One of the main functions of the kidney is to regulate acid–base homeostasis, maintaining the intracellular pH within a narrow window. The normal values for plasma pH differ between the venous and arterial system, as carbon dioxide is produced by tissue metabolism, resulting in a lower pH of the venous system. In the blood, acid is buffered by the bicarbon- ate system, with the following reaction representing the equilibrium which determines the free proton concentration:
H++HCO3−↔H CO2 3↔CO2+H O2
In this reaction, H + (the proton concentration in the blood) and HCO 3 - (the bicarbonate concentration) are in equilibrium with carbonic acid, H 2 CO 3 . Carbonic acid can be converted to carbon dioxide and water, catalyzed by the enzyme carbonic anhydrase. Carbon dioxide exists as a dissolved gas, and removal is regulated by the respiratory system. The concentra- tion of H + in the blood is determined by this equilibrium and can be calculated using the Henderson-Hasselbalch Equation:
-
3 2
pH 6.1 log ([HCO ]/(0.03 pCO ))= + × where pH = −log[H + ].
The medullary thick ascending limb and the S3 segment of the proximal tubule are particularly susceptible to ischemic damage due to their high metabolic activity in low-oxygen environment.
The acidity of the blood is determined by the ratio of the concentration of bicarbonate and the carbon dioxide tension. Excess acid in the blood, acidemia, occurs when there is a low pH, while an increase in serum pH is called alkalemia. In contrast, the term acidosis refers to a process which leads to an increase in the serum H + concentration, while alkalosis is a process which leads to a decrease in proton concentration. The maintenance of pH within a narrow range is accomplished by the combination of a complicated buffering system, respiratory adjustment of carbon dioxide tension, and renal regulation of proton secretion. A disruption of any one of these systems can result in a predictable disturbance of the serum pH (Fig. 6-15 ).
In the event of an acid load, the normal response involves buffering and cellular distribu- tion, respiratory compensation and renal hydrogen excretion. The time course for each of these mechanisms varies (Fig. 6-16 ). In response to an acid load, there is immediate distribu- tion of the acid and buffering by extracellular mechanisms, primarily the bicarbonate sys- tem. Within several hours, there is additional buffering from intracellular buffers such as phosphates, proteins, and hemoglobin. Bone represents another important reservoir for buff- ering, with as much as 40% of an acid load being buffered by bone. Skeletal muscle is an additional buffer that can be important in end stage renal disease. Respiratory compensation, with an increase in ventilation in response to acidemia, begins within 1 hour, has a maximal response at 6–12 h and is complete within 24 h. Renal acid excretion takes a number of days, and a maximum response may not be seen for 4–6 days. It is important to remember that the net result of renal secretion of one proton, H + , results in the addition to the blood of a bicar- bonate ion, HCO
3 - , which can then be used to buffer the daily acid load.
There are a number of sources for acid production (Table 6-8 ), including consumption of acidic foods, metabolism of dietary products and loss of bicarbonate in stool (Fig. 6-17 ). Loss of bicarbonate in the stool contributes to the acid load, as for each bicarbonate molecule lost there is retention of a H + molecule in the extracellular fl uid. Metabolism of carbohydrates and fats leads to generation of carbon dioxide, a volatile acid, which can be removed by respiration.
Nonvolatile acids are formed from the metabolism of proteins. Nonvolatile acids are initially buffered in the blood, but ultimately must be excreted by the kidneys in order to maintain a
The regulation of pH is accom- plished by the combination of a complicated buffering system, respiratory adjustment of carbon dioxide, and renal regulation of proton secretion.
FIGURE 6-15
Acid–base nomogram demonstrating the different primary acid–base disturbances and their relationship to blood pH, CO 2 tension, and H + and HCO 3 - concentrations. (Adapted from Disorders in Acid Base, Brenner and Rector's The Kidney, 8th ed 2007)
60
100 90 80 70 60 50 40
90 100 110
120 80 70
Metabolic alkalosis Chronic
respiratory acidosis
Chronic respiratory
alkalosis
Pco2(mm Hg) Metabolic
acidosis Acute respiratory
acidosis
Acute respiratory alkalosis Normal
60 50 40
35
30
25
20
15
10
30 20
56 52 48 44 40 36 32
Arterial plasma [HCO3–] (mmoI/L)
Arterial blood [H+] (nmoI/L)
28 24 20 16 12 8 4 0
7.0 7.1 7.2 7.3 7.4
Arterial blood pH
7.5 7.6 7.7 7.8
SOURCES OF ACID LOADS 1. Dietary consumption
2. Secondary to metabolism of endogenous compounds 3. Loss of buffer (i.e. stool bicarbonate loss)
4. Rapid growth
TABLE 6-8
SOURCES OF ACID LOAD FIGURE 6-16
Graph depicting the time course of distribution, buffering, respira- tory compensation and renal excretion of an acid load (Reproduced with permission from Cogan ( 1991 ) )
% of total response
Distribution and extra- celluar buffering
Cell buffering
Respiratory compensation
Renal H+
excretion
6 12
Hours
24 72
100 H+
Load
50
stable serum pH. Protons can be secreted by the kidneys as titratable acids or by generation of ammonium. Although production of an acidic urine is an important part of the process for proton secretion, the actual concentration of free H + molecules within the range of attainable urine pH is negligible. Under normal circumstances, the amount of endogenous acid production is rela- tively small (~1 mEq/kg/day), but this can increase in pathological states such diabetic ketoaci- dosis. The endogenous acid load in growing children is also higher, reaching 2 mEq/kg/day.
In a normal adult, there is a daily acid load of about 50–100 mEq which must be excreted in order to maintain acid–base balance. In addition, in a healthy adult with a normal GFR, FIGURE 6-17
Diagram depicting the renal regulation of acid–base balance.
Acid is generated by growth, metabolism, stool losses, and diet. The kidney must reabsorb fi ltered HCO 3 - and excrete net acid as ammonium or titratable acid to regulate the load
Diet
Growth Stool losses Metabolism Filtered HCO3– Generation of
daily acid load
Renal H+ production Ammonium generation,
net H– secretion
H+ combines with HCO3– Recovery of filtered HCO3– H+ combines with
titratable acid
about 4,300 mEq of bicarbonate is fi ltered by the kidneys and must be recovered. About 90%
of the fi ltered bicarbonate is reabsorbed in the proximal tubule. Within the tubular cell, a proton and bicarbonate are formed from water and carbon dioxide, under the action of car- bonic anhydrase (Fig. 6-18 ). A proton, H + , is then secreted into the lumen primarily by Na + / H + exchange, with a small proportion transported by H + ATPase. The net result is the addition of H + to the lumen and HCO
3 - to the blood. H + in the lumen then combines with fi ltered bicar- bonate to form water and CO
2 within the lumen. The energy for bicarbonate recovery from the cell comes from the Na + -K + -ATPase on the basolateral membrane. Active transport of sodium out of the tubular cell lowers the intracellular sodium concentration, creating a nega- tive potential within the cell which facilitates transport of bicarbonate out of the cell by the Na + -3HCO
3 - cotransporter. Filtered bicarbonate, which is not reabsorbed in the proximate tubule, is recovered distally in the thick ascending limb and collecting duct. In the cortical collecting duct, Type A intercalated cells respond to an acid load by insertion of H + ATPase, stored in cytoplasmic vesicles, into the luminal membrane. Bicarbonate is then transported out of the cell into the blood by a Cl - /HCO
3 - exchanger in the basolateral membrane.
As was previously discussed, secretion of the daily acid load can be accomplished by one of two processes: through excretion by urinary titratable acids or by secretion of ammonium (Fig. 6-17 ). Secretion of actual free hydrogen ions has a minimal effect, since within the range of achievable urine pH, a negligible amount of the daily acid load can be secreted.
There are a limited number of titratable acids which can contribute to proton secretion since acids can only work as buffers near their pKa values. The main titratable acid is phosphate (H 2 PO
4 - ), which has a pKa of 6.8. Other acids, such as creatinine and uric acid, play a minor role. Within the lumen, the addition of a proton to HPO
4 2- results in the formation of H
2 PO
4 - , which can then be excreted.
2
4 2 4
H++HPO −→H PO −
The ability of this buffering system is limited by the quantity of titratable acids which are present in the urine. Under normal conditions in an adult, 10–40 mEq of H + can be buffered by titratable acids. While this is helpful to excrete the daily acid load, there is a limited
FIGURE 6-18
Diagram depicting the recovery of fi ltered bicarbonate in the proxi- mal tubule, which is mediated primarily by Na + -H + exchange, as well as an H + -ATPase, across the apical membrane. Carbonic anhydrase along the apical membrane ( CA IV ) and in the cytosol ( CA II ) facilitates the hydration and dehydration of H 2 CO 3 . The bicarbonate ion that is actually reabsorbed comes from the splitting of H 2 CO 3 within the cell and exits with Na + across the basolateral membrane via the Na + - 3HCO 3 - cotransporter
H2CO3 H2CO3
HCO3– 3HCO3– H+
H+ H+ H+
Na+
Proximal Tubule Cell Solutes
Lumen
CA (II)
CA = carbonic anhydrase CA (IV)
K+ Na+
Na+
Na+ HCO3–
H2O + CO2 H2O + CO2
–
Volatile acids can be removed by respiration, while ultimately non-volatile acids must be excreted by the kidneys as titratable acids or through ammonium generation.
capacity to increase excretion in the event of a disturbance. One exception to this inability to increase excretion occurs in diabetic ketoacidosis, in which the generation of ketone anions, such as betahydroxybutyrate, can act as titratable acid. In most conditions, the major adap- tive mechanism to respond to an acid load is the generation and secretion of ammonium, which can result in the secretion of up to 300 mEq H + /day in the face of acidosis. The pro- duction of ammonium is a complicated process which involves multiple segments of the nephron. In the early (S1) proximal tubule, ammonia (NH 3 ) is formed from glutamine. In the tubular lumen, the ammonia is then protonated to form ammonium (NH 4 + ) (Fig. 6-19 ).
NH (ammonia)3 +H+↔NH (ammonium)4+
The proximal tubule is impermeable to the charged molecule, and thus, the NH 4 + is trapped in the lumen. Within the loop of Henle, there is equilibrium between ammonia and ammo- nium. Through substitution in potassium channels (primarily Na + -K + -2Cl - cotransporter), NH 4 + is transported into the cells of the thick ascending limb. The NH 4 + then dissociates to a proton and NH 3 . NH 3 is unable to diffuse back into the lumen because this portion of the nephron is impermeable to NH 3 . Instead, NH 3 diffuses into the medullary interstitium. From there, some NH 3 is recycled back to the proximal tubule, while the rest diffuses throughout the interstitium. In the collecting duct, there is a low concentration of NH 3 within the lumen.
This portion of the nephron can have a pH as low as 4.5 due to proton secretion. This favors the formation of NH 4 + from any NH 3 within the lumen, thereby keeping the concentration of NH 3 within the lumen low. Since the collecting duct is permeable to NH 3 , ammonia diffuses down a concentration gradient from the ammonia rich interstitium into the lumen of the col- lecting duct. Within the lumen, the ammonia is protonated to NH 4 + which is then excreted.