ROLE OF KIDNEYS IN ACID-BASE BALANCE

Extracellular volume contraction

- Extracellular volume contraction—via ANG II, aldosterone, and sympathetic activity—stimulates renal H + secretion - A decrease in effective circulating volume stimulates Na + reabsorption by four parallel pathways, including activation of the renin-angiotensin-aldosterone axis (and thus an increase in ANG II levels) and stimulation of renal sympathetic nerves (and thus the release of norepinephrine). -Both ANG II and norepinephrine stimulate Na-H exchange in the proximal tubule. ~Because the proximal tubule couples Na + and H + transport, volume contraction increases not only Na + reabsorption but also H + secretion. -Similarly, ANG II stimulates acid secretion by α-intercalated cells in the distal nephron. - Volume expansion has the opposite effect. -On a longer time scale, volume depletion also increases aldosterone levels, thereby enhancing H + secretion in cortical and medullary collecting ducts. - Thus, the regulation of effective circulating volume takes precedence over the regulation of plasma pH. - elevation in bicarbonate reabsorptive capacity with volume depletion.

Thiazide-type diuretics

Act on DCT, inhibiting Na+/Cl- symporter

the body deals with the 70-mmol/day acid challenge in three steps:

Step 1: Extracellular HCO3- neutralizes most of the H+ load: - Thus, HCO3- decreases by an amount that is equal to the H+ it consumes, and an equal amount of CO2 is produced in the process. -Non-HCO3- buffers (B-) in the blood neutralize most of the remaining H+ load > Thus, B− , too, decreases by an amount that is equal to the H+ it consumes. > A very tiny fraction of the H+ load (<0.001%) escapes buffering by either HCO3- or B−; This remnant H+ is responsible for a small drop in the extracellular pH. Step 2: The lungs excrete the CO2 Step 3: The kidneys regenerate the HCO3- and B− in the ECF by creating new HCO3- at a rate that is equal to the rate of H+ production (i.e., ~70 mmol/day). HCO3 + BH ---> B- + CO2 + H2O - Thus, over the course of a day, 70 mmol more HCO3- exits the kidneys via the renal veins than entered via the renal arteries. -Most of this new HCO3- replenishes the HCO3- consumed by the neutralization of nonvolatile acids, so that extracellular [HCO3-] is maintained at ~24 mM. -The remainder of this new HCO3- regenerates B− - Thus, by generating new HCO3-, the kidneys maintain constant levels of both HCO3- and the deprotonated forms of non-HCO3- buffers (B− ) in the ECF

Regulation of Renal Acid Excretion

The extracellular pH normally plays the major role but, when present, effective circulating volume depletion and changes in the plasma potassium concentration can also affect acid secretion, possibly leading to alkalosis or acidosis.

Loop diuretics

inhibit sodium reabsorption in the loop of Henle

Respiratory acidosis stimulates H + secretion in at least three ways:

(1) First, an acute elevated PCO2 directly stimulates proximal-tubule cells to secrete H+ (2) Second, acute respiratory acidosis also causes exocytotic insertion of H pumps into the apical membranes of intercalated cells in distal nephron segments. (3) Third, chronic respiratory acidosis leads to adaptive responses that upregulate acid-base transporters.

two major mechanisms by which chloride depletion can increase net distal bicarbonate reabsorption: increased hydrogen secretion and reduced bicarbonate secretion:

(1) Increased Hydrogen Secretion - The collecting duct H+/ATPase is associated with passive cosecretion of chloride to maintain electroneutrality. -A reduction in the tubular fluid chloride concentration will enhance the gradient for chloride secretion out of the cell, indirectly promoting hydrogen secretion. (2) Reduced Bicarbonate Secretion -Normally, elevated plasma bicarbonate concentration will result in decreased bicarbonate reabsorption. - In addition, some of the urinary bicarbonate is derived from a subpopulation of intercalated cells (type B) in the cortical collecting duct that, in the presence of alkalemia, are able to secrete bicarbonate from the cell into the lumen. - In these cells, the site of the transporters for hydrogen and bicarbonate is the opposite of that seen in the hydrogen-secreting alpha cells: The H+/ATPase pump is located on the basolateral membrane, while the Cl-/HCO3- exchanger is located on the apical membrane. -The energy for bicarbonate secretion is supplied by the favorable inward gradient for chloride. -Thus, a reduction in the tubular fluid chloride concentration will diminish net bicarbonate secretion, thereby perpetuating the alkalosis.

Acid-Base Transport by Different Segments of the Nephron

**The nephron reclaims virtually all the filtered HCO3- in the proximal tubule (~80%), thick ascending limb (~10%), and distal nephron (~10%)** - PCT: By the end of the proximal tubule, luminal pH falls to ~6.8, which represents only a modest transepithelial H+ gradient compared with the plasma pH of 7.4. > Thus, the proximal tubule is a high-capacity, low-gradient system for H+ secretion. - The thick ascending limb of the loop of Henle (TAL) reabsorbs an additional 10% of filtered HCO3-, so that by the time the tubule fluid reaches the distal convoluted tubule (DCT), the kidney has reclaimed ~90% of the filtered HCO3-. - The rest of the distal nephron—from the DCT to the inner medullary collecting duct (IMCD)—reabsorbs almost all the remaining ~10% of the filtered HCO3-. - Although the latter portion of the nephron reabsorbs only a small fraction of the filtered HCO3-, it can lower luminal pH to ~4.4. > Thus, the collecting tubules and ducts are a low-capacity, high-gradient system for H+ transport - the kidneys reclaim ~99.99% of the filtered HCO3-.

generation of new HCO3-

- **The nephron generates new HCO3-, mostly in the proximal tubule** - The kidney generates new HCO3- in two ways. ~It titrates filtered buffers such as HPO42- to produce "titratable acid," and it titrates secreted NH3 to NH4+. - In healthy people, NH4+ excretion is the more important of the two and contributes ~60% of net acid excretion or new HCO3-

hyperkalemia is often associated with metabolic acidosis.

- A contributory factor may be reduced NH4+ excretion, perhaps because of lower synthesis in proximal-tubule cells, possibly due to a higher intracellular pH. - In addition, with high luminal [K + ] in the TAL, K + competes with NH4+ for uptake by apical Na/K/Cl cotransporters and K + channels, thereby reducing NH4+ reabsorption. - As a result, the reduced NH4+ levels in the medullary interstitium provide less NH3 for diffusion into the medullary collecting duct. - Finally, with high [K + ] in the medullary interstitium, K + competes with NH4+ for uptake by basolateral Na-K pumps in the medullary collecting duct. - The net effects are reduced NH4+ excretion and acidosis.

Hypokalemia increases renal H + secretion (alkalosis)

- Acid-base disturbances can cause changes in K + homeostasis. > The opposite is also true. -Because a side effect of K + depletion is increased renal H + secretion, K + depletion is frequently associated with metabolic alkalosis. - in the proximal tubule, hypokalemia leads to a marked increase in apical Na-H exchange and basolateral Na/HCO 3 cotransport. -As in other cells, in tubule cells the pH falls during K + depletion. - The resulting chronic cell acidification may lead to adaptive responses that activate Na-H exchange and electrogenic Na/HCO 3 cotransport, presumably by the same mechanisms that stimulate H + secretion in chronic acidosis. -In the proximal tubule, K + depletion also markedly increases NH3 synthesis and NH4+ excretion, thus increasing urinary H + excretion as NH4+. -Finally, K + depletion stimulates apical K-H exchange in α-intercalated cells of the ICT and CCT and enhances H + secretion as a side effect of K + retention.

Hypokalemia increases renal H + secretion

- Because a side effect of K + depletion is increased renal H + secretion, K + depletion is frequently associated with metabolic alkalosis. - in the proximal tubule, hypokalemia leads to a marked increase in apical Na-H exchange and basolateral Na/HCO 3 cotransport. - As in other cells, in tubule cells the pH falls during K + depletion. > The resulting chronic cell acidification may lead to adaptive responses that activate Na-H exchange and electrogenic Na/HCO 3 cotransport, presumably by the same mechanisms that stimulate H + secretion in chronic acidosis. - In the proximal tubule, K + depletion also markedly increases NH3 synthesis and NH4+ excretion, thus increasing urinary H+ excretion as NH4+. - Finally, K + depletion stimulates apical K-H exchange in **α-intercalated cells of the ICT and CCT** and enhances H + secretion as a side effect of K + retention.

Titratable Acidity:

- Bicarbonate reabsorption reclaims filtered bicarbonate but does not participate in the excretion of the dietary acid load. -The latter process requires the combination of secreted hydrogen ions with buffers or the formation of ammonium (NH4+). -Weak acids filtered at the glomerulus can act as buffers in the urine; their ability to do so is related both to the quantity of buffer present and to its pKa. - Monobasic phosphate (HPO42-) is the most prevalent effective buffer in the tubular fluid. - The pKa is 6.80 for the phosphate buffering reaction - As a result, almost all of the filtered HPO42- will be converted to H2PO4- as the tubular fluid pH falls below 5.8 (1.0 pH unit from the pKa). - Although there is some buffering via this mechanism in the proximal tubule, the majority of HPO42- buffering occurs more distally as urine pH falls - Note that each secreted hydrogen ion that combines with a titratable acid leaves a bicarbonate ion within the cell. > This bicarbonate is returned to the systemic circulation (via the chloride-bicarbonate exchanger in the basolateral membrane) to replace a bicarbonate ion initially consumed by buffering of the dietary acid load. > The energy for this process is derived from the favorable inward gradient for chloride, which has a high concentration in the extracellular fluid and a low concentration in the cells. - Titratable acidity normally accounts for the excretion of 10 to 40 mEq of hydrogen per day. - titratable acidity cannot be easily increased in the presence of an acid load, since this process is limited by the quantity of potential buffer (particularly phosphate) excreted in the urine. > One important exception occurs in diabetic ketoacidosis where large quantities of β-hydroxybutyrate are excreted in the urine. > In this setting, titratable acid excretion can be augmented by more than 50 mEq/day. > Although the pKa for β-hydroxybutyrate is approximately 4.80, it can act as an effective buffer in the distal nephron where the tubular fluid pH can fall to 5.0 in patients with ketoacidosis.

Plasma Potassium Concentration

- Both bicarbonate reabsorption and ammonium excretion vary inversely with the plasma potassium concentration. - With potassium loss, for example, the fall in plasma potassium concentration is minimized by diffusion of potassium out of the cells - electroneutrality is maintained by the movement of extracellular hydrogen and sodium into the cell. - The net effect is an intracellular acidosis that will stimulate both bicarbonate reabsorption and ammonium excretion. - The increased loss of acid will promote the development of metabolic alkalosis. -These changes are reversed with hyperkalemia, which is associated with an intracellular alkalosis and diminished acid excretion. - The ensuing acid retention can lead to a mild metabolic acidosis.

Both glucocorticoids and mineralocorticoids stimulate acid secretion

- Chronic adrenal insufficiency leads to acid retention and, potentially, to life-threatening metabolic acidosis. -Both glucocorticoids and mineralocorticoids stimulate H + secretion, but at different sites along the nephron. -Glucocorticoids (e.g., cortisol) enhance the activity of Na-H exchange in the proximal tubule and thus stimulate H + secretion. - In addition, they inhibit phosphate reabsorption, raising the luminal availability of buffer anions for titration by secreted H + . -Mineralocorticoids (e.g., aldosterone) stimulate H + secretion by three coordinated mechanisms—one direct and two indirect. (1) First, mineralocorticoids directly stimulate H + secretion in the collecting tubules and ducts by increasing the activity of the apical electrogenic H+ pump and basolateral Cl-/HCO3 exchanger. (2) Second, mineralocorticoids indirectly stimulate H + secretion by enhancing Na + reabsorption in the collecting ducts, which increases the lumen-negative voltage. -This increased negativity may stimulate the apical electrogenic H pump in α-intercalated cells to secrete acid. (3) Third, mineralocorticoids—particularly when administered for longer periods of time and accompanied by high Na + intake—cause K + depletion and indirectly increase H+ secretion.

Relationship between Urinary Bicarbonate Sodium, Potassium, and Chloride

- If bicarbonate is excreted because the filtered load exceeds reabsorptive capacity, then to maintain electroneutrality either sodium or potassium must accompany the bicarbonate. - In the proximal tubule and loop of Henle, bicarbonate reabsorption occurs via Na+/H+ exchange; inhibiting this transporter in metabolic alkalosis will deliver both sodium and bicarbonate to the distal nephron. - bicarbonate reabsorption or secretion in the cortical collecting duct occurs in the intercalated cells; in comparison, the adjacent principal cells reabsorb sodium and chloride and secrete potassium in part under the influence of aldosterone. - The process of sodium reabsorption through sodium channels in the apical membrane creates a lumen-negative potential that can be attenuated by the reabsorption of chloride or by the secretion of potassium.

Vomiting patient/ patient on dieuretics

- In a hypovolemic patient with metabolic alkalosis, the associated secondary hyperaldosteronism will stimulate collecting duct sodium reabsorption - This process will continue until almost all of the chloride has been reabsorbed. - At this point, nonreabsorbable bicarbonate is the major anion left in the tubular lumen. - As a result, electroneutrality can be maintained with further sodium reabsorption only if it is accompanied by potassium secretion. - Although volume depletion will cause sodium conservation, the obligation to excrete the excess bicarbonate may cause sodium wasting; metabolic alkalosis with bicarbonaturia is a sodium- and potassium-wasting condition

glomerulotubular balance for HCO3-

- Increasing either luminal flow or luminal [HCO3-] significantly enhances HCO3- reabsorption, probably by raising effective [HCO3-] (and thus pH) in the microenvironment of H + transporters in the brush-border microvilli. -Because a high luminal pH stimulates NHE3 and the H pumps located in the microvilli of the proximal tubule, increased flow translates to enhanced H + secretion. - This flow dependence is important because it minimizes HCO3- loss, and thus the development of a metabolic acidosis, when GFR increases. - Conversely, this GT balance of HCO3- reabsorption also prevents metabolic alkalosis when GFR decreases. -The flow dependence of HCO3- reabsorption also accounts for the stimulation of H + transport that occurs after uninephrectomy (i.e., surgical removal of one kidney), when GFR in the remnant kidney rises in response to the loss of renal tissue.

hyperkalemia is often associated with metabolic acidosis

- Just as hypokalemia can maintain metabolic alkalosis, hyperkalemia is often associated with metabolic acidosis. - A contributory factor may be reduced NH4+ excretion, perhaps because of lower synthesis in proximal-tubule cells, possibly due to a higher intracellular pH. - In addition, with high luminal [K + ] in the TAL, K + competes with NH4+ for uptake by apical Na/K/Cl cotransporters and K + channels, thereby reducing NH4+ reabsorption. - As a result, the reduced NH4+ levels in the medullary interstitium provide less NH3 for diffusion into the medullary collecting duct. - Finally, with high [K + ] in the medullary interstitium, K + competes with NH4+ for uptake by basolateral Na-K pumps in the medullary collecting duct. - The net effects are reduced NH4+ excretion and acidosis.

compensatory response to metabolic acidosis

- Metabolic acidosis stimulates both proximal H + secretion and NH3 production - The first compensatory response to metabolic acidosis is increased alveolar ventilation, which blows off CO2 and thus corrects the distorted [HCO3-]/[CO2] ratio in a primary metabolic acidosis. - Proximal-tubule cells can directly sense an acute fall in basolateral [HCO3-], which results in a stimulation of proximal H + secretion. - In intercalated cells in the distal nephron, metabolic acidosis stimulates apical membrane H pump insertion and activity. > The mechanism may be proton-sensitive G protein-coupled receptors on the basolateral membrane of intercalated cells, and an HCO3--sensitive soluble adenylyl cyclase (sAC) in the cytosol. - In chronic metabolic acidosis, the adaptive responses of the proximal tubule are probably similar to those outlined above for chronic respiratory acidosis. > These include upregulation of apical NHE3 and electrogenic H pumps, as well as basolateral NBCe1, perhaps reflecting increases in the number of transporters on the surface membranes - In addition to increased H+ secretion, the other ingredient needed to produce new HCO3- is enhanced NH3 production. - Together, the two increase NH4+ excretion - the ability to increase NH3 synthesis is an important element in the kidney's defense against acidotic challenges. > The adaptive stimulation of NH3 synthesis, which occurs in response to a fall in pHi, involves a stimulation of both glutaminase and phosphoenolpyruvate carboxykinase (PEPCK). > The stimulation of mitochondrial glutaminase increases the conversion of glutamine to NH4+ and glutamate.

compensatory response to metabolic alkalosis

- Metabolic alkalosis reduces proximal H + secretion and, in the CCT, may even provoke secretion - when [HCO3-] in the peritubular blood is higher than normal—that is, during metabolic alkalosis—H+ secretion is lower - the proximal-tubule cell directly senses the increase in plasma [HCO3-], depressing the rates at which NHE3 moves H + from cell to lumen and NBCe1 moves HCO3- from cell to blood. - In the ICT and CCT, metabolic alkalosis can cause the tubule to switch from secreting H + to secreting HCO3- into the lumen - The α-intercalated cells in the ICT and CCT secrete H + by using an apical H pump and a basolateral Cl-HCO3 exchanger, which is AE1 (SLC4A1). -Metabolic alkalosis, over a period of days, shifts the intercalated-cell population, increasing the proportion of β-intercalated cells at the expense of α cells. - Because β cells have the opposite apical-versus-basolateral distribution of H pumps and Cl-/HCO3- exchangers, they secrete HCO3- into the lumen and tend to correct the metabolic alkalosis. > The apical Cl-HCO3 exchanger in β cells is **pendrin** (SLC26A4).

glutamine nitrogen as a source of ammonium and bicarbonate synthesis

- NH4+ is released from glutamine by glutaminase and from glutamate by glutamate dehydrogenase, resulting in the formation of α-ketoglutarate - α-Ketoglutarate is used as a fuel by the kidney and is oxidized to CO2, converted to glucose for use in cells in the renal medulla, or converted to alanine to return ammonia to the liver for urea synthesis. - The rate of glutamine uptake from the blood and its use by the kidney depends principally on the amount of acid that must be excreted to maintain a normal pH in the blood.

urinary buffers

- Nephrons cannot produce urine with a pH below 4.5. - To increase H+ secretion, urine must be buffered. > Phosphates and ammonia buffer the urine. > Phosphates enter via filtration. > Ammonia comes from the deamination of amino acids. - Some of these buffers the kidney filters —for example, phosphate, creatinine, and urate. > Because of its favorable pK of 6.8 and its relatively high rate of excretion, phosphate is the most important nonvolatile filtered buffer. - The other major urinary buffer is NH3/NH4+, which the kidney synthesizes. -After diffusing into the tubule lumen, the NH3 reacts with secreted H+ to form NH4+. -Through adaptive increases in the synthesis of NH3 and excretion of NH4+, the kidneys can respond to the body's need to excrete increased loads of H+ .

Extracellular pH

- Net acid excretion (primarily determined by the sum of titratable acidity and ammonium) varies inversely with the extracellular pH. - With acidemia (low pH, high hydrogen concentration), for example, the pH can be returned toward normal by increasing net acid excretion. - Each of the major factors involved in acid excretion participate in this response: (1) There is enhanced Na+−H+ exchange in the proximal tubule and loop of Henle, thereby raising hydrogen secretion in these segments. (2) Both increased activity of the exchanger and, later, the synthesis of new exchangers are seen. (3) Ammonium production and secretion in the proximal tubule are enhanced due to elevations in both the uptake of glutamine by the tubular cells and the metabolism of glutamine within the cells. (4) Increased activity of the Na/ HCO3- exchanger in the basolateral membrane of proximal tubule cells. (5) H+-ATPase activity in the collecting ducts increases due to the insertion of preformed cytoplasmic pumps into the apical membrane. **The net effect is more complete buffering by titratable acids, an elevation in ammonium secretion in the proximal tubule, and, due to a fall in urine pH, more efficient trapping of secreted ammonia as ammonium in the collecting ducts; The increase in net acid excretion will result in the return of an equivalent amount of new bicarbonate to the systemic circulation, thereby raising the extracellular pH toward normal.**

NH4+ secretion

- Of the new HCO3- that the nephron generates, ~60% (~40 mmol/day) is the product of net NH4+ excretion - result of five processes: (1) the proximal tubule actually secretes slightly more than ~40 mmol/day of NH4+, (2) the TAL reabsorbs some NH4+ and deposits it in the interstitium, (3) some of this interstitial NH4+ recycles back to the proximal tubule and thin descending limb (tDLH), (4) some of the interstitial NH4+ enters the lumen of the collecting duct, and finally, (5) some of the interstitial NH4+ enters the vasa recta and leaves the kidney. - The liver uses some of this NH4+ to generate urea, a process that consumes HCO3-. - Thus, the net amount of new HCO3- attributable to NH4+ excretion is (1) − (2) + (3) + (4) − (5)

Primary Hyperaldosteronism and Hypokalemia

- Patients with primary hypersecretion of aldosterone develop both hypokalemia and metabolic alkalosis due to increased urinary excretion of potassium and hydrogen. -These patients tend to be mildly volume expanded and hypertensive due to aldosterone-induced sodium retention; thus, hypovolemia cannot be responsible for the maintenance of the alkalosis. -Studies in animals and humans suggest that it is hypokalemia that plays the major role since the plasma bicarbonate concentration will fall toward normal with the administration of potassium chloride. -It is presumed that the intracellular acidosis induced by potassium depletion leads to increased hydrogen secretion and enhanced bicarbonate reabsorptive capacity

Respiratory Acidosis

- Respiratory acidosis is induced by a rise in PCO2 (hypercapnia) resulting from decreased alveolar ventilation and occurs in a variety of clinical setting associated with respiratory failure - Although correction of this disorder requires the restoration of normal pulmonary function, the kidney can minimize the change in extracellular pH by increasing acid excretion (primarily as ammonium), thereby generating new bicarbonate ions in the plasma and raising the plasma bicarbonate concentration. - This renal effect is presumably mediated by a fall in tubular cell pH as the excess CO2 diffuses into the cells. - Combination of this CO2 with H2O within the cells generates H2CO3, which then dissociates into a hydrogen ion (that is buffered by cell proteins or hemoglobin) and a bicarbonate ion. - The latter diffuses out of the cell into the extracellular fluid, thereby raising the plasma bicarbonate concentration. - In respiratory acidosis, in which the primary disturbance is an increase in arterial PO2, the compensatory response is an increase in renal H+ secretion, which translates to increased production of new HCO3- via NH4+ excretion. > The opposite occurs in respiratory alkalosis

Aldosterone

- Some of the excess sodium is reclaimed in the principal cells in the cortical collecting duct under the influence of aldosterone, the secretion of which is increased by the diuretic-induced fluid loss. -The reabsorption of cationic sodium creates a lumen-negative electrical potential, thereby favoring the urinary retention of hydrogen secreted by the adjacent intercalated cells. -Aldosterone also promotes hydrogen loss by directly stimulating the H+-ATPase pump. -Thus, in addition to secondary hyperaldosteronism resulting from volume depletion, metabolic alkalosis is also seen in conditions of primary aldosterone excess (such as an aldosterone-producing adrenal adenoma).

Effect of acidosis on other cations

- The initial response to the net acid retention is buffering by extracellular bicarbonate and by the cell and bone buffers. -Uptake of some of the excess hydrogen by the cells is accompanied in part by the loss of cell potassium and sodium into the extracellular fluid to maintain electroneutrality. - Thus, metabolic acidosis is often associated with an elevation in the plasma potassium concentration above the level expected from the state of potassium balance. - In some patients, the plasma potassium concentration is actually above normal (called hyperkalemia) even though body potassium stores are diminished. -This cation shift is reversed with correction of the acidosis.

alkaline challenge

- The kidneys also can control HCO3- and B− following an alkaline challenge, produced, for example, by ingesting alkali or by vomiting (which leads to a loss of HCl) - The kidney responds by decreasing net acid excretion—that is, by sharply reducing the excretion rates of titratable acid and NH4+. -The result is a decrease in the production of new HCO3-. - With an extreme alkali challenge, the excretion of urinary HCO3- also increases and may exceed the combined rates of titratable acid and NH4+ excretion. -In other words, component 3 exceeds the sum of components 1 and 2, so that "net acid excretion" becomes negative, and the kidney becomes a net excretor of alkali. -In this case, the kidneys return less HCO3- to the ECF via the renal veins than entered the kidneys via the renal arteries.

kidneys vs lungs

- Whereas the lungs excrete the large amount of CO2 formed by metabolism, the kidneys are crucial for excreting nonvolatile acids. - The kidneys play a critical role in helping the body rid itself of excess acid that accompanies the intake of food or that forms in certain metabolic reactions. - By far, the largest potential source of acid is CO2 production, which occurs during oxidation of carbohydrates, fats, and most amino acids > the lungs excrete this prodigious amount of CO2 by diffusion across the alveolar-capillary barrier, preventing the CO2 from forming H+ . - However, metabolism also generates nonvolatile acids —such as sulfuric acid, phosphoric acid, and various organic acids—that the lungs cannot handle. - In addition, metabolism generates nonvolatile bases, which end up as HCO3-. - Subtracting the metabolically generated base from the metabolically generated acid leaves a net endogenous H+ production of ~40 mmol/day for a person weighing 70 kg. - The strong acids contained in a typical Western acid-ash diet (20 mmol/day of H+ gained) and the obligatory loss of bases in stool (10 mmol/day of OH− lost) represent an additional acid load to the body of 30 mmol/day. - Thus, the body is faced with a total load of nonvolatile acids (i.e., not CO2 ) of ~70 mmol/day—or ~1 mmol/kg body weight—derived from metabolism, diet, and intestinal losses. - The kidneys handle this acid load by "dividing" 70 mmol/day of carbonic acid (H2 CO3): excreting ~70 mmol/day of H + into the urine and simultaneously transporting 70 mmol/day of new HCO3- into the blood. - Once in the blood, this new HCO3- neutralizes the daily load of 70 mmol of nonvolatile acid. - Were it not for the tightly controlled excretion of H+ by the kidney, the daily load of ~70 mmol of nonvolatile acids would progressively lower plasma pH and, in the process, exhaust the body's stores of bases, especially HCO3-. - The result would be death by relentless acidification.

Metabolic Acidosis

- characterized by a fall in extracellular pH that is induced by a reduction in the plasma bicarbonate concentration. - This can result from decreased renal acid excretion (retention of H+), bicarbonate loss in the gastrointestinal tract or the urine, or increased acid generation. - neither hydrogen ions nor bicarbonate ions can freely diffuse across the lipid bilayer of the cell membrane. > the bicarbonate exit step across the basolateral membrane—Na+/3HCO3- cotransport in the proximal tubule and Cl−/HCO3- exchange in the collecting ducts—serves as the mechanism by which changes in the plasma bicarbonate concentration are sensed by the cells. > If an increased acid load lowers the plasma bicarbonate concentration, there will now be a greater concentration gradient for bicarbonate to diffuse out of the tubular cells. > This loss of intracellular bicarbonate will lower the intracellular pH, providing the signal to increase hydrogen and ammonium secretion. - Although buffering is initially protective, the restoration of acid-base balance requires increased net acid excretion, a response that begins on the first day and reaches its maximum within 5 to 6 days as the changes in proximal and distal acidification described above increase in intensity. - The elevation in acid excretion is mostly as ammonium, since titratable acidity is limited by the rate of phosphate excretion. > Diabetic ketoacidosis represents one exception to this general rule, since urinary β-hydroxybutyrate can act as a titratable acid. - In addition to the renal response, the extracellular pH in metabolic acidosis is also protected by a rise in alveolar ventilation, thereby lowering the PCO2.

Respiratory Alkalosis

- characterized by a primary increase in alveolar ventilation that lowers the PCO2 (hypocapnia) and is seen in many clinical settings including respiratory disorders such as pneumonia, anxiety, severe infection, and liver failure. - intracellular alkalosis-induced decrease in net acid excretion due to both bicarbonate loss in the urine (as less is reabsorbed) and diminished ammonium excretion

Diuretics can change H + secretion, depending on how they affect transepithelial voltage, ECF volume, and plasma [K+]

- diuretics fall broadly into two groups: those that promote the excretion of a relatively alkaline urine and those that have the opposite effect. -To the first group belong CA inhibitors and K + -sparing diuretics. > The CA inhibitors lead to excretion of an alkaline urine by inhibiting H + secretion. > Their greatest effect is in the proximal tubule, but they also inhibit H + secretion by the TAL and intercalated cells in the distal nephron. > K + -sparing diuretics —including amiloride, triamterene, and the spironolactones—also reduce acid excretion. > Both amiloride and triamterene inhibit the apical epithelial Na + channels (ENaCs) in the collecting tubules and ducts, rendering the lumen more positive so that it is more difficult for the electrogenic H pump to secrete H + ions into the lumen. > Spironolactones decrease H + secretion by interfering with the action of aldosterone. - The second group of diuretics—those that tend to increase urinary acid excretion and often induce alkalosis—includes loop diuretics such as furosemide (which inhibits the apical Na/K/Cl cotransporter in the TAL) and thiazide diuretics such as chlorothiazide (which inhibits the apical Na/Cl cotransporter in the DCT). > These diuretics act by three mechanisms: (1) First, all cause some degree of volume contraction, and thus lead to increased levels of ANG II and aldosterone, both of which enhance H + secretion. (2) Second, these diuretics enhance Na + delivery to the collecting tubules and ducts, thereby increasing the electrogenic uptake of Na+ , raising lumen-negative voltage, and enhancing H + secretion. (3) Third, this group of diuretics causes K + wasting; K + depletion enhances H + secretion

titratable acid

- ex: H2PO4 - the amount of base one must add to a sample of urine to bring its pH back up to the pH of blood plasma. - The titratable acid does not include the H+ the kidneys excrete as NH4+

factors that determine how much hydrogen is secreted:

- extracellular pH normally plays the major role - effective circulating volume depletion - changes in the plasma potassium concentration

To maintain acid-base balance...

- the kidney must not only reabsorb virtually all filtered HCO3- but also secrete generated nonvolatile acids. - the major task of the kidney is to secrete acid into the urine and thus to neutralize the nonvolatile acids that metabolism produces. - before the kidney can begin to achieve this goal, it must deal with a related and even more serious problem: retrieving from the tubule fluid virtually all HCO3- filtered by the glomeruli.

Each of these three buffers competes with the other two for available H+:

- the kidneys secrete 4390 mmol/day of H+ into the tubule lumen. - The kidneys use most of this secreted acid—4320 mmol/day or ~98% of the total—to reclaim filtered HCO3- . - The balance of the total secreted H+, 70 mmol/day, the kidneys use to generate new HCO3- by binding to titratable acids/ NH3

three factors determine the rate at which titratable acid buffers act as vehicles for excreting acid:

1. The amount of the buffer in the glomerular filtrate and final urine: The filtered load of HPO42-, for example, is the product of plasma [HPO42-] and glomerular filtration rate (GFR). - Plasma phosphate levels may range from 0.8 to 1.5 mM. - Therefore, increasing plasma [HPO42-] allows the kidneys to excrete more H+ in the urine as HPO42. - Conversely, decreasing the GFR (as in chronic renal failure) reduces the amount of HPO42- available for buffering, lowers the excretion of titratable acid, and thus contributes to metabolic acidosis. - Ultimately, the key parameter is the amount of buffer excreted in the urine. - In the case of phosphate, the fraction of the filtered load that the kidney excretes increases markedly as plasma [phosphate] exceeds the maximum saturation (Tm). - For a plasma [phosphate] of 1.3 mM, the kidneys reabsorb ~90%, and ~30 mmol/day appear in the urine. 2. The pK of the buffer: To be most effective at accepting H+ , the buffer (e.g., phosphate, creatinine, urate) should have a pK value that is between the pH of the glomerular filtrate and the pH of the final urine. - For example, if blood plasma has a pH of 7.4, then only ~20% of its phosphate (pK = 6.8) will be in the form of HPO42-. - Even if the final urine were only mildly acidic, with a pH of 6.2, ~80% of the phosphate in the urine would be in the form of HPO42-. - In other words, the kidney would have titrated ~60% of the filtered phosphate from HPO42- to H2PO4-. - Because creatinine has a pK of 5.0, lowering the pH of the tubule fluid from 7.4 to 6.2 increases the fractional protonation of creatinine from ~0.4% to only ~6%. - However, urate has a pK of 5.8, so lowering pH from 7.4 to 6.2 would increase its fractional protonation from 2.5% to 28.5%. 3. The pH of the urine: Regardless of the pK of the buffer, the lower is the urinary pH, the more protonated is the buffer and the greater is the amount of acid excreted with this buffer. - As discussed, lowering the pH of the tubule fluid from 7.4 to 6.2 increases the protonation of creatinine from 0.4% to only ~6%. - However, if the pH of the final urine is 4.4, the fractional protonation of creatinine increases to ~80%. - Thus, creatinine becomes a much more effective buffer during acidosis, when the kidney maximally acidifies the urine.

2 major components of the body's major buffering system:

CO2 and HCO3-

secreted H+ from the blood to the lumen can have three fates:

It can titrate: (1) filtered HCO3-: H+ transported into the lumen by the tubule cell titrates filtered HCO3- to CO2 plus H2O via CA - The apical membranes of these H+ -secreting tubules are highly permeable to CO2, so that the CO2 produced in the lumen, as well as the H2O, diffuses into the tubule cell. - Inside the tubule cell, the CO2 and H2O regenerate intracellular H+ and HCO3- with the aid of CA. - Finally, the cell exports these two products, thereby moving the H+ out across the apical membrane into the tubule lumen and the HCO3- out across the basolateral membrane into the blood. - Thus, for each H+ secreted into the lumen, one HCO3- disappears from the lumen, and one HCO3- appears in the blood. - However, the HCO3- that disappears from the lumen and the HCO3- that appears in the blood are not the same molecule! (2) filtered phosphate (or other filtered buffers that contribute to the "titratable acid"): The major proton acceptor in this category of buffers excreted in the urine is HPO42-, although creatinine also makes an important contribution; urate and other buffers contribute to a lesser extent. - For each H+ it transfers to the lumen to titrate HPO42-, the tubule cell generates one new HCO3- and transfers it to the blood (3) NH3, both secreted and, to a lesser extent, filtered: However, unlike either HCO3- or the bases that give rise to "titratable acid" (e.g., HPO42-), glomerular filtration contributes only a negligible quantity of NH3 because plasma [NH3 ] concentration is exceedingly low. - Instead, urinary NH3 derives mainly from diffusion into the lumen from the proximal-tubule cell, with some NH4+ entering the lumen directly via the apical Na-H exchanger NHE3. - In the case of the proximal tubule, the conversion of glutamine to α-ketoglutarate (α-KG) generates two NH4+ ions, which form two NH3 and two H+ ions. - In addition, the metabolism of α-KG generates two OH− ions, which CA converts to HCO3- ions. > This new HCO3- then enters the blood.

load of fixed acid (protons) generated as a result of metabolism in an individual on a typical western diet

approximately 1 mmol of protons per kg body weight per day

Components of Net Urinary Acid Excretion

excrete H+ bound to a phosphate (i.e. titratable acid) + excrete H+ bound to NH3 - excretion of unfiltered HCO3- - If no filtered HCO3- were lost in component 3, the generation of new HCO3- by the kidneys would be the sum of components 1 and 2. - To the extent that filtered HCO3- is lost in the urine, the new HCO3- must exceed the sum of components 1 and 2.