ACID–BASEBALANCE ANDREGULATION 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 produceddaily by metabolism.

d Outline the defence mechanisms which act to prevent an abrupt change in pH inresponse 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 somecauses and give an approach to the differential diagnosis.

g Recognize metabolic alkalosis, list some causes, and explain the pathophysiologyof this disturbance during prolonged vomiting.

4

CO2 + H2O ∫ H2CO3 ∫ H+ + HCO3-

Introduction

Just as the kidney is a critical organ in defending the normal set points for extracellular fluid (ECF)volume, osmolality and potassium concentration, italso plays a central role in the homeostasis of theplasma pH. While chemical buffering mechanisms and respiratory elimination of carbon dioxide areimportant in immediate responses to disturbances inacid–base balance, it falls to the kidney to make long-term adjustments in the rate of acid excretion whichallows the external balance with respect to hydrogenion concentration to be maintained. This chapter willfocus on the mechanisms whereby the kidney achievesthis role, and the origin of some disturbances of thissystem in disease.

See box 1.The clue in this case that there is a disturbance of

acid–base metabolism is that the bicarbonate concen-tration, representing the base component of the prin-cipal physiological buffer system, is greatly reducedbelow the normal range. This is consistent with acidaccumulation in the ECF, for which we must exploreboth the cause and the consequences.

The key parameter involved in acid–base regulationis the concentration of H+ in the ECF. The physiologicalset point for this parameter is 40nmol/L, usuallyexpressed (using the negative base 10 logarithm) as thepH, which is normally 7.40. So important is homeosta-sis of this parameter to the normal operation of meta-bolism and cellular function that pH is tightly regulatedin the range 7.38–7.42, although a somewhat widerrange is compatible with life (7.0–7.8).

Two forms of acid are generated as a result of normalmetabolic processes. Oxidative metabolism produces alarge amount of CO2 daily, and this so-called ‘volatileacid’ is excreted through the lungs. Carbon dioxideeffectively acts as an acid in body fluids because of thefollowing reactions:

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Acid–base balance and regulation of pH box 1

A case of acidosis

Mrs Mary Loy is a 48-year-old woman of Chinesebackground who has been sent by her family doctorto the Emergency Department because of his concernabout her clinical condition and some biochemicalresults.

She had been complaining for some weeks ofincreasing lethargy, an extensive rash and ‘heavybreathing’. She had been receiving treatment for 4 years for systemic lupus erythematosus (SLE), a multiorgan autoimmune condition for which a con-sultant rheumatologist had prescribed prednisone.However, Mrs Loy confessed to having discontinuedthis medication some 10 months earlier because shewas unhappy about its side effects.

On examination she was febrile, unwell and had anerythematous rash on her face and limbs. Her bloodpressure was 110/80, pulse rate 100 beats/min andrespiratory rate 20/min, the breathing being deepand sighing. The referring doctor’s letter indicatedthat he had obtained a urinalysis result that morningshowing: pH 7, blood +++ and protein ++.

He had also obtained plasma biochemistry the pre-vious day, the results of which are as follows:

Sodium 135mmol/L*Potassium 3.1mmol/L*Chloride 113mmol/L*Bicarbonate 13mmol/LUrea 8.0mmol/LCreatinine 0.09mmol/L.

The family doctor is particularly concerned about thelow bicarbonate, which he interprets as a sign of acidbuild-up, and seeks full evaluation of her clinical andmetabolic problem.

(*Results outside the normal range; see Appendix.)

The first reaction (formation of carbonic acid, H2CO3)is the rate-limiting step and is normally slow, but inthe presence of the enzyme carbonic anhydrase (c.a.)the reaction is greatly accelerated. The subsequent ion-ization of carbonic acid proceeds almost instanta-neously. This equation can be rearranged to enhanceits physiological utility in the form shown in Fig. 4.1,as the Henderson–Hasselbalch equation.

The other form of acid, the so-called ‘non-volatileacid’, results from the metabolism of dietary protein,resulting in the accumulation of some 70mmol of acidper day in an average adult on a typical western meat-containing diet.

c.a.

The most important mechanism preventing change inthe pH of the ECF is the carbonic acid/bicarbonatebuffer system outlined above. The importance of thisbuffer pair relates to certain key properties: bicarbon-ate is present in a relatively high concentration in theECF (24 mmol/L) and the components of the buffersystem are effectively under physiological control: theCO2 by the lungs, and the bicarbonate by the kidneys.These relationships are illustrated in Fig. 4.1.

It is clear from this relationship that a shift in pH canbe brought about by either a primary change in thebicarbonate concentration (metabolic disturbances) or

Role of the kidney in H+ balance

Before we can make further progress in analysing theacid–base problem in our patient, it is necessary to consider the role the kidney plays in maintainingacid–base balance under normal conditions. Giventhat bicarbonate buffer is freely filtered at the glomeru-lus and that there is a daily load of non-volatile acidto be excreted into the urine, there must be two com-ponents to the nephron’s task: reabsorption of filteredbicarbonate, and addition of net acid to the tubularfluid.

Bicarbonate reabsorption

Bicarbonate is the principal physiological buffer in theplasma and it is freely filtered at the glomerulus. If thisbicarbonate were not fully reabsorbed by the tubularsystem, there would be ongoing losses of essentialbuffer into the urine, resulting in progressive acidifi-cation of the body fluids as metabolic acid productioncontinued. In fact, bicarbonate excretion is essentiallyzero under normal conditions because of the extensiveand efficient reabsorption of bicarbonate, principallyin the proximal tubule as shown in Fig. 4.2.

As discussed in Chapter 2, the cells in this tubularsegment contain a sodium–hydrogen exchange carriermolecule known as NHE-3 in the apical cell mem-brane. As sodium enters the cell from the luminal fluiddown its electrochemical gradient via this carrier, iteffectively removes hydrogen ions from the cell cyto-plasm and adds them to the luminal fluid. The hydro-gen ions are generated within the cell by the action ofthe enzyme carbonic anhydrase, which catalyses thereaction between CO2 and water to produce carbonicacid. This rapidly breaks down to produce the hydro-gen ions that are secreted into the lumen, and a bicar-bonate ion which is transported across the basolateralcell membrane into the plasma. (Note that this isequivalent to saying that the dissociation of cellularwater yields a hydrogen ion and a hydroxyl ion, whichreacts with cytoplasmic CO2 under the influence of car-bonic anhydrase to produce the bicarbonate for baso-lateral extrusion.) Carbonic anhydrase also exists onthe brush border membrane on the luminal surface ofthese cells. Here it catalyses the breakdown of carbonicacid formed as the secreted hydrogen ion reacts withfiltered bicarbonate, releasing water and CO2 whichpasses freely across the cell membrane, allowing thecycle to repeat.

The net outcome of this process is that the filteredsodium bicarbonate passing through the proximaltubule is effectively reabsorbed, although the bicar-bonate added to the plasma in a given turn of the cycle

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1° changes inmetabolic disturbances

2° changes afterrenal compensation forrespiratory disturbances*

1° changes inrespiratory disturbances

2° changes afterrespiratory compensation formetabolic disturbances

pH=6.1+ log[HCO3

- ]0.03 × pCO2

Fig. 4.1Effect of changes in HCO3

- and pCO2 on net pH of theplasma. This is an applied version of theHenderson–Hasselbalch equation. Normal plasma [HCO3

-] = 24mmol/L, normal pCO2 = 40mmHg, giving anormal plasma pH of 7.40. The pH will return to 7.40 aslong as the ratio of [HCO3] : [0.03 ¥ pCO2] is 20 :1. *Notethat changes in HCO3

- concentration are also made aspart of the renal correction of sustained metabolicacid–base disturbances as long as the kidney itself is notthe cause of the primary disturbance.

Lumen

2K+

3Na+

ATP

Blood

H+

CO2 + H2O

HCO3-

c.a.

Na+

H2CO3

HCO3-

‘reabsorbed’HCO3

- + H+

H2CO3

H2O + CO2

c.a.

filteredNa+HCO3

-

Fig. 4.2Mechanism of proximal tubular bicarbonatereabsorption. Details of the bicarbonate exit mechanismacross the basolateral membrane are not shown in thisor subsequent figures. c.a., carbonic anhydrase.

in the partial pressure of CO2 in the blood (respiratorydisturbances). However, it can also be seen that alter-ations in each of these parameters may represent acompensatory change whereby either the kidney orthe lung can act to limit the extent of pH change whichwould occur because of a primary disturbance in res-piratory function or in metabolism, respectively. Thepatterns of resulting clinical acid–base disturbanceswill be discussed later in this chapter.

(HPO42-), which is titrated in the distal lumen to dihy-

drogen phosphate (H2PO4-), which is excreted in the

urine with sodium. This reaction has limited capacity(removing up to 30 mmol of H+/day) and tends toproceed as the urine pH falls along the distal nephronsegments, typically from 7 down to 6 and below, the

is not the same one appearing in the lumen withsodium. This process accounts for reabsorption ofsome 85% of filtered bicarbonate, and operates at a high capacity but generates a low gradient of hydrogen ion concentration across the epithelium,with the luminal pH falling only slightly from 7.4 atthe 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 andbecause the epithelium is ‘leaky’ to hydrogen ions.

Net acid excretion

It is important to understand that the processdescribed above has not done anything to remove netacid from the body, since the fate of the secreted H+ inthis segment is effectively to conserve most of the filtered bicarbonate. Under circumstances requiringremoval of net acid from the body, the tubules muststill carry out two more steps.

• Secrete further acid into the tubular lumen beyondthat needed to reabsorb all filtered bicarbonate.

• Provide a buffer in the tubular fluid to assist in theremoval of this acid (this is necessary since themaximum acidification which can be achieved inthe lumen – around pH 4.5 – would not allow forexcretion of the metabolic acid load needingelimination).

These two requirements are fulfilled in more distalnephron segments. As shown in Figs 4.3 and 4.4, acid is secreted into the lumen of the late distal tubuleand collecting ducts by an H+-ATPase located in theapical cell membrane. This pump has been found inthe intercalated cells within the cortical collecting duct and in the apical membrane of the outermedullary collecting duct cells. The H+ undergoingsecretion in this way is generated within the tubularcells by a reaction facilitated by carbonic anhydrase, asdescribed for the proximal tubule. Again, the bicar-bonate generated within the cell by this process passesacross the basolateral membrane (actually via a chloride–bicarbonate exchange carrier not shown inFig. 4.3) into the plasma. However, here the bicarbon-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 inthe body.

Two types of buffer are involved in excretion of thisnet acid. The glomerular filtrate contains a limitedamount of non-bicarbonate buffer which is capable oftaking up some of the H+, as shown in Fig. 4.3. Themain molecule involved is monohydrogen phosphate

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Lumen

ATP

Blood

H+

CO2 + H2O

HCO3-

c.a.

H2CO3

HPO42-+ H+

Excreted

Filtered

H2PO4-

Late distal/collecting ductAcid-secreting cell

Fig. 4.3Titration of filtered buffer (phosphate) by acid secretedin the distal nephron. Movements of filtered sodiumions are not shown. c.a., carbonic anhydrase.

Lumen

ATP

Blood

H+

CO2 + H2O

HCO3-

c.a.

H2CO3

H+

Excreted

+NH3

NH4+

NH3

Glutamine

Glutamate

glutaminase

Late distal/collecting ductAcid-secreting cell

Fig. 4.4Titration of manufactured buffer (ammonia) by acidsecreted in the distal nephron. Ammonia synthesis isshown for convenience occurring in an adjacent distalcell; in fact, it is largely synthesized in proximal tubularcells. c.a., carbonic anhydrase.

pK (acid dissociation constant) of this buffer systembeing 6.8. This form of excreted H+ is sometimes called‘titratable acid’ as it can be quantitated by back-titrating a specimen of urine.

The other form of buffer involved in removal ofsecreted acid is that manufactured by the kidney itself, namely ammonia (NH3). Renal tubular cells,especially those of the proximal tubule, contain theenzyme glutaminase, which catalyses the produc-tion of NH3 from the nitrogen-rich amino acid gluta-mine. Ammonia itself is a lipid-soluble gas, which diffuses freely through the kidney tissue and is converted to its protonated form ammonium (NH4

+) in acidic environments (it is also concentrated in therenal medulla by recirculation in the loop of Henle). As the luminal pH falls from the proximal to the distal nephron segments, the NH4

+ becomes increas-ingly ‘trapped’ in the luminal fluid compartment where it is washed away into the urine, associatedwith chloride ions. Again this constitutes removal ofan unwanted H+ from the body, with restoration of a ‘new’ bicarbonate molecule to the ECF. The im-portance of this mechanism for acid excretion is that it is linked to an abundant and regulated source ofbuffer production (NH3) of essentially unlimitedcapacity. Thus, under conditions of acid build-up(especially chronic acidosis), NH3 synthesis is stimu-lated and acid excretion (as ammonium) is greatlyincreased, allowing systemic acid–base balance to bemaintained.

Note that despite the action of NH3 to buffer thebuild-up of free acid in the late segments of thenephron, the pH of the tubular fluid does fall along the collecting duct system, resulting in final urinarypH as low as 4.5. This occurs both because the distalnephron is relatively impermeable to H+ and becausethere is no carbonic anhydrase in the luminal com-partment in these tubular segments. This means thatthe dehydration of carbonic acid formed in the lumenis slow, allowing H+ to accumulate.

In summary, under conditions of normal dietaryprotein consumption, a slightly alkaline plasma pH of7.40 is maintained despite the generation of about 70mmol of hydrogen ion (as non-volatile acid) per day.The kidney’s role in maintaining this pH homeostasisis achieved by generating an acidic urine in which thenet daily excess of acid can be removed. It does this inthe following ways.

• Reabsorbing all bicarbonate buffer filtered into theurine.

• Secreting H+ for excretion with filtered bufferssuch as phosphate.

• Secreting H+ for excretion with the manufacturedbuffer ammonia.

Disturbances of acid–base balance: acidosis

Following from the above principles, we can nowexamine how the kidney is involved in the response toacid–base disturbances, and will consider first the situation of excess acid accumulation, or acidosis. Thismay arise as a result of either of two primary distur-bances.

Respiratory acidosis

Respiratory acidosis results from the accumulation ofCO2 in the body as a result of failure of pulmonary ven-tilation. This itself may occur after lesions either in the central nervous system (e.g. depression of cerebralfunction, spinal cord injury) or in peripheral nervouspathways involved in ventilating the lungs (peripheralnerve and muscle disorders), or in some forms of lungdisease involving impaired gas diffusion.

The decrease in body fluid pH resulting from car-bonic acid generation is initially buffered to a limitedextent by the reaction of carbonic acid with intracellu-lar buffers such as haemoglobin, leading to the releaseof small amounts of bicarbonate into the plasma.However, longer term restoration of body fluid pHbalance requires the excretion by the kidney of the netacid retained during the period of hypoventilation.

This is achieved by the three steps described above,namely total reabsorption of filtered bicarbonate, titra-tion of all available filtered buffers, and increased generation of ammonia within the kidney to allow fora higher-than-baseline level of net acid excretion asammonium ion. This latter step is stimulated both byintracellular acidosis and by the elevated pCO2 whichis associated with respiratory acidosis. Over a fewdays, a new steady state is achieved in which renalexcretion of net acid matches that being retained by thelungs, the urine pH being low and the plasma bicar-bonate being raised above baseline values (Fig. 4.5).

Metabolic acidosis

Metabolic acidosis (or, more correctly, non-respiratoryacidosis), on the other hand, is associated with theaccumulation of non-volatile acid within the body.There are essentially three components to the protec-tive response which limits the fall in pH which wouldotherwise occur.

Physicochemical bufferingThe first defence against a fall in the pH of the bodyfluids after addition of an acid load is the buffering ofH+ by available bases, particularly bicarbonate which isabundant in the ECF. This results in a fall in the plasmabicarbonate, and hence a lesser fall in the plasma pH

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pCO2Ventilatory

failure pH(days)

acid excretionas NH4

+

H+secretion

NH3synthesis

plasma HCO3

-

Renal compensation for chronic respiratory acidosis

pCO2

ventilation

pH(hours)

acid excretionas NH4

+

H+secretion

NH3synthesis

plasmaHCO3

-raisedtowardsnormal

Respiratory and renal compensation for (non-renal) metabolic acidosis

H+accumulation

(days)

Brainstem

plasma HCO3

-

blunts

Fig. 4.5Mechanisms of renal and respiratory compensation for acid–base disturbances. The immediate action ofphysicochemical buffers is omitted for clarity.

is not fully normalized, and never ‘overshoots’, as aresult of respiratory compensation alone.

Renal responseSteady state correction of the acid–base disturbancerequires the development over several days of anincreased capacity by the kidney to excrete the meta-bolic acid load. This involves reabsorption of all filteredbicarbonate, maximum titration of filtered buffers withsecreted H+, and increased intrarenal synthesis ofammonia, which combines with secreted hydrogenions in the luminal compartment and appears in theurine as large quantities of ammonium. The urine pHfalls to minimum levels (around 4.5) and the plasmabicarbonate, lowered initially by the reaction withadded acid and subsequently by the hyperventilationresponse, is elevated back up into the normal range. Thenet result is a restoration of plasma pH to normal.

Before leaving the subject of renal acid secretion, anumber of factors which have been identified as regu-lators of this process should be listed. The principalfactors causing an increase in H+ secretion by thenephron include:

than would otherwise have occurred. Avariety of extra-cellular and intracellular proteins provide a furtherreserve of H+ binding sites, and a limited amount oftissue phosphate also contributes some buffer capacity.These reactions are essentially complete within a fewminutes of addition of acid to the body fluids, thoughfurther buffering occurs in bone and other tissues overthe ensuing hours and days.

Respiratory responseDespite initial buffering, the pH of the plasma will stillfall somewhat during acidosis, and this acts as a potentstimulus to increase the ventilation rate via the activa-tion of chemoreceptors within the brainstem (ventralmedulla) which respond to a fall in pH of the cere-brospinal fluid. Clinically this manifests as a deep,rapid breathing pattern (Kussmaul respiration). Overa matter of minutes to hours, this response drives theCO2 below normal, and thus serves to blunt the fall inECF pH by shifting the carbonic acid equilibrium reac-tion (see Fig. 4.1). This respiratory response providesa medium-term compensation for the acidosis pro-duced by the metabolic disturbance. Note that whilethe resulting plasma pH is brought up towards 7.40, it

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• increase in filtered load of bicarbonate• decrease in ECF volume• decrease in plasma pH• increase in blood pCO2

• hypokalaemia• aldosterone.

Note that the first two factors listed result in increasedproximal bicarbonate reabsorption, while the laterfactors act in distal nephron segments to enhance netacid excretion. The common mediator in the case of thelast four factors is probably a decrease in the intracel-lular pH of the tubular cells, which not only activatesthe hydrogen ion secretory mechanism but alsoenhances tubular ammonia synthesis.

See box 2.

Patterns of metabolic acidosis

Two basic types of metabolic acidosis can be distin-guished, on the basis of the effect they have on readilymeasurable plasma parameters. In one type, acidmight be added as hydrochloric (mineral) acid, orthere might be a primary loss of bicarbonate bufferfrom the ECF. In this pattern, there is no addition tothe plasma of a new acid anion. In the second type, theaccumulating acid might be in the form of an organicacid where the acid anion accumulates in the plasmato replace the falling bicarbonate.

These concepts are shown in diagrammatic form inFig. 4.6. When the concentrations of the commonlymeasured cations in the blood (sodium and potassium)are added, there is in normal plasma an apparent dis-crepancy of some 15mmol/L over and above the sumof the two commonly measured anions (chloride andbicarbonate). This ‘anion gap’ is largely explained bythe multiple negative charges on plasma protein mol-ecules. It can be seen that, where mineral acid is addedor bicarbonate is lost (pattern A), the fall in plasmabicarbonate is compensated by a rise in chloride,resulting in no change in the apparent anion gap. Inpattern B, however, the bicarbonate may fall to thesame extent, but this is accounted for by the additionof the organic acid anion, which, being itself unmea-sured, adds to the apparent anion gap, and the plasmachloride does not change from normal. This simpleanalysis provides an initial tool for the diagnosis of thecause of a metabolic acidosis, where this is notobvious.

Some causes of normal anion gap metabolic acido-sis are given in Table 4.1. Rarely, the cause is additionof hydrochloric acid or ammonium chloride, usually in a setting of medical investigation or treatment. More commonly, there is a problem either in the gastrointestinal tract involving loss of bicarbonatefrom the lower bowel, or in the kidney. In the lattercase, the normal mechanisms for H+ secretion into the lumen of the nephron may be impaired, either in the proximal tubule (such as by the carbonic anhydrase inhibitor acetazolamide), or in the distalnephron (where the processes involved in urinaryacidification are defective). As a group, these disordersof renal acid excretion are called renal tubular aci-doses, and will be discussed further later in thischapter.

Causes of the increased anion gap pattern of meta-bolic acidosis are given in Table 4.2. The organic acidload in these conditions may be classified as towhether it is of endogenous or exogenous origin. Insome cases, when specifically suspected, such aslactate in lactic acidosis, the organic acid anion can bemeasured in the blood. In other cases, however, the

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Acid–base balance and regulation of pH box 2

The arterial blood gases

Returning to the case of Mrs Loy, crucial early dataneeded to clarify her acid–base status are the pH andpCO2 of the arterial blood. These are obtained imme-diately after her admission to hospital, and give thefollowing results:

pH 7.37*pCO2 22mmHg*HCO3

- 13mmol/LpO2 103mmHg.

These data confirm that her problem is primarily an acidosis (pH < 7.40) of metabolic origin (low HCO3

-) which has undergone a considerable degreeof respiratory compensation (low pCO2). However,the presence of the low bicarbonate concentrationimplies that the kidney has not achieved long-termcorrection of the underlying acid accumulation.

The question now arises: what is the source of themetabolic acid load that is playing a major part inthis presentation?

Before completing an analysis of her acid–baseproblem, we might take note of one clue present inthe data available already. Whatever the cause ofmetabolic acid build-up, there is some problem withkidney function in this case since urinalysis showed apH of 7. According to the description above of anexpected renal response to acidosis involving excre-tion of a maximally acidic urine (pH < 5), the urinepH in this case is quite inappropriate and wouldappear to point to a primary problem located withinthe kidney itself. As will be seen, this was indeed thecase.

not associated with accumulation of any organic acidanion, and so the anion gap remains normal. Two basicvariants of the condition, which can be either congen-ital or acquired, are described.

clinical history provides a strong clue as to the cause,e.g. the accumulation of ketoacids in diabetic ketoaci-dosis, or of salicylate following aspirin intoxication(this latter disorder being complicated by respiratoryalkalosis because of ventilatory stimulation). Of noteis the predisposition of alcoholic patients to a numberof forms of increased anion gap metabolic acidosis.These include starvation ketosis, lactic acidosis andintoxication by methanol or ethylene glycol (whenconsumed as alternatives to alcohol). Where metabolicacidosis is associated with advanced renal failure, thecause is usually the accumulation of complex organicacids normally excreted by filtration and proximaltubular secretion, and the result is an increased aniongap.

See box 3.

Renal tubular acidosis

Metabolic acidosis can arise as a result of failure of renal tubular segments to secrete hydrogen ions inthe absence of any major impairment of glomerular filtration rate. This acidosis of renal tubular origin is

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Na+

+

K+

HCO3-

Cl-

Normal

25

105

145

‘Anion gap’=15

Na+

+

K+

HCO3-

Cl-

Pattern ANormal anion gap

15

145

AG=15

115

Pattern BIncreased anion gap

AG=25 (includes A-)

Na+

+

K+

HCO3-

Cl- 105

145

15

Metabolicacidosis

HCO3- loss

H+Cl-gain H+A-gain

Fig. 4.6Patterns of metabolic acidosis. All figures are in mmol/L. AG, anion gap.

Table 4.1Causes of normal anion gap metabolic acidosis

Disorder Mechanism

Inorganic acid addition:Infusion/ingestion of HCl, Exogenous acid load

NH4ClGastrointestinal base loss:

*Diarrhoea Loss of bicarbonate from gutSmall bowel fistula/drainage Loss of bicarbonate from gutSurgical diversion of urine Secretion of KHCO3 by bowel

into gut loops mucosaRenal base loss/acid retention:

Proximal renal tubular Renal tubular bicarbonateacidosis wasting

Distal renal tubular acidosis Impaired renal tubular acidsecretion

*Diarrhoea alone is rarely associated with marked acidosis unlessit is severe and prolonged.

• In proximal renal tubular acidosis (RTA), thedefect lies in the mechanism normally presentwithin the proximal tubular epithelium forreabsorbing bicarbonate (refer to Fig. 4.2). Thus,either because of a specific defect in one of thecomponents of the cellular acid secretorymechanism in this segment or because of non-specific damage to, or malfunction of, the proximaltubular epithelium as a whole, filtered bicarbonateis incompletely reabsorbed. This results in a largeflow of bicarbonate, together with sodium,

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Acid–base balance and regulation of pH box 3

The diagnosis

Mrs Loy’s electrolyte profile was examined and ananion gap of 12mmol/L was calculated (see originalbiochemistry data). There was no history of gastroin-testinal disturbance and the urine pH was noted tobe inappropriately high at 7. An interim diagnosis ofrenal tubular acidosis was made.

Further investigation, directed toward defining theimmunological activity of her underlying connectivetissue disease, revealed that the levels of antinuclearantibodies (including antibodies to double-strandedDNA) were elevated, and serum complement levelswere low, consistent with activated SLE. In addition,the urine contained many red cells and red cell casts(see Chapter 7), and a large amount of protein. Renalbiopsy confirmed severe diffuse inflammation affect-ing the glomeruli as well as the tubulointerstitium.

A diagnosis of reactivated SLE was made, with thecomplications of diffuse lupus nephritis (see Chapter7) and renal tubular acidosis. The distal tubular dys-function in this setting reflects a disruptive effect ofthe interstitial inflammatory changes on the trans-port properties of the tubules.

through later nephron segments. Plasmabicarbonate falls, blood pH falls, and bicarbonateappears in the urine.

• In distal RTA, the defect is in the late distal tubuleand collecting duct segments, where acid secretionis mediated by an H+-ATPase. In the classic formof this disorder, the hydrogen pump itself isprobably defective. In other forms, such as thatinduced by amphotericin (an antifungal antibiotic),the impairment of net acid secretion results fromback-leak of hydrogen ions across an epitheliumwhich is made abnormally permeable to theseions.

Some causes of proximal and distal RTA are given in Table 4.3. Both proximal and distal RTA may beinherited as a primary defect, but a number of otherconditions may produce secondary RTA in eithersegment. Notably, an alteration in proximal tubularfunction can be induced by high paraprotein levels as in myeloma, or by hyperparathyroidism, or by the carbonic anhydrase inhibitor acetazolamide. Distal

Table 4.2Causes of increased anion gap metabolic acidosis

Disorder Anion(s) Clues to diagnosis

Endogenous acid load:Diabetic ketoacidosis Acetoacetate, beta-OH butyrate Hyperglycaemia, ketonuriaStarvation ketosis Acetoacetate, beta-OH butyrate HypoglycaemiaLactic acidosis Lactate Shock, hypoxia, liver diseaseRenal failure Organic acids Reduced glomerular filtration rate

Exogenous acid load:Salicylate poisoning Salicylate Associated with respiratory alkalosisMethanol poisoning Formate Visual complaints, often alcoholicEthylene glycol poisoning Glycolate, oxalate Oxalate crystalluria, often alcoholic

Table 4.3Some causes of renal tubular acidosis (RTA)

Proximal RTACongenital (Fanconi syndrome, cystinosis, Wilson’s disease)Paraproteinaemia (e.g. myeloma)HyperparathyroidismDrugs (carbonic anhydrase inhibitors)

Distal RTA (‘classic’ type)CongenitalHyperglobulinaemiaAutoimmune connective tissue diseases (e.g. systemic lupus

erythematosus)Toxins and drugs (toluene, lithium, amphotericin)

Hyperkalaemic distal RTAHypoaldosteronismObstructive nephropathyRenal transplant rejectionDrugs (amiloride, spironolactone)

retention stabilizes, albeit at a reduced plasma bicar-bonate concentration.

There are also differences in some of the associatedfeatures of proximal versus distal RTA. The proximaltype may be associated with loss of other moleculesnormally reabsorbed in the proximal tubule, givingrise to amino aciduria, glycosuria and phosphaturia. Adifferent problem occurs in distal RTA as a result ofprogressive accumulation of acid over many years. Asa consequence of buffering of H+ in bone, calcium isreleased from the skeleton and may be deposited in thetissues, including the kidney (nephrocalcinosis). Furthermore, the high urinary excretion of calciummay result in stone formation (see Chapter 10), oftenassociated with urinary tract infection. Impairment ofskeletal growth can occur in this condition, and also inproximal RTA when the disorder is congenital or startsin early childhood.

Much of the symptomatology of both kinds of RTA relates to electrolyte depletion. Urinary losses ofsodium are abnormally high in both forms, resultingin a degree of hypovolaemia. Both forms are typicallyalso associated with hypokalaemia because of stimu-lated potassium secretion in the late distal and corticalcollecting ducts. This is caused by a high luminal flow of sodium and bicarbonate in proximal RTA, andby electrically-driven potassium secretion to replacefaulty H+ secretion in distal RTA.

An important variant of distal RTA is hyperkalaemicdistal RTA (sometimes called type 4 RTA). In this casethe normal anion gap metabolic acidosis is associatedwith hyperkalaemia, which points to a different site ofdefect in the acid-secreting segment of the nephron. Asshown in Fig. 4.7, if a disruption occurs in the normal

RTA, on the other hand, can be caused by conditionsassociated with polyclonal hyperglobulinaemia,including SLE, as in the patient studied in this chapter.Other forms of structural tubulointerstitial disease can produce the same defect, and a number of drugsand toxins are also prone to damage this segmentselectively.

Apart from the differences in clinical setting and aeti-ology between the proximal and distal types of RTA, anumber of physiological differences exist. In the distalform, the impaired operation of the collecting duct H+

pump means that, no matter how severe the systemicacidosis, the urine pH can never be lowered appropri-ately, and generally remains above 5.5. Bicarbonate lossis not prominent since proximal reabsorption is gener-ally intact. However, in early or mild forms of proximalRTA there is considerable leak of bicarbonate into theurine, which again has an inappropriately high pHsince the distal segments are unable to acidify the urineas long as large amounts of bicarbonate are floodingthrough the lumen from the proximal segments.However, when acidosis is more severe in proximalRTA, the plasma bicarbonate falls because of bufferingof the accumulated acid. As a result, a point may bereached where the reduced filtered amount of bicar-bonate can be largely reabsorbed by the defective prox-imal tubular reabsorptive mechanism. The intact distalsegments can then reabsorb a small distal leak of bicar-bonate, as normally occurs. In this situation the distaltubular secretory pump can operate normally and gen-erate a transtubular H+ concentration gradient, result-ing in a lowering of the final urine pH. When thisoccurs, bicarbonate loss ceases and ammonium excre-tion rises so that a new steady state arises in which acid

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Lumen

ATP

Blood

2K+

Principal cell

HCO3-

Intercalated cell

ATPH+

3Na+

Cl-

Cl-

K+

Na+Site of defect inhyperkalaemic

distal RTA

Site of defectin ‘classical’

distal RTA

Cortical collecting duct

Fig. 4.7Site of defect in two variants ofdistal renal tubular acidosis (RTA).

operation of the principal cell type in this tubularsegment, sodium reabsorption will be impaired, re-sulting in a loss of the normal lumen negativity (seeChapter 2). This electrical change impairs the rate ofsecretion of both potassium and hydrogen ions into thelumen, resulting in systemic acidosis with hyper-kalaemia. This lesion has been described in a varietyof conditions causing distal tubulointerstitial damage(such as urinary tract obstruction with infection), andalso during treatment with drugs interfering withprincipal cell sodium transport (such as amiloride). Asimilar defect results from deficiencies in aldosteronesecretion or action, including diseases of the adrenalcortex and of the renin secretory mechanism in thekidney.

The management of all forms of RTA is directed in the first instance toward reversing the underlying condition affecting tubular function, if possible. Thenext principle is that sufficient bicarbonate buffer must be provided to replace that consumed by the acid being accumulated. Provision of some of thisbicarbonate as potassium salt will help replete potas-sium lost in classic forms of the disorder, while in the hyperkalaemic variant of distal RTA, measures to assist in the excretion of potassium (e.g. loop or thiazide diuretics, or corticosteroids, as appropriate)may be necessary. Treatment may also be required for specific complications in the various forms of the condition, such as removal of stones and treatmentof infections which sometimes complicate classic distal RTA.

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Disturbances of acid–base balance:alkalosis

To complete our survey of acid–base disturbances, wecan consider the two primary perturbations whichmight result in alkalosis.

Respiratory alkalosis

Any form of sustained hyperventilation will pro-duce a reduction in the blood pCO2 with a result-ing increase in plasma pH. The respiratory stimu-lus most commonly arises from anxiety states, but it may also be due to drugs stimulating the respira-tory centre, other brain disorders and chronic liverdisease.

The homeostatic response to respiratory alkalosisinvolves an initial phase of physicochemical bufferingby intracellular proteins, which give up H+, resultingin a small decrease in the plasma bicarbonate. Moresustained compensation occurs over the ensuing days,during which renal tubular H+ secretion is inhibited by the high extracellular pH and the reduced pCO2.Bicarbonate reabsorption is inhibited, as is ammoniumexcretion, and the result is a reduction in net acidexcretion and a fall in the plasma bicarbonate. In manycases the respiratory disturbance is not unduly pro-longed, and the renal compensation subsides as venti-lation is normalized.

Metabolic alkalosis

In this disorder there is a primary increase in theplasma bicarbonate concentration and the plasma pH.The causes fall into two groups according to whetherthere is associated contraction of the ECF volume or not.

Hypovolaemic metabolic alkalosis is the commonestpattern, and includes disorders such as vomiting and gastric suction, in which acid-rich gastric juices are lost from the body. Metabolic alkalosis associated with volume contraction also occurs duringtreatment with most diuretics (other than carbonicanhydrase inhibitors and potassium-sparing drugs).Here there is increased acid loss into the urine relatedto the diuretic action on the tubules. The alkalosis associated with volume contraction is perpetuated bysecondary renal responses, described in more detailbelow.

Normovolaemic (or hypervolaemic) metabolic alkalosisoccurs when the primary disturbance provokes bothbicarbonate retention and a degree of volume expan-sion. This most commonly occurs in corticosteroid

Acid–base balance and regulation of pH box 4

Treatment and outcome

Mrs Loy’s treatment focused on the control of herunderlying connective tissue disease. Immunosup-pression using prednisone and cyclophosphamide wasinitiated with a view to reducing the activity of herSLE. The metabolic acidosis and hypokalaemia werecorrected initially with infusions, and later with oral supplements, of alkaline salts of sodium andpotassium.

Over the ensuing weeks her condition improveddramatically, with the fevers and rash subsiding,urinary protein and red cell excretion reduced, andplasma electrolyte profile reverted towards normal.Within several weeks it was possible to discontinueher electrolyte and buffer therapy, and ongoingmanagement was directed towards long-term stabi-lization of the connective tissue disease.

Vomiting

Gastric loss of

Na+(Cl-)/H2OH+ (Cl-)

Hypovolaemia

aldosterone proximal Na+HCO3

-

reabsorption

Hypokalaemia

distal H+ secretion

NH3synthesis

H+ excretion

Metabolicalkalosis

K+ (Cl-)

(Kidney)

Generation

Maintenance

Fig. 4.8Vomiting: generation and maintenance of metabolicalkalosis. Note that the gastric loss of H+ is primarilyresponsible for generating the systemic alkalosis, whilethe other mechanisms shown act through the kidney tomaintain the alkalosis as long as sodium and potassiumlosses are uncorrected. Chloride is the deficient anionaccompanying all cations shown.

alkali in the urine. Replacement of potassium helpscorrect the hypokalaemia and its consequences in thekidney.

The non-hypovolaemic forms of metabolic alkalo-sis, by way of contrast, are resistant to treatment with sodium chloride, but can usually be managed by cessation of alkali therapy or correction of min-eralocorticoid excess. The latter may involve eitheradrenal gland surgery or blockade of mineralo-corticoid effect in the kidney by treatment withspironolactone.

excess states such as primary hyperaldosteronism(Conn’s syndrome), Cushing’s syndrome and relateddisorders. Occasionally, overuse of antacid salts canproduce a similar pattern.

The homeostatic response to metabolic alkalosisinvolves initial buffering of the rise in plasma bicar-bonate by titration of extracellular and intracellularbuffers, including plasma proteins. Soon afterwards,the increased pH acts to inhibit ventilation through themedullary chemoreceptors, such that the pCO2 startsto rise. Since, however, this is ultimately associatedwith an unacceptable degree of hypoxia, the extent towhich this form of compensation occurs is limited,such that the maximum pCO2 attained is rarely morethan 55mmHg.

In the absence of counterbalancing stimuli, theexpected renal response to sustained metabolic alka-losis would be to decrease tubular acid secretion,inhibit bicarbonate reabsorption and excrete the ex-cess bicarbonate into the urine. However, in the com-monest form of metabolic alkalosis, that caused 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 the alkalosis (‘generation’ phase), which is actuallyworsened by the losses of sodium, water and potas-sium (‘maintenance’ phase). The sodium losses areassociated with hypovolaemia, which triggers bothproximal bicarbonate reabsorption and aldosteronerelease, which stimulates distal acid secretion, therebyaggravating the systemic alkalosis. Furthermore, thehypokalaemia resulting from potassium loss (morethrough the kidney than from gastric fluid) also stim-ulates distal acid secretion and tubular ammonia synthesis (see earlier), both of which enhance acidexcretion and maintain the alkalosis. The net result is an inappropriately acid urine and a failure of thekidney to effect long-term correction of the systemicpH disturbance.

The cornerstone of management in hypovolaemicmetabolic alkalosis states, exemplified by vomiting, is to provide adequate volume replacement as sodiumchloride (isotonic saline infusions), which switches off the volume-conserving mechanisms mentionedabove and allows the kidney to excrete the excess

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Table 4.4Summary 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-

Summary of findings in principal acid–base disturbances

Table 4.4 provides an overview of the changes in pH,bicarbonate concentration and pCO2 in the four majorsimple acid–base disorders. Taken in conjunction withclinical information, the results of these analyses areusually sufficient to enable a diagnosis to be made ofthe nature and cause of the disturbance. Rules of

thumb are available to indicate the predicted compen-satory change in pCO2 or bicarbonate levels expectedin each of the simple (uncomplicated) acid–base dis-orders. When the available data for a given patient are not consistent with these changes, a complex or‘mixed’ acid–base disorder can be inferred, and the ele-ments of the disturbance usually deduced in conjunc-tion with a thorough clinical evaluation.

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Self-assessment case study

A consultation is requested on an 81-year-old man who hasbeen admitted to the hospital with an acute myocardialinfarction (heart attack). There has been significant damage tothe left ventricle such that cardiac output is markedly reduced.Furthermore, on day 5 after admission his course iscomplicated by the development of acute ischaemia in the leftleg, attributed to occlusion of a major leg artery followingembolization of a thrombus from the left ventricular cavity.

The patient’s plasma electrolyte results are as follows:

Sodium 135 mmol/L*Potassium 5.2 mmol/LChloride 97 mmol/L*Bicarbonate 14 mmol/L*Urea 14.0 mmol/L*Creatinine 0.14 mmol/L.(*Values outside normal range; see Appendix.)

Arterial blood gas analysis reveal the following: pH 7.33, pCO2

29 mmHg, pO2 (breathing room air) 58 mmHg.After studying this chapter you should be able to answer

the following questions:

b What is the overall pattern of acid–base disturbance in thispatient?

c What is the anion gap in this patient?

d What is the likely cause of the disturbance in this case?

e What would you expect the urine pH to be?

f What are the principles of treatment?

g What would the effect of a bicarbonate infusion be on hisplasma potassium concentration?

Answers see page 146

Self-assessment questions

b What would the effect on systemic acid–base balance be if apatient were given long-term treatment with a carbonicanhydrase inhibitor such as acetazolamide?

c Where in the nephron is the steepest gradient of pHbetween the plasma and the luminal fluid?

d Name three changes in the plasma which stimulate anincrease in hydrogen ion secretion by the nephron.

e Give three causes of a metabolic acidosis with a normalanion gap.

d Name three factors which perpetuate the systemic alkalosiswhich follows prolonged vomiting.

Answers see page 146