Renal regulation of acid-base balance

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	===Renal acid excretion===		===Renal acid excretion===
	*There are two main acids excreted by the kidney: ammonia (NH4+) and titratable acids (TA)		*There are two main acids excreted by the kidney: ammonia (NH4+) and titratable acids (TA)
-	**In this context, titratable can be defined as "able to accept a proton"	+	**In this context, titratable can be defined as "able to give a proton." NH4+ is not titratable because it will not give up a proton below a 9.2 pH.
	*There is one main base excreted by the kidney: bicarbonate (HCO3-)		*There is one main base excreted by the kidney: bicarbonate (HCO3-)
	*Therefore, the net acid secretion by the kidney is the acids - the base:		*Therefore, the net acid secretion by the kidney is the acids - the base:
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	*Recall that the type A intercalated cells of the collecting duct secrete H+.		*Recall that the type A intercalated cells of the collecting duct secrete H+.
	*Recall that H+ can readily cross back into the lining cells / interstitial fluid.		*Recall that H+ can readily cross back into the lining cells / interstitial fluid.
-	*In order to trap H+ in the filtrate, tubular cells of the nephron secrete titratable acids (that is, acids that can accept another H+).	+	*In order to trap H+ in the filtrate, tubular cells of the nephron secrete the conjugate base of titratable acids (that is, anions that can accept another H+).
	Where in the nephron does TA secretion occur?		Where in the nephron does TA secretion occur?
	**So, as TA secretion increases, the pH of the filtrate (urine) decreases.		**So, as TA secretion increases, the pH of the filtrate (urine) decreases.

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Current revision as of 20:05, 14 September 2015

• started here on 03/30/11.

Contents 1 Renal regulation of acid-base balance 1.1 Objectives 1.2 Renal acid excretion 1.3 Acid-base regulation overview 1.3.1 Reabsorption of filtered bicarbonate 1.3.2 Mechanism for reabsorption of filtered bicarbonate 1.3.3 Formation of titratable acid 1.3.4 Mechanism for formation of titratable acid 1.3.5 Excretion of ammonia 1.3.6 Mechanism for excretion of ammonia 1.4 Most H+ secretion occurs in the proximal tubule 1.5 Factors that affect H+ secretion and excretion at the kidney 1.6 Timeline of acid-base compensation mechanisms

[edit] Renal regulation of acid-base balance

[edit] Objectives

• Describe the three processes involved in urinary acidification: reabsorption of filtered bicarbonate, formation of titratable acid, and excretion of ammonia.
• Explain why most of the hydrogen ions secreted by the renal tubules are not excreted. Explain why excretion of titratable acid and ammonia (as NH4+) adds new bicarbonate to the blood. Be able to calculate net acid excretion from measurements of urinary ammonia, titratable acid, and bicarbonate excretion.
• Discuss the factors that influence renal secretion and excretion of hydrogen ions.
• Describe the renal compensation for each kind of acid-base disturbance.

[edit] Renal acid excretion

• There are two main acids excreted by the kidney: ammonia (NH4+) and titratable acids (TA)
  • In this context, titratable can be defined as "able to give a proton." NH4+ is not titratable because it will not give up a proton below a 9.2 pH.
• There is one main base excreted by the kidney: bicarbonate (HCO3-)
• Therefore, the net acid secretion by the kidney is the acids - the base:
  • Renal acid secretion = TAs + NH4 - HCO3
  • Normal acid secretion = 70 = 24 + 48 - 2 (mEq / day)

• The kidney can adjust acid secretion over a wide range
  • Note that excreting acid is equivalent to adding new bicarbonate to the blood.
• Note that the amount of free H+ in the urine is very small.

• Acid excretion pathology:
  • Acid secretion is elevated in diabetes mellitus:
    • Diabetes mellitus renal acid secretion = 700 mEq / day = 200 (mEa TAs) + 500 (mEq NH4+) - 0 (mEq HCO3-)
  • Acid secretion is most often elevated when consuming mixed meat / vegetable diets.
    • Vegetarians excrete less acid.

[edit] Acid-base regulation overview

• Recall from the Acid-base balance lecture that there are three regulation mechanisms: chemical buffering, pulmonary compensation, and renal compensation.
• We will now discuss the kidney's function in acid-base balance more fully.
  • Recall that we previously discussed the kidney's ability to secrete H+ and / or HCO3- to rebalance the pH.
• The kidney is also capable of generating novel HCO3 and secreting titratable acids made of sulfates, chlorides, and phosphates.
• There are three processes involved in acidifying the urine:
  • reabsorption of filtered bicarbonate (the more that is reabsorbed, the more acidified the urine)
  • formation of titratable acid (to bind H+ cations)
  • excretion of ammonia
• The production of TAs and the secretion of NH4 / NH3 results in novel bicarbonate added to the blood to replace bicarb consumed in buffering against increased acids.

[edit] Reabsorption of filtered bicarbonate

• Normally, 99.9% of filtered bicarbonate is reabsorbed by the nephron.
  • When plasma HCO3 is low, there is 0 excretion.
• Note, however, that there is a threshold at which the flow rate (and therefore the amount of filtered HCO3) is so high that it cannot all be reabsorbed.
• So, this first step in urine acidification is pretty constant: the HCO3 population of base in the urine is almost always, almost completely removed and does not increase the plasma HCO3- level.

[edit] Mechanism for reabsorption of filtered bicarbonate

• As with so many things, bicarbonate is reabsorbed using the Na gradient.
  • Bicarbonate from the filtrate is reabsorbed using two Na exchangers, one on the apical membrane and another on the basolateral membrane.
• Recall that HCO3- requires a transporter to cross the membrane but CO2 can diffuse across.
  • Recall that in RBCs we use CA (carbonic anyhdrase) to convert HCO3- to CO2 so it can diffuse over the membrane.
  • Recall that in RBCs we use a HCO3-Cl exchanger to move HCO3 in and out of the cell.
• So, in order to facilitate HCO3- reabsorption we convert it to CO2:
  • Recall: H+ + HCO3- <-> H2CO3 <-(CA)-> H20 + CO2
  • Filtered HCO3- exists as HCO3- in the filtrate; so we need to provide H+ to get the reaction to head toward CO2.
  • A Na-H exchanger on the apical membrane reabsorbs Na and moves H+ into the filtrate.
  • HCO3- + H+ -> H2CO3 -(CA)-> CO2 + H20
  • CO2 enters the tubule cell.
  • CO2 + H20 (both in the cell) -(CA)-> H2CO3 -> H+ + HCO3
    • A Na-HCO3 cotransporter on the basolateral surface moves Na and HCO3 into the plasma.
    • The aforementioned, apical Na-H exchanger moves H+ into the filtrate (to facilitate another conversion of HCO3 into CO2).

[edit] Formation of titratable acid

• Recall that the type A intercalated cells of the collecting duct secrete H+.
• Recall that H+ can readily cross back into the lining cells / interstitial fluid.
• In order to trap H+ in the filtrate, tubular cells of the nephron secrete the conjugate base of titratable acids (that is, anions that can accept another H+).

Where in the nephron does TA secretion occur?

• • So, as TA secretion increases, the pH of the filtrate (urine) decreases.
• The pH of filtrate decreases as it passes along the nephron.

[edit] Mechanism for formation of titratable acid

• Note that formation of titratable acid generates NEW bicarbonate for the blood.
• Recall the Na-H exchanger on the apical surface of proximal tubule cells that was used to reabsorb HCO3-.
• Recall the Na-HCO3- cotransporter on the basolateral surface of proximal tubule cells that was used to reabsorb HCO3-.
• The same source of H (the apical Na-H) provides H+ to protonate filtered TA-salts (like HPO4-2Na) to titratable acids (like H2PO4-1Na).
• The exchange of Na for H (Na moves into the cell, H+ moves into the filtrate) requires an intracellular supply of H+.
• CA provides the H+ by combining CO2 and H20 to generate H2CO3 and then H+ and HCO3-.
  • As the CA-produced H+ is moved into the filtrate in exchange for Na, the CA-produced HCO3- is moved into the blood along with Na (via the aforementioned Na-HCO3 cotransporter).
• Note that production of titratable acids uses CA and thus generates NEW bicarbonate for the plasma.

[edit] Excretion of ammonia

• First, note that when we say "ammonia" we mean both ammonium ion (NH4+) and the free base NH3.
  • Recall that ammonium ion and ammonia free base live in equilibrium: NH4+ <-> NH3+ + H+
  • Recall that pH can be calculated by the Henderson-Hasselbach equation if the pK_a is known for an conjugate acid / base pair.
  • In this case, the pK_a of NH4+ / NH3+ is 9.0.
  • pH = pK_a + log([A-]/[HA])
  • pH = pk_a + log([NH3]/[NH4])
  • Normally, urine has a pH around 7 (though it can vary from 4.4 to 8).
  • 7.0 = 9.0 + log([NH3]/[NH4])
  • -2 = log([NH3]/[NH4])
  • antiLog(-2) = [NH3] / [NH4]
  • 10^-2 = 1/100 so the ratio of NH3 to NH4 is 1:100.
  • That is NH4 >>> NH3.
  • So there is very little free H+ in the urine!

• Ammonia secretion by the nephron accounts for 2/3 of the H+ secreted by the kidney.
  • So it is an important part of the kidney's acid-base regulation response.
• Ammonia is produced by proximal tubule cells from amino acid metabolism, especially glutamine.
• Recall that the goal is to reduce acid and increase bicarbonate.
• Note that while titratable acid production can generate new bicarbonate, it requires titratable salts (like HPO4-2Na, HSO4-Na) which are of limited supply in the filtrate.
  • Therefore acid secretion by NH4/NH3 secretion is the primary method secreting lots of acid and producing lots of HCO3.
  • Ammonia synthesis can be increased over a series of days and is a life saving adaptation.

[edit] Mechanism for excretion of ammonia

• Recall that we can help balance pH by secreting acid and that NH4/NH3 (ammonia) molecules are the primary acid secreted in the nephron proximal tubule.
• We will look at this process as two steps: secreting ammonia acid and generating new HCO3.

• Secreting ammonia acid:
  • Recall that glutamine is the primary source of nitrogen for generating ammonia for secretion.
  • Glutamine can be converted to 2 NH4 molecules by intracellular enzymes of the tubule cells.
  • Here we introduce a third surface membrane: the Na-NH4 exchanger: the apical Na-NH4 exchanger moves Na from the filtrate into the cell and NH4 from the cell into the filtrate.
  • Simple enough: convert glutamine into two NH4 molecules and use the Na-NH4 exchanger to secrete NH4 into the filtrate.

• Generating new HCO3 for the plasma:
  • Recall that we can generate HCO3 if we can find some place to dump the H+ generated by the CA reaction.
  • Recall that glutamine can be converted to alpha-ketoglutarate which--with the addition of hydrogens--can be converted to glucose.
  • So with alpha-ketoglutarate (from glutamate) as an H+ acceptor (and because glucose will be happy to move out of the cell into the plasma) we can drive the CA reaction and generate HCO3.
  • Once the CA reaction has generated HCO3, it can follow Na into the plasma via the same, basolateral Na-HCO3 cotransporter as was used in HCO3 reabsorption and titratable acid production.

[edit] Most H+ secretion occurs in the proximal tubule

• Recall that most of the NH4/NH3 secreted by the nephron occurs in the proximal tubule.
• Recall that most HCO3 is reabsorbed in the proximal tubule.
• There is little change in the filtrate pH in the proximal tubule because:
  • most of the secreted acid reacts with HCO3 to form H2CO3 and
  • the proximal tubule has a leaky epithelium through which hydrogen ions and HCO3- can pass

• The collecting duct is the site of the largest blood-urine pH gradients.
  • This makes sense because it has a tight epithelium that does not allow the passage of water, H+, or HCO3-.
  • Recall that type A intercalated cells actively secrete H+ into the filtrate to combat acidosis.
  • Recall that type B intercalated cells actively secrete HCO3- into the filtrate to combat alkalosis.
  • Highest pH blood-urine gradient is 7.4 to 4.5.
    • What is the increase in [H+] over this gradient?
    • 7.4 - 4.5 = 2.9
    • So 10^{2.9</sub> ~= 1000; so the urine has 1000-fold higher concentration of H+.}

[edit] Factors that affect H+ secretion and excretion at the kidney

• Intracellular pH

**....

• Arterial PCO2

**Arterial PCO2 must be maintained such that CA can't function too quickly or PCO2 levels would rise too high.

• Carbonic anhydrase activity

**CA has an inherent maximum functionality; this limits the amount of HCO3 that can be produced for release into the plasma.

• • Note that acetazolamide inhibits carbonic anhydrase and can thus be used as a diuretic as decreased production of intracellular H+ (from the CA reaction) means less H+ for the apical Na-H+ exchanger which means less Na reabsorption which means less water reabsorption.

• Sodium reabsorption
  • Increased Na reabsorption occurs by exchange with H+ ions (into the filtrate) which means that increased Na reabsorption leads to increased acid secretion.

• Plasma potassium concentration
  • If K is low, a K+-H+ exchanger moves H+ from plasma into the tubular cells and K+ from the tubular cells into the plasma.

**Rise of H+ in the tubular cell means that more H+ will be secreted.

• Aldosterone
  • Elevated plasma aldosterone leads to increased Na+ reabsorption and increased apical H+ ATPase activity (which secretes H+).

**This causes increased H+ secretion.... 

• Availability of buffers
  • As buffer availability increases, less acid needs to be secreted and less HCO3 needs to be produced.

[edit] Timeline of acid-base compensation mechanisms

• Recall that the three acid-base compensation mechanisms have differing time frames:
  • chemical buffering is very fast (seconds)
  • pulmonary compensation is fast (minutes to hours)
  • renal compensation is slow (hours to days)

• stopped here on 03/30/11.