The Renal Role in Acid Base Balance Dr

The Renal Role in Acid Base Balance Dr. Dave Johnson Associate Professor Dept. Physiology UNECOM

Review of Basics n Acid/Base refers to anything having to do with the concentrations of free H+ ions in aqueous solutions n p. H = - log [H+] n Therefore, the ‘normal’ p. H of 7. 40 means there are 10 -7. 40 moles of free H+ ions in a liter of plasma. n This is equivalent to about 40 n. Mol / L

Acid Base Pairs n An acid is a compound that can donate a proton to a solution. n An base is a compound that can take up a proton from a solution. n When an acid loses it’s proton, it becomes the conjugate base of that acid.

Biological Buffers n The 3 major buffering systems of biological fluids are: 1. 2. 3. Bicarbonate buffering system Protein buffering system Phosphate buffering system

Isohydric Principle n The isohydric principle simply denotes the fact that, even though there are 3 principle types of buffering systems in biological fluids, in an acid/base crisis, they all work together. This is because the H+ ion is common to all of them.

Bicarbonate Buffer n The major components of the bicarbonate buffering system are carbon dioxide (C 02), which serves as the conjugate acid, and bicarbonate ion (HCO 3 -), which serves as the conjugate base. n This acid/base pair is unusual, since C 02 has no proton associated with it - therefore it is usually described as a ‘potential’ acid, since increases in C 02 can potentially increase free H+ ion concentrations, and thus lower p. H. n n C 02 + H 2 O H 2 CO 3 H+ + HCO 3 - The concentration of H 2 CO 3 is about 340 times LESS than dissolved C 02 and 6800 times LESS than HCO 3 - at normal p. H, so it is usually ignored and the equation is written as: n n C 02 + H 2 O H+ + HCO 3 - This reaction is greatly accelerated by the presence of carbonic anhydrase!

Dissolved CO 2 n CO 2 is a gas, and only CO 2 dissolved in the ECF is available to participate in acid base reactions. n It is known that the ‘normal’ partial pressure exerted by CO 2 in plasma is 40 mm Hg (ie, p. CO 2 = 40). n It is also known that the solubility constant of C 02 (ie, how much C 02 gas dissolves for each mm Hg of partial pressure exerted by the gas in solution) is 0. 03. Therefore: 0. 03 m. Mol CO 2 / L / mm Hg n Thus, at normal p. CO 2 of 40 mm. Hg, there is 1. 2 m. Mol/L plasma of dissolved CO 2 in the ECF, that can participate in acid base reactions (40 x. 03 = 1. 2)

Henderson-Hasselbalch Equation n It is important to recognize that it is the RATIO of the log of the conjugate base to the log of the conjugate acid of ANY buffering system in solution that determines the p. H of that solution: p. H = p. K + log [A-] / [HA] Plugging in the values for the plasma concentration of ANY buffering pair in the ECF would give you the p. H of the ECF (isohydric principle). For the bicarbonate buffering system, it is written as follows: p. H = 6. 1 + log [HCO 3 -] / 0. 03 x PC 02 p. H = 6. 1 + log [24] / 0. 03 x 40 p. H = 6. 1 + log (24 / 1. 2) p. H = 6. 1 + log 20 p. H = 6. 1 + 1. 3 p. H = 7. 4

Role of the Kidneys n There are 3 major roles the kidneys play in maintaining acid base balance: 1. They must recapture the daily filtered load of HCO 3 - ions by reabsorbing them. 2. They must excrete into the urine any excess free H+ ions which are added to the body fluids daily 3. The kidneys must also replace any HCO 3 - used up titrating these excess acids produced daily.

n “Life is a struggle, not against sin, not against the Money Power, not against malicious animal magnetism, but against hydrogen ions". H. L. Mencken

Recapturing Filtered HCO 3 n HCO 3 - is readily filtered into Bowman’s space, but normally very little escapes into the urine. n Around 85% of the HCO 3 - filtered load of is reabsorbed in the proximal tubules, 10 -15% in Henle’s loop, and only 3 -5% at more distal sites. n Note the mechanism utilized: secreted protons combine with the filtered HCO 3 -.

Recapturing Filtered HCO 3 n It is important to recognize that the loss of any free HCO 3 - into the urine is equivalent to the addition of free H+ ions to the ECF: C 02 + H 2 O H+ + HCO 3 n The loss of HCO 3 - from the ECF lowers the ratio of base (HCO 3 -) to acid (CO 2) in the ECF, and will therefore result in an increase the free H+ ion concentration (and thus a decrease the p. H!)

Generating New HCO 3 CO 2 + H 20 H+ + HCO 3 - n During a metabolic acidemia, free H+ ions are added to the ECF for some reason, which “uses up” HCO 3 - in the buffering process. n The equation above shifts to the LEFT, generating CO 2. n This HCO 3 - that buffered the excess H+ ions is lost for good, and MUST BE REPLACED to bring plasma HCO 3 - levels back up to approximately 24 m. Mol/ L.

HCO 3 - Generation in the Proximal Tubules using Titratable Acids n PROXIMAL TUBULE: Similar to what you saw previously for HCO 3 REABSORBTION here, except now a H+ is excreted into the urine, generating a new HCO 3 -. n In this scenerio, filtered sodium monohydrogen phosphate (Na 2 HPO 4) serves as a proton acceptor (base), and is converted to the acid, Na 2 H 2 PO 4.

HCO 3 - Generation in Distal Tubules and Collecting Ducts using Titratable Acids n DISTAL TUBULE AND COLLECTING DUCTS: Similar to what you saw here previously for HCO 3 - REABSORBTION here, except now a H+ is excreted into the urine, generating a new HCO 3 - n As you just saw in the proximal tubule, a filtered Na 2 HPO 4 serves as the proton acceptor, and is converted to Na 2 H 2 PO 4.

What is Titratable Acidity? n The amount of strong base (such as Na. OH) that it takes to titrate a patient’s urine that is acidic back to normal p. H (~7. 42) is approximately equal to the amount of titratable acids that were in the urine (ie, if 45 m. Mol of Na. OH were required to titrate urine p. H up to 7. 42, the assumption can be made that 45 m. Mol of H+ ion were buffered by titratable acids, and 45 m. Mol of ‘new’ HCO 3 - were generated). n Dihydrogen phosphate is the major titratable acid measured in urine. n A healthy individual can easily generate some 50 to 100 m. Eq’s of H+ ions daily, However, titratable acidity normally can account for the excretion of only about 10 to 40 m. Eq of H+ ion per day.

Limitations of Titratable Acids n As the filtrate passes from Bowman’s space to the collecting tubules, the p. H can drop all the way to about 4. 50. This is an important concept, because urinary p. H cannot drop below approximately 4. 50. n Unfortunately almost all titratable acids will be fully protonated when the urine p. H reaches about 5. 20.

Importance of Urinary Acid Buffering…. . n Assumption: individual has to excrete 100 m. Eq (m. Mol) of H+ ion a day to stay in acid / base balance (this is about average). n As noted, the minimum p. H that can be achieved by the urine is about 4. 50. Although urine with a p. H of 4. 50 has a H+ concentration about 1000 times greater than healthy plasma (7. 42 vs 4. 50…. . about 3 log units), the H+ ion concentration of this urine with a p. H of 4. 5 is still only about 40 u. Mol/L (normal plasma is 40 n. Mol/L). n Thus, to get 100 m. Mol’s of unbuffered H+ ion into the urine each day you would have to produce about 2500 liters of this urine !! (2500 L x 40 u. Mol H+ ion/L = 100, 000 u. Mol H+ ion = 100 m. Mol of H+ ion )

Ammonia Buffering n Many years ago, it was observed that in those patients experiencing metabolic acidemia, there was not only a rise in urinary titratable acid’s, but also in urinary ammonium ion (NH 4+). n We now know that ammonium ion is a very important renal buffer, because the amount available is not directly dependant on diet or filtration, like titratable acids such as monohydrogen phosphate.

Ammonia Buffering n Ammonium ion can actually be produced in the cells lining the nephron, predominately in the proximal tubule, mostly (but not exclusively) from the deamination of of the amino acid glutamine. n The synthesis of ammonium ion in the proximal tubule occurs as follows: Glutamine----> 2 NH 4+ + -ketoglutarate

How Does This Help? n The subsequent metabolism of -ketoglutarate in the proximal tubular cell results in the CONSUMPTION OF TWO H+ ions. Removal of two H+ ions is equivalent to the GENERATION OF TWO NEW HCO 3 - ions in these cells. These two new HCO 3 - ions are transported across the basolateral membrane of the cell via a Na+/ HCO 3 - symporter, and returned to the general circulation. n The ammonium ion (NH 4+) is transported into the luminal fluid, mostly by substituting for H+ on the Na+/H+ antiporter, and passed out into the urine. Once in the tubule, it cannot diffuse back in due to it’s charge, and is thus lost in the urine. n The urinary excretion of NH 4+ plays NO DIRECT ROLE in removing protons: NH 4+ is merely a side product - or marker - of the formation of ketoglutarate in renal proximal tubular cells.

It Works n Therefore, proximal tubular secretion and subsequent urinary excretion of each NH 4+ ion is linked to the generation of a new HCO 3 - ion in proximal tubular cells, which will then be returned to the circulation to replace HCO 3 lost buffering excess plasma H+ ions.

Graphic Proof n Notice that AKG metabolism to C 02 and H 20 in proximal tubule cells consumes two H+ ions. n Now, an intracellular HCO 3 - in equilibrium with a H+ becomes a ‘free’ HCO 3 - n NH 4+ MUST be excreted in the urine after it is secreted from the cell. If it were reabsorbed, it would eventually be converted to urea in the liver, a process which generates two H+ ions (which would then consume two HCO 3 ions).