CASE 27. What is the response of the kidney to metabolic acidosis? What is the response of the kidney to a respiratory alkalosis?

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1 CASE 27 A 21-year-old man with insulin-dependent diabetes presents to the emergency center with mental status changes, nausea, vomiting, abdominal pain, and rapid respirations. On examination, the patient is noted to be hypotensive, breathing rapidly (tachypneic), and febrile. A fruity odor is detected on his breath. A random blood sugar is significantly elevated at 600 mg/dl. The patient also has hyperkalemia, hypomagnesemia, and elevated serum ketones. An arterial blood gas reveals a metabolic acidosis. The patient is diagnosed with diabetic ketoacidosis (DKA) and is admitted to the intensive care unit for intravenous (IV) hydration, glucose control, and correction of metabolic abnormalities. What is the response of the kidney to metabolic acidosis? What is the response of the kidney to a respiratory alkalosis? What is the predicted compensatory response to metabolic acidosis?

2 224 CASE FILES: PHYSIOLOGY ANSWERS TO CASE 27: ACID BASE PHYSIOLOGY Summary: A 21-year-old man with type I diabetes develops DKA and metabolic acidosis. Response of the kidney to metabolic acidosis: Increased excretion of the excess fixed hydrogen as ammonia and increased reabsorption of bicarbonate Response of the kidney to respiratory alkalosis: Decreased hydrogen excretion and decreased bicarbonate absorption Compensatory response to metabolic acidosis: Decrease in bicarbonate and in P CLINICAL CORRELATION This 21-year-old man with type I diabetes (insulin deficiency) has the clinical manifestations of DKA. The first priorities are always the ABCs: Because the airways and breathing are normal, the focus in this case is on the circulation. Two large-bore IV lines should be placed, and the patient should receive 2 L of isotonic solution. The cornerstones of therapy are insulin in an IV drip, correction of metabolic abnormalities, and detection of the underlying etiology of the DKA (such as an infection). Understanding how the body manages acid base changes is critical to make the correct diagnosis, develop a treatment plan, and monitor the effectiveness of the treatment. Respiratory acidosis and alkalosis primarily begin in the lungs, whereas metabolic acidosis and alkalosis begin with abnormalities of bicarbonate in the blood. An arterial blood gas can be done to help determine which type of acid base abnormality may be present. Metabolic acidosis can be differentiated into two groups: anion gap and non-anion gap. Examples of normal anion gap acidosis include renal tubular acidosis and gastrointestinal (GI) bicarbonate losses (diarrhea). Examples of increased anion gap acidosis include ingestion of methanol, ethanol or ethylene glycol (antifreeze), salicylates, cyanide, or paraldehyde; uremia or renal failure; lactic acidosis; and diabetic or alcoholic ketoacidosis. The serum anion gap can be calculated by determining the concentration of sodium minus the sum of the chloride and bicarbonate concentrations. The serum anion gap is increased if the concentration of an unmeasured anion is present and is normal if the concentration of chloride is increased to replace the bicarbonate. Treatment is based on diagnosing and treating the underlying disease process. In this example of DKA, the patient will be started on IV fluids, insulin to correct the DKA, and supportive care, depending on the severity of the symptoms. The potassium level will be monitored closely as the hyperkalemia will resolve with treatment of the acidosis and the addition of insulin.

3 CLINICAL CASES 225 APPROACH TO ACID BASE PHYSIOLOGY Objectives 1. Understand the role of the kidney in acid base balance. 2. Know how to calculate the anion gap and be able to list examples of disorders that cause anion gap acidosis. 3. Understand volatile and nonvolatile acids and buffers. 4. Understand the significance of the Henderson-Hasselbalch equation. Definitions 1. Hydrogen ion homeostasis: The process of maintaining the ph of the plasma at a constant value of Acid-base balance: Matching the daily intake or production of acids and bases with an equivalent daily excretion. 3. Carbonic acids: Substances such as fatty acids or carbohydrates whose end products of metabolism are and H 2 O. 4. Noncarbonic acids: Also known as fixed acids are substances such as phospholipids or sulfur containing amino acids whose end product of metabolism is a nonvolatile acid. DISCUSSION Acid base physiology includes H + ion homeostasis (maintaining the arterial ph at 7.4) and acid base balance: the ability to match the daily production of acids and bases with an equivalent excretion. A disturbance or change in the rates of ingestion, production, and excretion of acids or bases can alter the balance and cause a change in ph. The body has four lines of defense against an acid or base challenge to minimize the change in ph and restore acid base balance: 1. Simple chemical buffers in the blood (eg, the -bicarbonate buffer system, proteins such as hemoglobin and albumen) minimize a change in ph by reacting with an acid or base upon contact. 2. Intracellular buffering is afforded by the protein mass contained within the cells. This process requires the movement of protons (H + ) into the cell largely in exchange for potassium ions and is slower reacting than is the extracellular buffer pool. 3. Pulmonary compensation for a change in arterial ph or is effected by a neural feedback loop involving central and peripheral chemoreceptors that control the rate of ventilation. The -bicarbonate buffer system is unique in that one of its components,,is gaseous and is controlled by pulmonary ventilation. Changes in the rate of ventilation can increase or decrease the alveolar and thus the arterial concentration, compensating for changes in bicarbonate in response to a metabolic acidosis or alkalosis. The pulmonary response to changes in arterial ph or P is almost immediate.

4 226 CASE FILES: PHYSIOLOGY 4. The kidney responds to an acidosis or alkalosis by excreting nonvolatile acids or bases and controlling the rate of bicarbonate reabsorption. Unlike pulmonary ventilation, which is under the control of a neural feedback loop involving chemoreceptors that are sensitive to H +,, and O 2, renal function is controlled by mass action and the relative rates of H + secretion and bicarbonate filtration. Because the renal response is dependent on glomerular filtration and the transport of large amounts of electrolytes, it is somewhat slower responding than are the other buffer systems. It is worth noting that renal and pulmonary functions are coupled to each other because one of the main factors determining the rate of renal bicarbonate reabsorption is the arterial P. Many substances in the blood can serve as effective buffers; however, identifying each chemically distinct component is a monumental task. The task is simplified by the use of the isohydric principle, which states that in a mixed solution all acid base pairs are in equilibrium with each other. Thus, to assess the acid base status of a patient, it is not necessary to measure a hundred different species, but simply one representative pair. The most convenient and informative representative is the -HCO 3- -buffer system. The dissociation of an acid is governed by the physical chemical properties of acids and bases, and their behavior can be predicted from the Henderson- Hasselbalch equation: ph = pk + log [base] a [acid] The pk a or dissociation constant is characteristic for a specific acid base pair; thus, knowing any two of the three variables allows the calculation of the third. Physiologically, the most important pair is the and HCO 3 : + H 2 O H 2 CO 3 H + + HCO 3 This expression can be simplified by assuming that represents the free acid pool and HCO 3 is the conjugate base. The Henderson-Hasselbalch expression for the -HCO 3 buffer is ph pk log [HCO ] 3 = + a [CO ] where the pk a = 6.1 and the [ ] dis = 0.03 mmol/l_mm Hg. Under normal physiologic conditions, 2 dis [24 meq / L] ph = pk + log a [1.2 meq / L]

5 CLINICAL CASES 227 Perhaps one of the most important features of this expression is that the ph is not determined by the absolute concentration of either component, but is determined solely by the ratio [HCO 3- ]/[ ]. If the ratio gets larger (more HCO 3- or less ), the ph is more alkaline. If the ratio gets smaller (less HCO 3- or more ), the ph is more acidic. This greatly simplifies the understanding of the physiologic response to an acid base disturbance. For example, if the disturbance is of metabolic origin, there will be an initial change in [HCO 3 ]. A metabolic acidosis will decrease [HCO 3 ], and the ratio [HCO 3 ]/[ ] will shrink. To compensate for the change, there are two options: The [HCO 3 ] could be restored to normal, or the [ ] could be reduced. The pulmonary response to an acid base disturbance is mediated by central and peripheral chemoreceptors and is almost immediate. The initial response to a metabolic acidosis (fall in [HCO 3- ]) would be an increase in pulmonary ventilation (hyperventilation) to lower the P, thereby restoring the ratio [HCO 3 ]/[ ] more closely to normal. In this instance, the ph has been corrected, yet the acid base balance has been disturbed. To restore balance, the [HCO 3 ] must be restored to normal. The kidney will excrete the acid that caused the disturbance and generate bicarbonate at the same time to restore [HCO 3 ]. Because the lungs control the [ ] and the kidney controls the [HCO 3 ], one may view the Henderson-Hasselbalch equation metaphorically as follows: ph = pk + log [kidney] a [lung] Physiologically, acids can be divided into two groups. The distinction is made on the basis of their routes of production, the rates of production, and the routes of excretion. Carbonic acids often are referred to as volatile acids: 1. Carbonic acids are substances whose end product of metabolism is and water. is a volatile gas that is excreted by the lungs. Substances such as fats and carbohydrates are not acids or bases per se, but their metabolism yields and water. They are considered to be acids because the end product of their metabolism,, reacts with water to form carbonic acid: + H 2 O H 2 CO 3 H + + HCO 3 2. Noncarbonic or fixed acids are substances whose end products of metabolism are nonvolatile acids. For example, metabolism of phospholipids or proteins results in the production of H 3 PO 4 and H 2 SO 4. These are strong acids that readily dissociate in the blood and are nonvolatile substances that have to be excreted by the kidney. To understand the role of the kidney in acid base disturbances, it is necessary to understand the mechanism of bicarbonate reabsorption. In the tubular cells, secreted H + is formed by the dissociation of carbonic acid as follows: + H 2 O H 2 CO 3 H + + HCO 3

6 228 CASE FILES: PHYSIOLOGY For each H + that is formed and secreted, a bicarbonate ion is formed and transported into the blood. The secreted H + has several available fates. If it reacts with filtered bicarbonate, it is neutralized and there is no net gain or loss of bicarbonate. The secreted H + also can react with a titratable acid or NH 3. A bicarbonate is added to the blood, but the H + is excreted in the urine as titratable acidity (TA) or ammonium ion. In either case, there is a net gain of one bicarbonate and the excretion of one fixed acid. Titratable acids are weak acids in the glomerular filtrate, such as uric acid, which can react with secreted H +. They are formed at a steady rate and are of limited availability during an acid base disturbance. However, the primary adaptive response of the kidney to a chronic acidosis is ammoniagenesis, the increased production of NH 3 from glutamine. The maximal adaptive response may take several days and can augment the daily excretion of H + by twofold to threefold. In the case of an alkalosis, the situation is reversed. If the rate of bicarbonate filtration exceeds the rate of H + secretion, excess bicarbonate is not reabsorbed but simply is excreted in an alkaline urine. What factors control the rate of H + secretion? The bulk (~90%) of bicarbonate reabsorption and H + secretion occurs in the proximal tubule. The mechanism of H + secretion is via a Na + -H + exchanger in the apical membrane of the tubular cells. This exchanger is regulated by the intracellular ph, with activation occurring at more acidic cytosolic ph. In the present discussion, the key factors that will influence the intracellular ph are the arterial H + and the arterial P. An increase in either of those two factors will cause an increase in intracellular H + and activation of the Na + -H + exchanger. In the present case, there was an uncontrolled overproduction of ketoacids as a consequence of the insulin insufficiency. Normally, ketoacids are oxidized to and water and eliminated as through pulmonary ventilation. In a DKA, their production exceeds the oxidative capacity, with their accumulation in the blood. These ketoacids dissociate in the blood, yielding the carboxylate anion and H + that were buffered by the chemical buffers in the blood and the intracellular compartment. The H + reacted with bicarbonate, reducing its concentration with the production of, which was eliminated through pulmonary ventilation. This reaction created the anion gap. The fall in bicarbonate also resulted in a fall in the arterial ph that would stimulate peripheral chemoreceptors. Increased peripheral chemoreceptor activity would stimulate ventilation to initiate a compensatory fall in P. The function of the kidney in this circumstance is to restore acid base balance by eliminating all the excess fixed (or noncarbonic) acid that was generated in the episode and at the same time restore bicarbonate back to normal levels. Although the P is reduced, the arterial H + is elevated, and this will lead to a parallel rise in the intracellular H + concentration to ensure the activity of the Na + -H + exchanger. The plasma [HCO 3 ] is reduced; therefore, the filtered load of HCO 3 is reduced, and thus all filtered HCO 3 will be reabsorbed. The generation of additional HCO 3 requires that H + be excreted. In fact, under these conditions the rate-limiting factor for HCO 3 reabsorption is not H +

7 CLINICAL CASES 229 secretion but H + excretion. The availability of TA and NH 3 is limiting for binding to the secreted H +. In a chronic state, the kidney will increase production of NH 3, but this may take several days. Over a period of days, the fixed acid generated during the acidosis will be excreted with the addition of an equivalent amount of HCO 3 to the blood. As the HCO 3 levels in the blood are restored, there will be a gradual rise in the ph toward a normal 7.4, and as the ph rises, the hyperventilation will abate. When the entire acid load is excreted, HCO 3 will be restored to normal and acid base balance will be restored. COMPREHENSION QUESTIONS [27.1] Recovery from a severe metabolic acidosis is most dependent on which of the following? A. The rate of ventilation to blow off excess B. The rate of H + secretion by the kidney C. The rate of H + excretion by the kidney D. The arterial ph E. The arterial P [27.2] After a rapid ascent to very high altitude, one begins to hyperventilate because of hypoxic drive. The hyperventilation will cause a decrease in the arterial P. What is the renal response to this condition? A. Increased rate of acid excretion B. Decreased rate of acid excretion C. Increased rate of bicarbonate reabsorption D. Diuresis to eliminate excess fluid E. Increased ammoniagenesis [27.3] A 21-year-old man with gastroenteritis developed severe vomiting with a loss of stomach acids. A metabolic alkalosis is present. Which of the following is most likely to occur? A. The plasma bicarbonate concentration will decrease. B. H + will move from the plasma into the cells. C. Peripheral chemoreceptors will stimulate pulmonary ventilation. D. Renal H + excretion will decrease. Answers [27.1] C. The rate of recovery from a severe metabolic acidosis is most dependent on the rate of H + excretion. Pulmonary compensation occurs rapidly; however, it can only minimize the change in ph. Pulmonary compensation cannot restore the balance after a metabolic disturbance. Recovery necessitates the excretion of the entire acid load to the system. Renal acid excretion is limited by the availability of titratable acids and ammonia for ammonium ion formation from

8 230 CASE FILES: PHYSIOLOGY secreted H +. The primary adaptive response of the kidney to an acidosis is ammoniagenesis. Ammoniagenesis can augment the daily excretion of acids as much as threefold. When an equivalent amount of acid is excreted, acid base balance will be restored. [27.2] B. The two most important drivers of renal bicarbonate reabsorption are and H +. The hyperventilation experienced at high altitude decreases the P, which generates a respiratory alkalosis. Reducing both and H + will decrease renal H + secretion and thus bicarbonate reabsorption. The filtered bicarbonate load will exceed the rate of H + secretion with a loss of excess bicarbonate in the urine. [27.3] D. The loss of gastric (hydrochloric) acid leads to an increase in the plasma bicarbonate concentration and a metabolic alkalosis. The increase in the ph will depress peripheral chemoreceptors to slow ventilation and increase the P to compensate for the increased bicarbonate. The increase in P will bring the ph nearer to 7.4 and at the same time increase renal H + secretion. Because there is an increased level of bicarbonate in the glomerular filtrate, there will be an increase in bicarbonate reabsorption. The rate of filtration will exceed the rate of H + secretion, and there will be a continuous loss of bicarbonate. As the plasma bicarbonate falls, the ph will continue to approach the normal of 7.4 and the ventilatory rate will increase gradually. When all the excess bicarbonate has been excreted, the plasma bicarbonate and ph will have returned to normal with a normal respiratory rate. PHYSIOLOGY PEARLS Carbonic acids are substances whose end products of metabolism are and water, such as triglycerides and carbohydrates. Noncarbonic or fixed acids are substances whose end products of metabolism are nonvolatile, such as phosphoric acid and sulfuric acid produced from phospholipids and protein breakdown. The rate of bicarbonate reabsorption is dependent on the relative rates of bicarbonate filtration and H + secretion. The rate of urinary acid excretion is limited by the availability of titratable acids and NH 3. Ammoniagenesis is the primary adaptive response of the kidney to a chronic acidosis. The isohydric principle states that in a mixed solution all the acid base pairs are in equilibrium with each other. The Henderson-Hasselbalch equation relates the ph of the plasma to the concentrations of HCO 3 and. The ratio [HCO 3 ]/[ ] determines the ph. Respiratory function controls, and renal function controls [HCO 3 ].

9 CLINICAL CASES 231 REFERENCES Goodman HM. The pancreatic islets. In: Johnson LR, ed. Essential Medical Physiology. 3rd ed. San Diego, CA: Elsevier Academic Press; 2003: Rose BD, Post TW. Clinical Physiology of Acid-Base Disorders. 5th ed. New York: McGraw-Hill; 2001:

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