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  1. 1. ACID–BASE 4 BALANCE AND REGULATION OF pH Chapter objectives After studying this chapter you should be able to: b Define the normal range for plasma pH. c Explain the role of the kidney in the steady state elimination of acid produced daily by metabolism. d Outline the defence mechanisms which act to prevent an abrupt change in pH in response to an acid load. e Describe the mechanism for acid transport in the different nephron segments. f Recognize the clinical and biochemical features of metabolic acidosis, list some causes and give an approach to the differential diagnosis. g Recognize metabolic alkalosis, list some causes, and explain the pathophysiology of this disturbance during prolonged vomiting.
  2. 2. SYSTEMS OF THE BODY 4 Introduction Acid–base balance and regulation of ACID–BASE BALANCE AND REGULATION OF pH pH box 1 Just as the kidney is a critical organ in defending the normal set points for extracellular fluid (ECF) A case of acidosis volume, osmolality and potassium concentration, it also plays a central role in the homeostasis of the Mrs Mary Loy is a 48-year-old woman of Chinese plasma pH. While chemical buffering mechanisms background who has been sent by her family doctor and respiratory elimination of carbon dioxide are to the Emergency Department because of his concern important in immediate responses to disturbances in about her clinical condition and some biochemical acid–base balance, it falls to the kidney to make long- results. term adjustments in the rate of acid excretion which She had been complaining for some weeks of allows the external balance with respect to hydrogen increasing lethargy, an extensive rash and ‘heavy ion concentration to be maintained. This chapter will breathing’. She had been receiving treatment for focus on the mechanisms whereby the kidney achieves 4 years for systemic lupus erythematosus (SLE), a this role, and the origin of some disturbances of this multiorgan autoimmune condition for which a con- system in disease. sultant rheumatologist had prescribed prednisone. See box 1. However, Mrs Loy confessed to having discontinued The clue in this case that there is a disturbance of this medication some 10 months earlier because she acid–base metabolism is that the bicarbonate concen- was unhappy about its side effects. tration, representing the base component of the prin- On examination she was febrile, unwell and had an cipal physiological buffer system, is greatly reduced erythematous rash on her face and limbs. Her blood below the normal range. This is consistent with acid pressure was 110/80, pulse rate 100 beats/min and accumulation in the ECF, for which we must explore respiratory rate 20/min, the breathing being deep both the cause and the consequences. and sighing. The referring doctor’s letter indicated The key parameter involved in acid–base regulation that he had obtained a urinalysis result that morning is the concentration of H+ in the ECF. The physiological showing: pH 7, blood +++ and protein ++. set point for this parameter is 40 nmol/L, usually He had also obtained plasma biochemistry the pre- expressed (using the negative base 10 logarithm) as the vious day, the results of which are as follows: pH, which is normally 7.40. So important is homeosta- Sodium 135 mmol/L sis of this parameter to the normal operation of meta- *Potassium 3.1 mmol/L bolism and cellular function that pH is tightly regulated *Chloride 113 mmol/L in the range 7.38–7.42, although a somewhat wider *Bicarbonate 13 mmol/L range is compatible with life (7.0–7.8). Urea 8.0 mmol/L Two forms of acid are generated as a result of normal Creatinine 0.09 mmol/L. metabolic processes. Oxidative metabolism produces a large amount of CO2 daily, and this so-called ‘volatile The family doctor is particularly concerned about the acid’ is excreted through the lungs. Carbon dioxide low bicarbonate, which he interprets as a sign of acid effectively acts as an acid in body fluids because of the build-up, and seeks full evaluation of her clinical and following reactions: metabolic problem. c.a. (*Results outside the normal range; see Appendix.) CO2 + H2O ∫ H2CO3 ∫ H+ + HCO3- The first reaction (formation of carbonic acid, H2CO3) is the rate-limiting step and is normally slow, but in The most important mechanism preventing change in the presence of the enzyme carbonic anhydrase (c.a.) the pH of the ECF is the carbonic acid/bicarbonate the reaction is greatly accelerated. The subsequent ion- buffer system outlined above. The importance of this ization of carbonic acid proceeds almost instanta- buffer pair relates to certain key properties: bicarbon- neously. This equation can be rearranged to enhance ate is present in a relatively high concentration in the its physiological utility in the form shown in Fig. 4.1, ECF (24 mmol/L) and the components of the buffer as the Henderson–Hasselbalch equation. system are effectively under physiological control: the The other form of acid, the so-called ‘non-volatile CO2 by the lungs, and the bicarbonate by the kidneys. acid’, results from the metabolism of dietary protein, These relationships are illustrated in Fig. 4.1. resulting in the accumulation of some 70 mmol of acid It is clear from this relationship that a shift in pH can per day in an average adult on a typical western meat- be brought about by either a primary change in the 50 containing diet. bicarbonate concentration (metabolic disturbances) or
  3. 3. THE RENAL SYSTEM 4 in the partial pressure of CO2 in the blood (respiratory ACID–BASE BALANCE AND REGULATION OF pH disturbances). However, it can also be seen that alter- Role of the kidney in H+ balance ations in each of these parameters may represent a compensatory change whereby either the kidney or Before we can make further progress in analysing the the lung can act to limit the extent of pH change which acid–base problem in our patient, it is necessary to would occur because of a primary disturbance in res- consider the role the kidney plays in maintaining piratory function or in metabolism, respectively. The acid–base balance under normal conditions. Given patterns of resulting clinical acid–base disturbances that bicarbonate buffer is freely filtered at the glomeru- will be discussed later in this chapter. lus and that there is a daily load of non-volatile acid to be excreted into the urine, there must be two com- ponents to the nephron’s task: reabsorption of filtered bicarbonate, and addition of net acid to the tubular 1° changes in fluid. metabolic disturbances 2° changes after renal compensation for respiratory disturbances* Bicarbonate reabsorption - [HCO3 ] Bicarbonate is the principal physiological buffer in the pH=6.1+ log 0.03 × pCO2 plasma and it is freely filtered at the glomerulus. If this bicarbonate were not fully reabsorbed by the tubular 1° changes in system, there would be ongoing losses of essential respiratory disturbances buffer into the urine, resulting in progressive acidifi- 2° changes after cation of the body fluids as metabolic acid production respiratory compensation for continued. In fact, bicarbonate excretion is essentially metabolic disturbances zero under normal conditions because of the extensive Fig. 4.1 and efficient reabsorption of bicarbonate, principally Effect of changes in HCO3- and pCO2 on net pH of the in the proximal tubule as shown in Fig. 4.2. plasma. This is an applied version of the As discussed in Chapter 2, the cells in this tubular Henderson–Hasselbalch equation. Normal plasma segment contain a sodium–hydrogen exchange carrier [HCO3-] = 24 mmol/L, normal pCO2 = 40 mmHg, giving a molecule known as NHE-3 in the apical cell mem- normal plasma pH of 7.40. The pH will return to 7.40 as brane. As sodium enters the cell from the luminal fluid long as the ratio of [HCO3] : [0.03 ¥ pCO2] is 20 : 1. *Note down its electrochemical gradient via this carrier, it that changes in HCO3- concentration are also made as effectively removes hydrogen ions from the cell cyto- part of the renal correction of sustained metabolic plasm and adds them to the luminal fluid. The hydro- acid–base disturbances as long as the kidney itself is not gen ions are generated within the cell by the action of the cause of the primary disturbance. the enzyme carbonic anhydrase, which catalyses the reaction between CO2 and water to produce carbonic acid. This rapidly breaks down to produce the hydro- gen ions that are secreted into the lumen, and a bicar- Lumen Blood bonate ion which is transported across the basolateral filtered cell membrane into the plasma. (Note that this is - 3Na+ Na+HCO3 equivalent to saying that the dissociation of cellular ATP Na+ 2K+ water yields a hydrogen ion and a hydroxyl ion, which - - - reacts with cytoplasmic CO2 under the influence of car- HCO3 + H+ H+ HCO3 HCO3 ‘reabsorbed’ bonic anhydrase to produce the bicarbonate for baso- H2CO3 H2CO3 lateral extrusion.) Carbonic anhydrase also exists on c.a. c.a. the brush border membrane on the luminal surface of H2O + CO2 CO2 + H2O these cells. Here it catalyses the breakdown of carbonic acid formed as the secreted hydrogen ion reacts with filtered bicarbonate, releasing water and CO2 which passes freely across the cell membrane, allowing the Fig. 4.2 cycle to repeat. Mechanism of proximal tubular bicarbonate The net outcome of this process is that the filtered reabsorption. Details of the bicarbonate exit mechanism sodium bicarbonate passing through the proximal across the basolateral membrane are not shown in this tubule is effectively reabsorbed, although the bicar- or subsequent figures. c.a., carbonic anhydrase. bonate added to the plasma in a given turn of the cycle 51
  4. 4. SYSTEMS OF THE BODY 4 is not the same one appearing in the lumen with (HPO42-), which is titrated in the distal lumen to dihy- ACID–BASE BALANCE AND REGULATION OF pH sodium. This process accounts for reabsorption of drogen phosphate (H2PO4-), which is excreted in the some 85% of filtered bicarbonate, and operates at urine with sodium. This reaction has limited capacity a high capacity but generates a low gradient of (removing up to 30 mmol of H+/day) and tends to hydrogen ion concentration across the epithelium, proceed as the urine pH falls along the distal nephron with the luminal pH falling only slightly from 7.4 at segments, typically from 7 down to 6 and below, the the glomerulus to around 7.0 at the end of the proxi- mal tubule. This is both because of the presence of carbonic anhydrase in the luminal compartment and Late distal/collecting duct because the epithelium is ‘leaky’ to hydrogen ions. Acid-secreting cell Lumen Blood Net acid excretion It is important to understand that the process Filtered 2- - described above has not done anything to remove net HPO4 + H+ H+ HCO3 ATP acid from the body, since the fate of the secreted H+ in H2CO3 - this segment is effectively to conserve most of the H2PO4 c.a. filtered bicarbonate. Under circumstances requiring Excreted CO2 + H2O removal of net acid from the body, the tubules must still carry out two more steps. • Secrete further acid into the tubular lumen beyond that needed to reabsorb all filtered bicarbonate. Fig. 4.3 • Provide a buffer in the tubular fluid to assist in the Titration of filtered buffer (phosphate) by acid secreted removal of this acid (this is necessary since the in the distal nephron. Movements of filtered sodium maximum acidification which can be achieved in ions are not shown. c.a., carbonic anhydrase. the lumen – around pH 4.5 – would not allow for excretion of the metabolic acid load needing elimination). Late distal/collecting duct These two requirements are fulfilled in more distal Acid-secreting cell nephron segments. As shown in Figs 4.3 and 4.4, Lumen Blood acid is secreted into the lumen of the late distal tubule and collecting ducts by an H+-ATPase located in the apical cell membrane. This pump has been found in the intercalated cells within the cortical collecting - H+ H+ HCO3 duct and in the apical membrane of the outer ATP + medullary collecting duct cells. The H+ undergoing NH3 H2CO3 secretion in this way is generated within the tubular c.a. cells by a reaction facilitated by carbonic anhydrase, as CO2 + H2O described for the proximal tubule. Again, the bicar- + NH4 bonate generated within the cell by this process passes across the basolateral membrane (actually via a NH3 Glutamate chloride–bicarbonate exchange carrier not shown in Excreted glutaminase Fig. 4.3) into the plasma. However, here the bicarbon- Glutamine ate does not replace a filtered bicarbonate molecule, but represents a ‘new’ bicarbonate, effectively coun- teracting the consumption of buffer which would have occurred had the excreted acid been retained in the body. Fig. 4.4 Two types of buffer are involved in excretion of this Titration of manufactured buffer (ammonia) by acid net acid. The glomerular filtrate contains a limited secreted in the distal nephron. Ammonia synthesis is amount of non-bicarbonate buffer which is capable of shown for convenience occurring in an adjacent distal taking up some of the H+, as shown in Fig. 4.3. The cell; in fact, it is largely synthesized in proximal tubular 52 main molecule involved is monohydrogen phosphate cells. c.a., carbonic anhydrase.
  5. 5. THE RENAL SYSTEM 4 pK (acid dissociation constant) of this buffer system Disturbances of acid–base balance: acidosis ACID–BASE BALANCE AND REGULATION OF pH being 6.8. This form of excreted H+ is sometimes called ‘titratable acid’ as it can be quantitated by back- Following from the above principles, we can now titrating a specimen of urine. examine how the kidney is involved in the response to The other form of buffer involved in removal of acid–base disturbances, and will consider first the secreted acid is that manufactured by the kidney situation of excess acid accumulation, or acidosis. This itself, namely ammonia (NH3). Renal tubular cells, may arise as a result of either of two primary distur- especially those of the proximal tubule, contain the bances. enzyme glutaminase, which catalyses the produc- tion of NH3 from the nitrogen-rich amino acid gluta- Respiratory acidosis mine. Ammonia itself is a lipid-soluble gas, which diffuses freely through the kidney tissue and is Respiratory acidosis results from the accumulation of converted to its protonated form ammonium (NH4+) CO2 in the body as a result of failure of pulmonary ven- in acidic environments (it is also concentrated in the tilation. This itself may occur after lesions either in renal medulla by recirculation in the loop of Henle). the central nervous system (e.g. depression of cerebral As the luminal pH falls from the proximal to the function, spinal cord injury) or in peripheral nervous distal nephron segments, the NH4+ becomes increas- pathways involved in ventilating the lungs (peripheral ingly ‘trapped’ in the luminal fluid compartment nerve and muscle disorders), or in some forms of lung where it is washed away into the urine, associated disease involving impaired gas diffusion. with chloride ions. Again this constitutes removal of The decrease in body fluid pH resulting from car- an unwanted H+ from the body, with restoration of bonic acid generation is initially buffered to a limited a ‘new’ bicarbonate molecule to the ECF. The im- extent by the reaction of carbonic acid with intracellu- portance of this mechanism for acid excretion is that lar buffers such as haemoglobin, leading to the release it is linked to an abundant and regulated source of of small amounts of bicarbonate into the plasma. buffer production (NH3) of essentially unlimited However, longer term restoration of body fluid pH capacity. Thus, under conditions of acid build-up balance requires the excretion by the kidney of the net (especially chronic acidosis), NH3 synthesis is stimu- acid retained during the period of hypoventilation. lated and acid excretion (as ammonium) is greatly This is achieved by the three steps described above, increased, allowing systemic acid–base balance to be namely total reabsorption of filtered bicarbonate, titra- maintained. tion of all available filtered buffers, and increased Note that despite the action of NH3 to buffer the generation of ammonia within the kidney to allow for build-up of free acid in the late segments of the a higher-than-baseline level of net acid excretion as nephron, the pH of the tubular fluid does fall along ammonium ion. This latter step is stimulated both by the collecting duct system, resulting in final urinary intracellular acidosis and by the elevated pCO2 which pH as low as 4.5. This occurs both because the distal is associated with respiratory acidosis. Over a few nephron is relatively impermeable to H+ and because days, a new steady state is achieved in which renal there is no carbonic anhydrase in the luminal com- excretion of net acid matches that being retained by the partment in these tubular segments. This means that lungs, the urine pH being low and the plasma bicar- the dehydration of carbonic acid formed in the lumen bonate being raised above baseline values (Fig. 4.5). is slow, allowing H+ to accumulate. In summary, under conditions of normal dietary Metabolic acidosis protein consumption, a slightly alkaline plasma pH of 7.40 is maintained despite the generation of about Metabolic acidosis (or, more correctly, non-respiratory 70 mmol of hydrogen ion (as non-volatile acid) per day. acidosis), on the other hand, is associated with the The kidney’s role in maintaining this pH homeostasis accumulation of non-volatile acid within the body. is achieved by generating an acidic urine in which the There are essentially three components to the protec- net daily excess of acid can be removed. It does this in tive response which limits the fall in pH which would the following ways. otherwise occur. • Reabsorbing all bicarbonate buffer filtered into the Physicochemical buffering urine. The first defence against a fall in the pH of the body • Secreting H+ for excretion with filtered buffers fluids after addition of an acid load is the buffering of such as phosphate. H+ by available bases, particularly bicarbonate which is • Secreting H+ for excretion with the manufactured abundant in the ECF. This results in a fall in the plasma buffer ammonia. bicarbonate, and hence a lesser fall in the plasma pH 53
  6. 6. SYSTEMS OF THE BODY 4 Renal compensation for chronic respiratory acidosis H+ ACID–BASE BALANCE AND REGULATION OF pH secretion Ventilatory (days) plasma pCO2 pH failure HCO - 3 NH3 synthesis acid excretion as NH4 + Respiratory and renal compensation for (non-renal) metabolic acidosis ventilation H+ Brainstem accumulation pH pCO2 (hours) blunts plasma H+ HCO3- secretion plasma HCO3 - raised (days) towards normal NH3 synthesis acid excretion as NH4 + Fig. 4.5 Mechanisms of renal and respiratory compensation for acid–base disturbances. The immediate action of physicochemical buffers is omitted for clarity. than would otherwise have occurred. A variety of extra- is not fully normalized, and never ‘overshoots’, as a cellular and intracellular proteins provide a further result of respiratory compensation alone. reserve of H+ binding sites, and a limited amount of tissue phosphate also contributes some buffer capacity. Renal response These reactions are essentially complete within a few Steady state correction of the acid–base disturbance minutes of addition of acid to the body fluids, though requires the development over several days of an further buffering occurs in bone and other tissues over increased capacity by the kidney to excrete the meta- the ensuing hours and days. bolic acid load. This involves reabsorption of all filtered bicarbonate, maximum titration of filtered buffers with Respiratory response secreted H+, and increased intrarenal synthesis of Despite initial buffering, the pH of the plasma will still ammonia, which combines with secreted hydrogen fall somewhat during acidosis, and this acts as a potent ions in the luminal compartment and appears in the stimulus to increase the ventilation rate via the activa- urine as large quantities of ammonium. The urine pH tion of chemoreceptors within the brainstem (ventral falls to minimum levels (around 4.5) and the plasma medulla) which respond to a fall in pH of the cere- bicarbonate, lowered initially by the reaction with brospinal fluid. Clinically this manifests as a deep, added acid and subsequently by the hyperventilation rapid breathing pattern (Kussmaul respiration). Over response, is elevated back up into the normal range. The a matter of minutes to hours, this response drives the net result is a restoration of plasma pH to normal. CO2 below normal, and thus serves to blunt the fall in ECF pH by shifting the carbonic acid equilibrium reac- Before leaving the subject of renal acid secretion, a tion (see Fig. 4.1). This respiratory response provides number of factors which have been identified as regu- a medium-term compensation for the acidosis pro- lators of this process should be listed. The principal duced by the metabolic disturbance. Note that while factors causing an increase in H+ secretion by the 54 the resulting plasma pH is brought up towards 7.40, it nephron include:
  7. 7. THE RENAL SYSTEM 4 Acid–base balance and regulation of Patterns of metabolic acidosis ACID–BASE BALANCE AND REGULATION OF pH pH box 2 Two basic types of metabolic acidosis can be distin- The arterial blood gases guished, on the basis of the effect they have on readily measurable plasma parameters. In one type, acid Returning to the case of Mrs Loy, crucial early data might be added as hydrochloric (mineral) acid, or needed to clarify her acid–base status are the pH and there might be a primary loss of bicarbonate buffer pCO2 of the arterial blood. These are obtained imme- from the ECF. In this pattern, there is no addition to diately after her admission to hospital, and give the the plasma of a new acid anion. In the second type, the following results: accumulating acid might be in the form of an organic pH 7.37 acid where the acid anion accumulates in the plasma *pCO2 22 mmHg to replace the falling bicarbonate. *HCO3- 13 mmol/L These concepts are shown in diagrammatic form in pO2 103 mmHg. Fig. 4.6. When the concentrations of the commonly measured cations in the blood (sodium and potassium) These data confirm that her problem is primarily are added, there is in normal plasma an apparent dis- an acidosis (pH < 7.40) of metabolic origin (low crepancy of some 15 mmol/L over and above the sum HCO3-) which has undergone a considerable degree of the two commonly measured anions (chloride and of respiratory compensation (low pCO2). However, bicarbonate). This ‘anion gap’ is largely explained by the presence of the low bicarbonate concentration the multiple negative charges on plasma protein mol- implies that the kidney has not achieved long-term ecules. It can be seen that, where mineral acid is added correction of the underlying acid accumulation. or bicarbonate is lost (pattern A), the fall in plasma The question now arises: what is the source of the bicarbonate is compensated by a rise in chloride, metabolic acid load that is playing a major part in resulting in no change in the apparent anion gap. In this presentation? pattern B, however, the bicarbonate may fall to the Before completing an analysis of her acid–base same extent, but this is accounted for by the addition problem, we might take note of one clue present in of the organic acid anion, which, being itself unmea- the data available already. Whatever the cause of sured, adds to the apparent anion gap, and the plasma metabolic acid build-up, there is some problem with chloride does not change from normal. This simple kidney function in this case since urinalysis showed a analysis provides an initial tool for the diagnosis of the pH of 7. According to the description above of an cause of a metabolic acidosis, where this is not expected renal response to acidosis involving excre- obvious. tion of a maximally acidic urine (pH < 5), the urine Some causes of normal anion gap metabolic acido- pH in this case is quite inappropriate and would sis are given in Table 4.1. Rarely, the cause is addition appear to point to a primary problem located within of hydrochloric acid or ammonium chloride, usually the kidney itself. As will be seen, this was indeed the in a setting of medical investigation or treatment. case. More commonly, there is a problem either in the gastrointestinal tract involving loss of bicarbonate from the lower bowel, or in the kidney. In the latter • increase in filtered load of bicarbonate case, the normal mechanisms for H+ secretion into • decrease in ECF volume the lumen of the nephron may be impaired, either • decrease in plasma pH in the proximal tubule (such as by the carbonic • increase in blood pCO2 anhydrase inhibitor acetazolamide), or in the distal • hypokalaemia nephron (where the processes involved in urinary • aldosterone. acidification are defective). As a group, these disorders of renal acid excretion are called renal tubular aci- Note that the first two factors listed result in increased doses, and will be discussed further later in this proximal bicarbonate reabsorption, while the later chapter. factors act in distal nephron segments to enhance net Causes of the increased anion gap pattern of meta- acid excretion. The common mediator in the case of the bolic acidosis are given in Table 4.2. The organic acid last four factors is probably a decrease in the intracel- load in these conditions may be classified as to lular pH of the tubular cells, which not only activates whether it is of endogenous or exogenous origin. In the hydrogen ion secretory mechanism but also some cases, when specifically suspected, such as enhances tubular ammonia synthesis. lactate in lactic acidosis, the organic acid anion can be See box 2. measured in the blood. In other cases, however, the 55
  8. 8. SYSTEMS OF THE BODY 4 Normal ACID–BASE BALANCE AND REGULATION OF pH ‘Anion gap’=15 - 25 HCO3 Na+ 145 + K+ Cl- 105 + - + - H Cl gain H A gain - HCO3 loss Metabolic acidosis AG =15 AG =25 (includes A-) - 15 HCO3 - HCO3 15 Na+ Na+ 145 + 145 + K+ Cl- 115 K+ Cl- 105 Pattern A Pattern B Normal anion gap Increased anion gap Fig. 4.6 Patterns of metabolic acidosis. All figures are in mmol/L. AG, anion gap. clinical history provides a strong clue as to the cause, Table 4.1 e.g. the accumulation of ketoacids in diabetic ketoaci- Causes of normal anion gap metabolic acidosis dosis, or of salicylate following aspirin intoxication Disorder Mechanism (this latter disorder being complicated by respiratory alkalosis because of ventilatory stimulation). Of note Inorganic acid addition: is the predisposition of alcoholic patients to a number Infusion/ingestion of HCl, Exogenous acid load of forms of increased anion gap metabolic acidosis. NH4Cl Gastrointestinal base loss: These include starvation ketosis, lactic acidosis and *Diarrhoea Loss of bicarbonate from gut intoxication by methanol or ethylene glycol (when Small bowel fistula/drainage Loss of bicarbonate from gut consumed as alternatives to alcohol). Where metabolic Surgical diversion of urine Secretion of KHCO3 by bowel acidosis is associated with advanced renal failure, the into gut loops mucosa cause is usually the accumulation of complex organic Renal base loss/acid retention: Proximal renal tubular Renal tubular bicarbonate acids normally excreted by filtration and proximal acidosis wasting tubular secretion, and the result is an increased anion Distal renal tubular acidosis Impaired renal tubular acid gap. secretion See box 3. *Diarrhoea alone is rarely associated with marked acidosis unless it is severe and prolonged. Renal tubular acidosis Metabolic acidosis can arise as a result of failure not associated with accumulation of any organic acid of renal tubular segments to secrete hydrogen ions in anion, and so the anion gap remains normal. Two basic the absence of any major impairment of glomerular variants of the condition, which can be either congen- 56 filtration rate. This acidosis of renal tubular origin is ital or acquired, are described.
  9. 9. THE RENAL SYSTEM 4 Table 4.2 ACID–BASE BALANCE AND REGULATION OF pH Causes of increased anion gap metabolic acidosis Disorder Anion(s) Clues to diagnosis Endogenous acid load: Diabetic ketoacidosis Acetoacetate, beta-OH butyrate Hyperglycaemia, ketonuria Starvation ketosis Acetoacetate, beta-OH butyrate Hypoglycaemia Lactic acidosis Lactate Shock, hypoxia, liver disease Renal failure Organic acids Reduced glomerular filtration rate Exogenous acid load: Salicylate poisoning Salicylate Associated with respiratory alkalosis Methanol poisoning Formate Visual complaints, often alcoholic Ethylene glycol poisoning Glycolate, oxalate Oxalate crystalluria, often alcoholic Table 4.3 Acid–base balance and regulation of Some causes of renal tubular acidosis (RTA) pH box 3 Proximal RTA The diagnosis Congenital (Fanconi syndrome, cystinosis, Wilson’s disease) Paraproteinaemia (e.g. myeloma) Mrs Loy’s electrolyte profile was examined and an Hyperparathyroidism anion gap of 12 mmol/L was calculated (see original Drugs (carbonic anhydrase inhibitors) biochemistry data). There was no history of gastroin- Distal RTA (‘classic’ type) testinal disturbance and the urine pH was noted to Congenital be inappropriately high at 7. An interim diagnosis of Hyperglobulinaemia renal tubular acidosis was made. Autoimmune connective tissue diseases (e.g. systemic lupus erythematosus) Further investigation, directed toward defining the Toxins and drugs (toluene, lithium, amphotericin) immunological activity of her underlying connective tissue disease, revealed that the levels of antinuclear Hyperkalaemic distal RTA Hypoaldosteronism antibodies (including antibodies to double-stranded Obstructive nephropathy DNA) were elevated, and serum complement levels Renal transplant rejection were low, consistent with activated SLE. In addition, Drugs (amiloride, spironolactone) the urine contained many red cells and red cell casts (see Chapter 7), and a large amount of protein. Renal biopsy confirmed severe diffuse inflammation affect- through later nephron segments. Plasma ing the glomeruli as well as the tubulointerstitium. bicarbonate falls, blood pH falls, and bicarbonate A diagnosis of reactivated SLE was made, with the appears in the urine. complications of diffuse lupus nephritis (see Chapter • In distal RTA, the defect is in the late distal tubule 7) and renal tubular acidosis. The distal tubular dys- and collecting duct segments, where acid secretion function in this setting reflects a disruptive effect of is mediated by an H+-ATPase. In the classic form the interstitial inflammatory changes on the trans- of this disorder, the hydrogen pump itself is port properties of the tubules. probably defective. In other forms, such as that induced by amphotericin (an antifungal antibiotic), the impairment of net acid secretion results from back-leak of hydrogen ions across an epithelium • In proximal renal tubular acidosis (RTA), the which is made abnormally permeable to these defect lies in the mechanism normally present ions. within the proximal tubular epithelium for reabsorbing bicarbonate (refer to Fig. 4.2). Thus, Some causes of proximal and distal RTA are given either because of a specific defect in one of the in Table 4.3. Both proximal and distal RTA may be components of the cellular acid secretory inherited as a primary defect, but a number of other mechanism in this segment or because of non- conditions may produce secondary RTA in either specific damage to, or malfunction of, the proximal segment. Notably, an alteration in proximal tubular tubular epithelium as a whole, filtered bicarbonate function can be induced by high paraprotein levels is incompletely reabsorbed. This results in a large as in myeloma, or by hyperparathyroidism, or by flow of bicarbonate, together with sodium, the carbonic anhydrase inhibitor acetazolamide. Distal 57
  10. 10. SYSTEMS OF THE BODY 4 RTA, on the other hand, can be caused by conditions retention stabilizes, albeit at a reduced plasma bicar- ACID–BASE BALANCE AND REGULATION OF pH associated with polyclonal hyperglobulinaemia, bonate concentration. including SLE, as in the patient studied in this chapter. There are also differences in some of the associated Other forms of structural tubulointerstitial disease features of proximal versus distal RTA. The proximal can produce the same defect, and a number of drugs type may be associated with loss of other molecules and toxins are also prone to damage this segment normally reabsorbed in the proximal tubule, giving selectively. rise to amino aciduria, glycosuria and phosphaturia. A Apart from the differences in clinical setting and aeti- different problem occurs in distal RTA as a result of ology between the proximal and distal types of RTA, a progressive accumulation of acid over many years. As number of physiological differences exist. In the distal a consequence of buffering of H+ in bone, calcium is form, the impaired operation of the collecting duct H+ released from the skeleton and may be deposited in the pump means that, no matter how severe the systemic tissues, including the kidney (nephrocalcinosis). acidosis, the urine pH can never be lowered appropri- Furthermore, the high urinary excretion of calcium ately, and generally remains above 5.5. Bicarbonate loss may result in stone formation (see Chapter 10), often is not prominent since proximal reabsorption is gener- associated with urinary tract infection. Impairment of ally intact. However, in early or mild forms of proximal skeletal growth can occur in this condition, and also in RTA there is considerable leak of bicarbonate into the proximal RTA when the disorder is congenital or starts urine, which again has an inappropriately high pH in early childhood. since the distal segments are unable to acidify the urine Much of the symptomatology of both kinds of as long as large amounts of bicarbonate are flooding RTA relates to electrolyte depletion. Urinary losses of through the lumen from the proximal segments. sodium are abnormally high in both forms, resulting However, when acidosis is more severe in proximal in a degree of hypovolaemia. Both forms are typically RTA, the plasma bicarbonate falls because of buffering also associated with hypokalaemia because of stimu- of the accumulated acid. As a result, a point may be lated potassium secretion in the late distal and cortical reached where the reduced filtered amount of bicar- collecting ducts. This is caused by a high luminal bonate can be largely reabsorbed by the defective prox- flow of sodium and bicarbonate in proximal RTA, and imal tubular reabsorptive mechanism. The intact distal by electrically-driven potassium secretion to replace segments can then reabsorb a small distal leak of bicar- faulty H+ secretion in distal RTA. bonate, as normally occurs. In this situation the distal An important variant of distal RTA is hyperkalaemic tubular secretory pump can operate normally and gen- distal RTA (sometimes called type 4 RTA). In this case erate a transtubular H+ concentration gradient, result- the normal anion gap metabolic acidosis is associated ing in a lowering of the final urine pH. When this with hyperkalaemia, which points to a different site of occurs, bicarbonate loss ceases and ammonium excre- defect in the acid-secreting segment of the nephron. As tion rises so that a new steady state arises in which acid shown in Fig. 4.7, if a disruption occurs in the normal Cortical collecting duct Lumen Blood Principal cell 3Na+ Na+ ATP Site of defect in hyperkalaemic 2K+ distal RTA K+ - Cl Intercalated cell - HCO3 Site of defect H+ - in ‘classical’ ATP Cl distal RTA Fig. 4.7 Site of defect in two variants of 58 distal renal tubular acidosis (RTA).
  11. 11. THE RENAL SYSTEM 4 operation of the principal cell type in this tubular Disturbances of acid–base balance: ACID–BASE BALANCE AND REGULATION OF pH segment, sodium reabsorption will be impaired, re- alkalosis sulting in a loss of the normal lumen negativity (see Chapter 2). This electrical change impairs the rate of To complete our survey of acid–base disturbances, we secretion of both potassium and hydrogen ions into the can consider the two primary perturbations which lumen, resulting in systemic acidosis with hyper- might result in alkalosis. kalaemia. This lesion has been described in a variety of conditions causing distal tubulointerstitial damage (such as urinary tract obstruction with infection), and Respiratory alkalosis also during treatment with drugs interfering with principal cell sodium transport (such as amiloride). A Any form of sustained hyperventilation will pro- similar defect results from deficiencies in aldosterone duce a reduction in the blood pCO2 with a result- secretion or action, including diseases of the adrenal ing increase in plasma pH. The respiratory stimu- cortex and of the renin secretory mechanism in the lus most commonly arises from anxiety states, but kidney. it may also be due to drugs stimulating the respira- The management of all forms of RTA is directed tory centre, other brain disorders and chronic liver in the first instance toward reversing the underlying disease. condition affecting tubular function, if possible. The The homeostatic response to respiratory alkalosis next principle is that sufficient bicarbonate buffer involves an initial phase of physicochemical buffering must be provided to replace that consumed by the by intracellular proteins, which give up H+, resulting acid being accumulated. Provision of some of this in a small decrease in the plasma bicarbonate. More bicarbonate as potassium salt will help replete potas- sustained compensation occurs over the ensuing days, sium lost in classic forms of the disorder, while in during which renal tubular H+ secretion is inhibited the hyperkalaemic variant of distal RTA, measures by the high extracellular pH and the reduced pCO2. to assist in the excretion of potassium (e.g. loop or Bicarbonate reabsorption is inhibited, as is ammonium thiazide diuretics, or corticosteroids, as appropriate) excretion, and the result is a reduction in net acid may be necessary. Treatment may also be required excretion and a fall in the plasma bicarbonate. In many for specific complications in the various forms of cases the respiratory disturbance is not unduly pro- the condition, such as removal of stones and treatment longed, and the renal compensation subsides as venti- of infections which sometimes complicate classic lation is normalized. distal RTA. Metabolic alkalosis Acid–base balance and regulation of In this disorder there is a primary increase in the pH box 4 plasma bicarbonate concentration and the plasma pH. The causes fall into two groups according to whether Treatment and outcome there is associated contraction of the ECF volume Mrs Loy’s treatment focused on the control of her or not. underlying connective tissue disease. Immunosup- Hypovolaemic metabolic alkalosis is the commonest pression using prednisone and cyclophosphamide was pattern, and includes disorders such as vomiting initiated with a view to reducing the activity of her and gastric suction, in which acid-rich gastric SLE. The metabolic acidosis and hypokalaemia were juices are lost from the body. Metabolic alkalosis corrected initially with infusions, and later with associated with volume contraction also occurs during oral supplements, of alkaline salts of sodium and treatment with most diuretics (other than carbonic potassium. anhydrase inhibitors and potassium-sparing drugs). Over the ensuing weeks her condition improved Here there is increased acid loss into the urine related dramatically, with the fevers and rash subsiding, to the diuretic action on the tubules. The alkalosis urinary protein and red cell excretion reduced, and associated with volume contraction is perpetuated by plasma electrolyte profile reverted towards normal. secondary renal responses, described in more detail Within several weeks it was possible to discontinue below. her electrolyte and buffer therapy, and ongoing Normovolaemic (or hypervolaemic) metabolic alkalosis management was directed towards long-term stabi- occurs when the primary disturbance provokes both lization of the connective tissue disease. bicarbonate retention and a degree of volume expan- sion. This most commonly occurs in corticosteroid 59
  12. 12. SYSTEMS OF THE BODY 4 excess states such as primary hyperaldosteronism alkali in the urine. Replacement of potassium helps ACID–BASE BALANCE AND REGULATION OF pH (Conn’s syndrome), Cushing’s syndrome and related correct the hypokalaemia and its consequences in the disorders. Occasionally, overuse of antacid salts can kidney. produce a similar pattern. The non-hypovolaemic forms of metabolic alkalo- The homeostatic response to metabolic alkalosis sis, by way of contrast, are resistant to treatment involves initial buffering of the rise in plasma bicar- with sodium chloride, but can usually be managed bonate by titration of extracellular and intracellular by cessation of alkali therapy or correction of min- buffers, including plasma proteins. Soon afterwards, eralocorticoid excess. The latter may involve either the increased pH acts to inhibit ventilation through the adrenal gland surgery or blockade of mineralo- medullary chemoreceptors, such that the pCO2 starts corticoid effect in the kidney by treatment with to rise. Since, however, this is ultimately associated spironolactone. with an unacceptable degree of hypoxia, the extent to which this form of compensation occurs is limited, such that the maximum pCO2 attained is rarely more than 55 mmHg. Vomiting In the absence of counterbalancing stimuli, the expected renal response to sustained metabolic alka- losis would be to decrease tubular acid secretion, Gastric loss of inhibit bicarbonate reabsorption and excrete the ex- cess bicarbonate into the urine. However, in the com- monest form of metabolic alkalosis, that caused H+ (Cl-) Na+(Cl-)/H2O K+ (Cl-) by sustained vomiting, this response is distorted by other changes associated with the loss of gastric fluid. As shown in Fig. 4.8, the loss of H+ initiates Hypovolaemia the alkalosis (‘generation’ phase), which is actually (Kidney) worsened by the losses of sodium, water and potas- proximal aldosterone Hypokalaemia sium (‘maintenance’ phase). The sodium losses are Na+HCO3 - associated with hypovolaemia, which triggers both reabsorption proximal bicarbonate reabsorption and aldosterone distal NH3 H+ secretion synthesis release, which stimulates distal acid secretion, thereby aggravating the systemic alkalosis. Furthermore, the H+ excretion hypokalaemia resulting from potassium loss (more through the kidney than from gastric fluid) also stim- Maintenance ulates distal acid secretion and tubular ammonia synthesis (see earlier), both of which enhance acid Generation Metabolic excretion and maintain the alkalosis. The net result alkalosis is an inappropriately acid urine and a failure of the kidney to effect long-term correction of the systemic Fig. 4.8 pH disturbance. Vomiting: generation and maintenance of metabolic The cornerstone of management in hypovolaemic alkalosis. Note that the gastric loss of H+ is primarily metabolic alkalosis states, exemplified by vomiting, responsible for generating the systemic alkalosis, while is to provide adequate volume replacement as sodium the other mechanisms shown act through the kidney to chloride (isotonic saline infusions), which switches maintain the alkalosis as long as sodium and potassium off the volume-conserving mechanisms mentioned losses are uncorrected. Chloride is the deficient anion above and allows the kidney to excrete the excess accompanying all cations shown. Table 4.4 Summary of ‘simple’ acid–base disturbances Disorder pH Primary change Compensatory response Metabolic acidosis Decreased Decreased HCO3- Decreased pCO2 Metabolic alkalosis Increased Increased HCO3- Increased pCO2 Respiratory acidosis Decreased Increased pCO2 Increased HCO3- Respiratory alkalosis Increased Decreased pCO2 Decreased HCO3- 60
  13. 13. THE RENAL SYSTEM 4 thumb are available to indicate the predicted compen- Summary of findings in principal ACID–BASE BALANCE AND REGULATION OF pH satory change in pCO2 or bicarbonate levels expected acid–base disturbances in each of the simple (uncomplicated) acid–base dis- Table 4.4 provides an overview of the changes in pH, orders. When the available data for a given patient bicarbonate concentration and pCO2 in the four major are not consistent with these changes, a complex or simple acid–base disorders. Taken in conjunction with ‘mixed’ acid–base disorder can be inferred, and the ele- clinical information, the results of these analyses are ments of the disturbance usually deduced in conjunc- usually sufficient to enable a diagnosis to be made of tion with a thorough clinical evaluation. the nature and cause of the disturbance. Rules of Self-assessment case study d What is the likely cause of the disturbance in this case? e What would you expect the urine pH to be? A consultation is requested on an 81-year-old man who has been admitted to the hospital with an acute myocardial f What are the principles of treatment? infarction (heart attack). There has been significant damage to g What would the effect of a bicarbonate infusion be on his the left ventricle such that cardiac output is markedly reduced. plasma potassium concentration? Furthermore, on day 5 after admission his course is complicated by the development of acute ischaemia in the left Answers see page 146 leg, attributed to occlusion of a major leg artery following embolization of a thrombus from the left ventricular cavity. The patient’s plasma electrolyte results are as follows: Self-assessment questions Sodium 135 mmol/L *Potassium 5.2 mmol/L b What would the effect on systemic acid–base balance be if a Chloride 97 mmol/L patient were given long-term treatment with a carbonic *Bicarbonate 14 mmol/L anhydrase inhibitor such as acetazolamide? *Urea 14.0 mmol/L c Where in the nephron is the steepest gradient of pH *Creatinine 0.14 mmol/L. between the plasma and the luminal fluid? (*Values outside normal range; see Appendix.) d Name three changes in the plasma which stimulate an Arterial blood gas analysis reveal the following: pH 7.33, pCO2 increase in hydrogen ion secretion by the nephron. 29 mmHg, pO2 (breathing room air) 58 mmHg. After studying this chapter you should be able to answer e Give three causes of a metabolic acidosis with a normal the following questions: anion gap. b What is the overall pattern of acid–base disturbance in this d Name three factors which perpetuate the systemic alkalosis patient? which follows prolonged vomiting. c What is the anion gap in this patient? Answers see page 146 61