plasma flow also affects GFR
        
        When RPF is low, filtration of protein free fluid will result in a more rapid increase in oncotic pressure within glomerular capillary --> more rapid decline in net ultrafiltration pressure and GFR will fall
      - GFR affected by any of the five variables in the equation, but normally only regulated by changes in PGC, which in turn is regulated by glomerular arteriolar resistance
        
        decrease in afferent resistance increases PGC and GFR
        
        Increase in arterial BP will transiently increase PGC and GFR until autoregulatory mechanisms will increase afferent arteriolar resistance, returning PGC and GFR to normal
        
        Pathologic conditions may alter GFR by altering any of the variables
        
        Many kidney diseases reduce Kf by reducing no. of filtering glomeruli (SA for filtration)
        
        kidney stone obstruct urine flow, increase PBS, decrease GFR
        
        Hemorrhage decrease BP, thus decreasing PGC and GFR
      - Normal GFR
        
        Roughly 120ml/min (180L/day)
        
        Function of kidney, higher in men than women
      - Measurement of GFR
        
        Use inulin
        
        Freely filtered by glomeruli, neither reabsorbed nor secreted by tubules, and is neither produced nor metabolized by kidneys
        
        amount filtered = amount excreted
        
        GFR = ([inulin]u x urine flow)/[inulin]p
        
        However, inulin is an exogenous molecule and must be infused IV to measure GFR, limiting its clinical utility
        
        Creatinine is an endogenous substance formed from creatine or phosphocretine (produced at relatively constant rate, distributed throughout ECF)
        
        as it is secreted to a small extent by renal tubules, not as good as inulin
        
        Amount excreted will exceed amt filtered, GFR calculated will be slightly overestimated (GFR = ([Cr]u x urine flow)/[Cr]p
        
        Done so by collecting urine from patient for a specific perior of time (24 hrs), measure conc in urine and in a sample of plasma, express urine flow as vol per unit time
  - - - At normal plasma conc., filtered load of glucose is such that all filtered load is reabsorbed, no glucose in urine
      - At very high plasma glucose, reabsorptive mechanisms of tubules saturated, glucose appears in urine (clearance more than 0)
  - - - RPF determined by measuring clearance of organic acid para-aminohippuric acid (PAH), which is freely filtered at glomerulus, not absorbed by renal tubules
      - however, at low plasma conc, PAH is secreted by renal tubules to the point that no PAH is found in renal vein
      - Thus, amount of PAH entering kidneys = amoutn excreted
        RPF x [PAH]p = urine flow x [PAH]u
        Clearance of PAH = RPF = (urine flow x [PAH]u)/ [PAH]p
    - - Changing renal vascular resistance in response to changes in arterial P
      - Myogenic mechanism
        
        Arterial P increase -> smooth muscle of resistance vessels stretch -> wall tension increase -> smooth muscle contract in response -> caliber of resistance vessels decrases -> resistance increase, offset increase in P, maintain constant RBF
      - Tubuloglomerular feedback
        
        Arterial P increase, GFR increase, increased delivery of NaCl and fluid to macula dense (DCT)
        
        Juxtaglomerular apparatus send signal which lead to increase in afferent arteriolar resistance
        
        Increase in R returns GFR to normal, prevents reabsorptive capacity of individual nephrons from being overwhelmed
      - Important as changes in GFR affect water and solute excretion, if GFR and RBF increase or decrease in proportion to increases or decreases in BP, water and solute balance would be similarly affected and put patient in danger
      - By uncoupling renal function and solute excretion from arterial P, this ensures that water and solute excretion will remain constant in spite of changes in arterial P that occur everyday
    - - Sympathetic neurons innervate afferent and efferent arterioles, release norepinephrine
      - Epinephrine secreted by adrenal medulla, both cause vasoconstriction and decrease RBF and GFR
      - Sympathetic activity low at rest, but is increased by reductions in effective circulating volume
      - Angiotensin II constrict efferent arteriole, and to a lesser degree, the afferent arteriole
      - Prostaglandins PGI2 and PGE2 produced in and act in the kidneys (PGI2 in renal cortex and PGE2 in medulla)
        
        catabolized by lungs, do not have systemic effects
      - Although do not regulate GFR or RBF in healthy humans, it is increased when renal perfusion is diminished
        
        PGI2: vasodilatory prostaglandin that preserves renal perfusion when it is threatened,
        
        PGE2 is a natriuretic and diuretic prostaglandin that works on collecting tubules, limit Na reabsorption by renal tubules, help prevent hypoxia in medulla during states of diminished perfusion (decrease oxidative stress)
      - Nitric Oxide (NO): endothelium derived relaxation factor in response to shear force on arteriolar endothelial cells, dilates afferent and efferent arterioles, dampens effects of catecholamines and angiotensin II
      - Endothelin: vasoconstrictor in kidneys (both afferent and efferent) decreases RBF and GFR, production elevated in some glomerular diseased states
      - Bradykinin -> stimulates NO and prostaglandin release -> increase RBF and GFR
      - Adenosine: produced in kidneys and constricts afferent arteriole
      - Fall in arterial P (hemorrhage): renal sympathetic nerves release norepinephrine, constricting afferent and efferent arterioles, reducing RBF and GFR
        
        fall in arterial P -> RAAS -> increased renal vascular resistance and reduce RBF
        
        increase in resistance in kidney help maintain BP, maintain perfusion to vital organs, at the cost of lower RBF and GFR
      - If RBF decreased to an extent that renal ischemia and damage occur, offset by PGE2 and PGI2
- - - - When ingestion and production of solute exceed consumption and excretion -> positive balance
      - When net solute loss occurs, balance in negative
      - Kidney and greater regulatory system that controls it must sense overall body content of each solutes in question and adjust urine composition to keep body comp. in normal ranges
    - - Kidney maintains intravascular vol at needed level by controlling body's Na content
      - By adjusting intravascular vol, kidney plays an essential role in body P regulation
      - Total body Na can only be estimated by physical examination directed at symptoms or signs of volume excess of depletion
    - - Overall body water content, also maintained at narrow range
      - Kidney involved in both water excretion and retention to maintain tonicity
      - [Na] can be measured directly and is the surrogate measure for tonicity, BUT note that total body Na content is determinant of ECF vol.
    - - catabolism of endogenous or exogenous proteins lead to production of urea
      - Muscle turnover and digestion of muscle leads to production of creatinine
      - less well defined nitrogenous waste excreted in urine, as is sulfate from catabolism of methionine and cysteine and uric acid from purine degradation.
      - Some drugs also eliminated by kidney
    - - depending on diet, metabolism of food and catabolism of phospholipids produce protons that must be excreted to keep pH in range (function of enzymes depend on pH)
    - - Potassium, magnesium and calcium and phosphorous
      - Maintained through renal reabsorption in times of scarcity or loss, and excretion in times of excess
      - Table:
    - - Renin
        
        By granular cells of juxtamedullary apparatus
        
        Converts angiotensinogen to angiotensin I, which is converted to angiotensin II by ACE, a vasoconstrictor and promote tubular Na reabsorption
      - Erythropoietin
        
        stimulate erythroid precursors in marrow, necessary for maintenance of HCT
      - 1,25 di OH Vit D
        
        increase gut reabsorption of Ca and inhibit PTH secretion
      - production reduced in patients with renal insufficiency, resulting in anemia and a variety of abnormalities of Ca, P and bone metabolism
        
        renin production is abnormal, but not necessarily decreased
  - - - Active transport at basolateral membrane: Na+ - K+ - ATPase, which move sodium out and potassium in against the conc gradient at the expense of energy
        
        help keep gradient (sodium in cell low)
        
        allows for most co-transports (which are Na co-transports, like SGLT1 and 2 for glucose co-transporters)
      - Tight junction allow paracellular movement of Cl and water, which will follow Na to maintain clectroneutrality and osmotic gradients
      - Transcellular secretion of certain substances (drug, toxins) due to transporters
    - - have microvilli brushborder on peritubular side (increase SA)
      - at basolateral surface, abundant mitochondria to provide ATP needed for Na-K-ATPase
      - Brush border contain carbonic anhydrase, essential for HCO3- reabsorption
      - Solute transport:
      - Three significant characteristics of transport in proximal tubule
        
        Isotonic reabsorption of 67% of filtered Na and Water
        
        Reabsorption of certain substances coupled to Na co-transporter
        
        glucose, responsible for preventing unwanted glucose wasting in urine
        
        Phosphate: responsible for 80% of renal phosphate reabsorption, under hormonal control, down reg by PTH
        
        Lactate and charged amino acid reabsorption
        
        Reabsorption of filtered bicarb
        
        Not directly absorbed, Na+-H+ counter transporter pump H+ out, which combine with filtered bicarb and in presence of carbonic anhydrase, carbonic acid converted to CO2 and water
        
        CO2 diffuse across membrane, where it combines with water and intracellular CA to produce H+ and HCO3-, which is transported out of cell via Na-HCO3- co transporters or Cl-HCO3- counter transporters
        
        90% of filtered bicarb reabsorption
      - Tubular fluid to plasma ratio ([TF]/[P])
        
        at 1, no concentration gradient between tubular fluid and plasma, satisfied for Na and osmolality as proximal tubule cannot sustain a Na+ or water gradient between lumen and blood
        
        <1: preferentially reabsorbed
        
        Pi, HCO3-, glucose, Lactate
        
        1: Cl-, not because it is secreted, but just that water reabsorption increases [Cl]
    - - Thin descneding loop permeable to water but not solutes
        
        few mitochondria needed
      - Ascending limb is thick and heavily active in solute transport, impermeable to water but reabsorbs solute (TAL)
        
        1 co-transporter (Na+-K+-2Cl- co-transporter) mediate electro-neutral reabsorption of Na+, K+ and 2 Cl-
        
        inhibited by loop diuretics like furosemide
        
        Impt for 3 reasons
        
        TAL responsible for 25% of filtered Na reabsorption
        
        Na-K-Cl is electroneutral (lumen), but with Na-K-ATPase (basolateral), electric gradient work to move K into cell, providing gradient for K to leak out of cell via apical K channels (ROMK)
        
        Gradient set up equilibrium potential so lumen is +ve wrt cell, which drives paracellular reabsorption of positively charged ions like Mg and Ca
        
        Concentration and dilution of urine
        
        for water to be reabsorbed in the collecting duct, interstitum must have high tonicity to provide driving force, TAL help concentrate interstitium with NaCl since solute is reabsorbed
        
        Counter current to help concentrate urine, vasa recta carrying NaCl goes in opp direction, and goes towards descending limb, where concentration gradient allows for water reabsorption, resulting in concentrated urine at the tip of the loop
    - - DCT
        
        Have Na-Cl cotransporter, responsible for 5-8% of filtered Na reabsorption
        
        Early DCT impermeable to water, so when NaCl is reabsorbed, urine is diluted
        
        Na-Cl cotransporter blocked by thiazide diuretics
        
        Ca reabsorption occurs via apical Ca channel, stimulated by PTH and 1,25 di OH Vit D.
        
        Later segments of DCT change function and blend into CD
        
        fine tuning of tubular fluid, responsible for final 1-2% of Na reabsorption
        
        2 main cells
        
        Principal cell
        
        Reabsorb Na and secrete K
        
        As Na reabsorbed through ENaC, lumen develop -ve potential, drive K secretion through ROMK (key mechanism in maintaining K balance)
        
        Intercalated cell
        
        alpha intercalated cell secrete H+, primary way kidney excretes daily load of fixed acid
        
        Done with either H+ ATPase or K+/H+ counter transporter
        
        Intracellular CA create carbonic acid, which dissociate into H+ and HCO3-, Protons pumped out into lumen and bicarb transported out in exchange for Cl-
        
        H+ pump also stimulated by aldosterone
        
        Also play a role in reabsorbing water
        
        in presence of ADH, water channels (aquaporins) are inserted into apical membrane of PRINCIPAL cells
        
        in absence of ADH, segment is impermeable to water -> diluted urine
    - - Interfere with reabsorption of salt and water, technically, it is anyth that increases urine flow
      - Usually interfere with Na+ transporters, leading to natriuresis (loss of Na), which would affect reabsorption of other solutes too
      - Carbonis anhydrase inhibitors
        
        inhibit CA within proximal tubule, block Na+-HCO3- reabsorption
        
        Not good enough due to loop and distal tubule compensation
      - Loop Diuretics
        
        Inhibit Na-K-2Cl cotransporter
        
        drugs like furosemide, bumetanide and torsamide
        
        clinically relevant as this transporter is responsible for 25% of Na reabsorption, and blockin gthis will block the ability to create a concentrated medullay interstitum
        
        Render kidney unable to concentrate urine
        
        Due to high levels of distal Na delivery, K wasting is common (ENaC ROMK channels)
      - Thiazide diuretics
        
        Inhibit Na-Cl cotransporter in early DCT
        
        Cause a loss of 5-10% of filtered Na
        
        Due to higher levels of distal Na delivery, K wasting is common
      - Osmotic diuretics
        
        Promote diuresis secondary only to change in osmotic driving forces
        
        Something filtered and not reabsorbed like mannitol will increase luminal osmolality
        
        Since water reabsorption requires small gradient of 3-5 mosm/L diff, presence of unabsorbed osmoles in lumen will prevent water reabsorption, thus promoting water loss
        
        Glycosuria works with the same principal -> commonly seen in diabetics with chronically elevated blood glucose levels