increase plasma osmolality due to vigorous exercise on a hot day -> loss of water through sweating (hypotonic) -> ADH secretion stimulated

however, ADH cannot restore water deficit, only can retard further water loss
can only be corrected by drinking water -> stimulus to drink is thirst

Thirst elicited by increases in plasma osmolality of 2-3%, satiated temporarily by drinking, even before enough water had been absorbed

Satiation short-lived, thirst will recur until plasma osmolality is fully corrected

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)

RMB: perturbations in plasma [Na] reflect changes in TBW, not changes in total body Na, perturbation in total body Na do not usually perturb plasma [Na]

Consider when we add NaCl to ECF, resultant rise in plasma [Na] and plasma osmolality will stimulate thirst and ADH secretion

• ingestion of water and reabsorption of water by CD will restore plasma [Na] and osmolality back to normal
• end result is isoosmotic solution added to ECF

Changes in total body Na thus leads to change in ECF (extracellular volume)

in daily life, kidneys maintain constant ECF vol by altering excretion of NaCl to match intake

• Dietary intake varies

sensors sense effective circulating volume to maintain a constant ECF vol, and act on kidneys to alter excretion of NaCl

portion of ECF that is in the arterial system and is effectively perfusing tissues

In normal human, ECV varies directly with ECF vol (in particular, intravascular vol), arterial BP and cardiac output. a decrease in any will be sensed as a decrease in ECV, renal Na excretion will decrease, and ECV will increase

In diseased states, ECV may be independent o intravascular vol, BP or cardiac output -> states of ineffective arterial blood vol

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

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.

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

stretching increase receptor discharge, conducted to medullary cardiovascular centers via vagus and glossopharyngeal nerves

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

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)
  

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

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

K is principal intracellular cation, bulk of K is intracellular (98%)

Citrus fruits, tomatoes, peaches, melon, beans and meat are high in K

K nearly completely absorbed from diet, with a small amt being excreted in feces (~5 mEq/day) with the rest being excreted by kidney as external balance is maintained

Diffusion potentials generated when this conc difference cause net movement of a few ions across membrane

Diffusion does not continue unabated as potential diff will become large enough to oppose further diffusion, and the p.d. that this happens is the equilibrium potential

in our body, ECF has high Na and low K, while ICF has high K and low Na, which is maintained at the expense of ATP by Na-K-ATPase

• this pump moves 3 Na out and 2 K in, which is critical in establishing the conc difference

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)

Cells that are excitable (nerve and muscle) can generate A.P., where they become rapidly depolarized and repolarized -> nerve conduction and muscle contrcation

resting membrane potential is measured p.d. across one of these cells at rest, and is permeable to K ions while poorly permeable to Na+ ( due to open K channels and inactivation of voltage gated Na channels)

• thus RMP apprximates K equilibrium potential

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

both will cause arrhythmia (increase hyperkalemia, increase arrhythmia -> V fib)

Changes in [K+] may arise from changes in total body K content or from shift of K between small ECF and much larger intercellular pool

K uptake by cells is rapid (if not, hyperkalemia will occur with each meal)

• same for IV, but need to take note not to exceed rate of cellular uptake

Diabetics thus at high rik for developing hyperkalemia since they have absolute or relative insulin deficiency

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+

metabolic alkalosis, H+ shifts out of cells in exchange for K+ -> partial correction of extracellular alkalosis but lowers plasma [K+]

Shift is greater when inorganic acid is responsible, while organic acidoses such as diabetic ketoacidosis and lactic acidosis have a much smaller effect

cells have very high content of K+, hemolysis can release enough to cause hyper kalemia

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+]

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

principal determinant of K excretion is secretion in distal nephron

As K+ is freely filterable, approx 720 mEq filtered on a daily basis (180 (GFR) x 4mEq/L)

2/3 reabsorbed in PCT through diffusion at paracellular pathway and by solute drag as water is reabsorbed

if balance considerations call for conservation, rest of filtered K+ is reabsorbed in the loop and DCT -> net reabsorption

Significant K+ secretion occurs in TAL via ROMK channels to provide substrate for Na:K:2CL cotransporter, but overall balance favor reabsorption (also through paracellular pathway)

in DCT and CD, reabsorption is via K+ H+ ATPase on the luminal side of the intercalated cell, where it reabsorbs one K+ for ea H+ excreted

K+ cannot be completely reabsorbed, difficult to excrete less than 20mEq per day

If balance calls for excrestion of excess K+, additional K+ is excreted at distal nephron through principal cells (ENaC, ROMK)

cell to lumen K+ gradient, which depends on both activity of Na-K-ATPase and luminal [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

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+]

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

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

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

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

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

Normal metabolism result in production of roughly 1 mEq/kg/day of H+

Oxidation of sulfhydryl groups of cystine and methionine to form H2SO4

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

Under basal conditions, normal adults gnerate about 15000 mmoles ea day of CO2 from metabolism of fats and carbs

• CO2 considered volatile acid, and must be considered in the balance as it can combine with water to form carbonic acid through CA

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

Acidosis -> pathological addition of acid or loss of base in a process tending to lower pH

Alkalosis -> loss of acid or gain of base that tends to raise pH

While bicarb is an excellent buffer in metabolic acidosis, it is not effective in respiratory acidosis as it is due to elevated levels of pCO2 as any H+ accepted by bicarb just generates CO2 that cant be excreted due to the primary disorder.

• In this case, majority of buffering is intracellular (hemoglobin, proteins)

increasing ventilation in response to incrased production of CO2 to maintain pH

In pathological conditions of metabolic acidosis or metabolic alkalosis, w a primary change in bicarb conc, ventilation increases or decreases respectively to return [HCO3-]LpCO2 back to normal value -> reduce effect on pH

• respiratory compensation for metabolic disorder

Establishes normal bicarb conc by reclaiming filtered bicarb from proximal tubular lumen

In distal nephron, kidney excretes new H+, which generates any new bicarb required

Bicarb reclaimed in PCT through secretion of H+ in exchange for Na+ in lumen, secreted protons combine with filtered bicarb to form carbonic acid, which is immediately converted to CO2 (small, uncharged, lipid soluble gas) and H2O by brush border CA

CO2 freely diffuse back into cell, where after combining with water (again with CA), yields H+ and HCO3-, and is transferred to the blood through a Na+ HCO3- cotransporter and H+ is available again for secretion into lumen and the cycle repeats

Bicarb reabsorption has a threshold, where initial excretion of bicarb is nil, but once it rose to 26, threshold was exceeded. PCT was incapable of reabsorbing the additional filtered load

Amt of bicarb reabsorbed stayed at a plateau value while the amt excreted increased

this helps maintain normal bicarb conc, where in the case that [HCO3-] increases due to a perturbation, threshold will be exceeded and excess will be excreted

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

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

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

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

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

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

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

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

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

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

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

Could be due to loss of bicarb in stool with diarrhea and inability of ddiseased kidney to excrete daily proton load

elevated arterial pH and bicarb, with compensatory increase in pCO2

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