What is meant by "acid-base balance"

This chapter is relevant to Section J1(ii) of the 2017 CICM Primary Syllabus, which expects the exam candidates to "explain the principles underlying acid-base chemistry". Specifically, as the term "acid-base balance" is thrown around quite a lot, to explore its meaning feels like a responsible step.

In short:

Of all sampled literature, the best and most readable source was Johnston & Alberti (1983), as the two authors take the reader by the hand and patiently lead them on a walk through the dark forest of metabolic biochemistry. Other excellent resources also exist, notably Halperin (1982),  Seifter & Chang (2017) and Willner & Weissman (2011), L.I.G Wortheley (1977) and probably endless others, but the exam candidate revising  this topic will never suffer for lack of literature and would probably appreciate a smaller curated collection to an unmanageably large bibliography.

The definition of acid-base balance

Unlike sepsis and obscenity, this widely used term does actually seem to have a well-accepted valid definition. Ole Sigaard-Anderson expressed this as an act of accounting: 

"the balance between input (intake and production) and output (elimination) of hydrogen ion"

To put it in another way, the pH of the body fluids is constantly downtrending because of the acidifying activities of metabolism and the acid content of diet. This would lead to the development of acidaemia if it were not offset by the alkalinising effects of buffer systems and acid excretion mechanisms. The difference between these influences must therefore be minimal in order for the pH to remain stable. To call this "acid-base homeostasis" or even "acid-base equilibrium" would immediately remove all ambiguity and retain the necessary meaning, but for some reason "balance" remains a widely used term.

From these sorts of definitions, one can develop the impression that we can somehow quantity and balance the hydrogen ion account of the human body. This illusion is sustained by the occasional occurrence of a value, in a paper of textbook, that describes the "total body acid production" of the human organism.

Total body acid input

Whatever the truth in it, the quantified amount of acid "input (intake and production)" is a widely quoted factoid. It is unfortunate that every figure you find is different, occasionally by a massive factor, and uses a different unit of measurement. Observe, the products of a fifteen-minute Google search:

• 150g/day (Alberti & Cuthbert, 1982)
• Around 580 mol/day  (Johnston & Alberti, 1983)
• 50-70 meQ/day (Elkington, 1962)
• 70 mEg/day, i.e. 1mEq/kg/day (Hamm et al, 2015)
• 1-1.5 mmol/kg/day (Kerry Brandis, 2021), referring strictly to novolatile acids
• 15,000 mEq/day of "volatile acids" and 70–100 mEq/day of "metabolic acids", whatever those are, as well as "whole-body H⁺ turnover" (150,000 mEq/day) - Poupin et al, 2012

Now, each estimate or measurement is actually independently quite accurate, at least with respect to the calculations or whatever experimental variables those authors were measuring, but the reader would have to agree that from an exam standpoint this is probably absolute garbage. It is not clear whether CICM First Part examiners enjoy obscure factoids more than the author of Deranged Physiology, but they do appear to have some attachment to fact in the broadest sense, and would probably never ask the exam candidates to demonstrate that they have memorised a variable with no accepted normal value. Of course there could never be such a value, as the human organism is capable of a massive range of metabolic performance and dietary weirdness, such that the total daily "H+ flux capacity" or whatever you want to call it would be totally different from person to person, to say nothing of the difficulty of actually measuring it. All these chemists can do is estimate the total daily metabolism of some familiar substrates on the basis of CO₂ production and renal urinary acid excretion,  and extrapolate from these equations the total amount of H⁺ released in the course of metabolic activity. And of course this would always be a massive underestimate because 99% of all the molecular transactions that consume or produce a hydrogen ion are concealed from the physiologist because they do not consume or produce anything that ever enters or leaves the cell, making it impossible to detect these activities. In short, the "total acid production" of the human body should be viewed as an allegory, a metaphorical narrative device of teaching about acid-base physiology, and not as a genuinely meaningful metric.

So, in that spirit, let us consider the physiological processes that can acidify the body fluids. These would have to be:

• Ingestion, infusion or inhalation of acidic substances
• The loss of buffer substances
• The acidifying effects of metabolism
  • Metabolism of carbohydrates
  • Metabolism of lipids
  • Metabolism of proteins
  • Metabolism of purines
• The acidifying effects of ATP use

The temptation to submerge into this topic is too great, as it has all the most attractive properties, appearing to be an obscure laboratory subject distant to clinical reality, and at the same time somehow fundamental to the understanding of the human organism. The author reassures himself with the thought that the busy exam candidates would have moved on harmlessly after reading the grey summary box at the beginning, and then anybody who has continued reading and reached this point in the chapter will likely have already formed an opinion as to whether their time is being wasted. 

Dietary origins of exogenous acid

Following from the above, the sideways step into a discussion of the acid-base properties of food will not seem strange or irrelevant. It appears to be the last variable untouched by the endless capacity of the modern human to feel guilt about what they eat, in the sense that we obsess over calories macronutrients and vitamins, but not yet the pH. One does not find the manufacturers pressured to report this variable in their nutritional content labels. There is, fortunately, an abundance of resource on this topic, ranging from the lay to the extremely detailed and scientific. Without going on a ridiculous tangent, one can report a range of common edibles with representative values:

• Raw egg (pH 8.20)
• Tofu (pH 7.20)
• Broccoli (pH 6.30)
• Tomato (pH 5.50)
• Cherries (pH 4.0)
• Apple (pH 3.40)
• Vinegar (pH 3.0)
• Coka Cola (pH 2.50)
• Lemon juice (pH 2.0)

However, the better option would be to represent the pH range of common foods in this borrowed graphic from Bridges & Mattice (1939):

As one can see, most of these cluster well below what one might describe as a neutral pH; though the authors did point out that generally foods in the pH range of 5.0 and up do not tend to taste sour, and even foods and drinks with an unpalatable sounding pH below 3.0 are consumed with great appetite by lovers of salad dressings and carbonated beverages. There are actually very few alkaline foods, of which stored eggs and various shellfish are basically the only representatives.

On the basis of these data, one might observe that a normal diet will most likely consist of largely acidic ingredients, and would conclude that this acid load would be additive with whatever ends up being generated in the process of its metabolism. However, this is far from reality. The reported pH of a food substance is minimally important in comparison to the effect of its metabolic products. Consider that citric acid in lemon juice will plug into the citric acid cycle and be metabolised into CO₂ and water, whereas a relatively alkaline egg would transform into amino acids, liberating sulfate and phosphate.  Taking the stance that obvious things still need to be demonstrated experimentally, Bischoff et al (1934) fed some weird stuff to a series of volunteers, trying to determine exactly how much acid or alkali one might have to consume to cause an actual change in pH. After struggling through days of different diets specifically formulated to be alkaline to acidic, they gave up (no change in blood pH was observed) and tried some preposterous keto/palaeo abomination ("brains, ham, chicken, veal, beef, and eggs were used") at a dose of approximately 1.5Kg/day. The experiment had to end because the subject became nauseated on the third day and refused to continue, but the bloods collected during this period also remained stable.

The reader should not take away the message that the influence of the pH of ingested materials on extracellular fluid pH is uniformly trivial; only that it is usually trivial, provided the ingested materials resemble conventional food. Obviously if one is really determined, one may directly influence the pH of one's body fluids by consuming a vast amount of something ridiculous. For example, DeMars et al (2001) presented a case of a prisoner who consumed an unknown but presumably very largely quantity of DepotPac Toilet Bowl and Bathroom Cleaner, a concentrated solution of citric acid containing approximately 530g/L of citrate with a pH of around 2. He managed to get his blood pH down to 7.03, with a plasma bicarbonate of 12 mmol/L and an anion gap of 32. The acidosis resolved very rapidly (over less than 12 hours) as the citrate was rapidly metabolised. This is a helpful demonstration of what sort of oral acid dose is required to directly influence the pH of the extracellular fluid. 

The reader also should not take away the message that dietary acid load is somehow unimportant unless unless one decides to chug litres of toilet cleaner. Diet still has the capacity to influence acid-base balance; and though under most circumstances this goes unnoticed because normal renal and respiratory mechanisms are able to manage it, occasionally one needs to think about these issues in the context of patients with renal failure. This is usually expressed in terms of PRAL, or potential renal acid load. Remer (2000) gives a good account of how this can be calculated using various known values for metabolic parameters, urinary electrolytes, and intestinal absorption fractions. The PRAL is expressed in mEq, as it represents a molar amount of renally excreted acid, and it can also be a negative value (if the food substance contains bicarbonate precursors, for the classical interpreter, or increases the strong ion difference for a disciple of Stewart).

To oversimplify the model, one can say that foods that have a large quantity of anions (chloride, sulfate, phosphate) are generally higher in PRAL, whereas foods that contain large quantities of cations are lower, or negative.  From model calculations and from direct measurements it follows that a normal North American diet contains approximately 100-150 mEq of PRAL, mostly originating from the metabolism of the protein it contains; which offers a helpful segue into a series of explanations about how the extracellular fluid is acidified by the metabolism of macronutrients.

Origins of acid produced in the course of metabolism

In the course of manipulating nutrients, one's metabolism acidifies the body fluids in two main ways:

• by generating CO₂, for some reason referred to as "volatile acid"
• by generating soluble acidic breakdown products ("fixed" or nonvolatile acids)

This is as good a place as any to discuss this "fixed" and "volatile" terminology.

Volatile and non-volatile ("fixed") acids

This seems to appear in many CICM and ANZCA exam preparation resources and so feels like an essential part of the syllabus, insofar as those resources have become a shadow syllabus for the exams they describe. There was frankly no other convenient place to put it, and so it ended up taking up space here. 

For some reason, the textbooks and papers continue to refer to these "volatile acids eliminated by the lungs", as if this euphemism is somehow more economical then simply to write "CO₂". Indeed, CO₂ is the only substance which is reliably eliminated by ventilation in sufficient amounts to be important to acid-base balance. That is not to say that there are no other volatile acids; only that CO₂ is by far the most important quantitatively. Yes, other acids are also exhaled, but their concentration in exhaled air is thankfully very low, as it would be impossible to share a room otherwise. Substances that meet the criteria for being eliminated by respiration (has to be smaller than 600 Daltons, has to be gaseous at body temperature, etc) are generally short chain fatty acids, alcohols,  aldehydes, terpenes like isoprene, and thousands of others, lovingly catalogued by the good people of the Breath Biopsy VOC Atlas. Even for the most abundant and acidic of these (acetic, propionic and butyric acids) the exhaled concentration is measured in parts per billion. In short, the only volatile acid worth talking about is CO₂.

Constant rate of CO₂ production by metabolism

CO₂ is constantly produced in the course of oxidative metabolism, at a fairly predictable rate that is mostly determined by the substrate and the energy demands of the organism, all other things remaining equal. The ratio of O₂ consumed to CO₂ produced (the respiratory quotient) is 1.0 for carbohydrates, 0.71 for fat and 0.8 for protein. Additionally, CO₂ is generated by de novo lipogenesis, where excess dietary carbohydrates are transformed into fatty acids - this process has a respiratory quotient of 8.0, i.e. it produces approximately eight  CO₂ molecules for every oxygen molecule it consumes. It is of course impossible to generalise a single figure to describe the rate of CO₂ production, as any single value would only be correct for a minority of cases, but most textbooks quote values in the ballpark of 2-3ml/kg/min, or 10mmol per minute in total ( which is 224 mL/min). It appears this is supported by radiolabeled measurements in resting humans (giving a range of around 9-11 mmol/min). It is probably irrelevant to know this parameter, except in the sense that it can be applied to critical care; for example it means that a 100ml bottle of sodium bicarbonate contains enough potential CO₂ for ten minutes of ventilation, and this could be meaningful if your capacity to increase your CO₂ elimination is for some reason impaired, for example in severe asthma, ARDS, or really any paralysed patient being ventilated with a mandatory mode.

Anyway. The reader does not need to be reminded of how CO₂ acidifies the body fluids, but just in case,

CO₂ + H₂O ⇌ H₂CO₃ ⇌ HCO₃^- + H⁺

With its pKa of 3.49, carbonic acid is extremely keen to ionise at normal physiological pH, giving a reaction that strongly favours the products. CO₂ is therefore a rich source of acid.  In the quietly asphyxiating subject who is not eliminating it, the PaCO₂ increases by about 3.4 mmHg with every minute, which acidifies the body fluids from a pH of 7.4 to a pH of 7.2 over the course of six minutes, adding about 20 nmol/L of H⁺ (from around 40 nmol/L to about 60 nmol/L). Given that every 10mmol (3.4 mmHg) of CO₂ adds about 2.49 nmol/L of hydrogen ions, and 10mmol per minute translates to 14,400 mmol per day, the total daily acid production due to CO₂ should be something rather impressive.

How much H+ is produced in this way, if one had to quantify it for some reason? There are various values thrown around in the literature. For example, Alberti & Cuthbert (1982) blame CO₂ for 10% of the total metabolic H+ production, though it is not clear what they mean by "total" (this statement is not referenced and follows a discussion of some cellular mechanics that suggest the authors were referring to the whole of H+ production everywhere in the human body, even where it is immediately consumed by another reaction). Johnston & Alberti (1983) point to the fact that all this CO₂ is converted to H₂CO₃  which readily dissociates into HCO₃^- + H⁺,  suggesting that we should expect an equimolar amount of H⁺ to be produced, i.e.  14-15 mol. Of course nobody ever sees this acid all in one place because it is eliminated in both directions (this being an extremely elastic open buffer system), which means it is a fairly meaningless thing to be discussing. 

But that should not stop us:

Hidden cellular mechanisms of H⁺ production

The feeling of pointlessness experienced when contemplating all those hydrogen ions produced in the course of making CO₂  is the result of their impermanence. These 14-15 moles of H⁺ are a chemically accurate representation, but  CO₂ is eliminated by ventilation as soon as it is produced, which means it reconstitutes back into CO₂ and H₂O so all these hydrogen ions can return harmlessly to their constant game of autoionisation waterpolo. In fact this is seen everywhere you look, because many biochemical reaction equations produce a H⁺ somewhere, which generally goes unaccounted for because it ends up being trampled by other molecules in the cytoplasm, or more likely reabsorbed into the reverse version of whatever reaction had formed it.  Consider, the following ubiquitous chemical reactions that produce H⁺ are all reversible:

ATP^4- + H₂O → ADP^3- + HPO₄^2- + H⁺ (hydrolysis of ATP)

2Fe³⁺ + 2H → 2Fe²⁺ + 2H⁺ (electron transport chain)

NAD⁺ + 2H.R → NADH + H⁺ + R (reduction of NAD)

(listed by Alberti & Cuthbert, 1982)

That's right, every time an ATP molecule does anything useful a hydrogen ion is produced. But ADP is resynthesised into ATP again, NADH is reoxidised into NAD, and so forth, and often within the span of the same millisecond.

It is, of course, possible to estimate the rough volume of H+ turnover resulting from these various chemical transactions, for example by taking the total daily consumption of substrate for oxidative phosphorylation (which should roughly represent the ATP expenditure).  Johnston & Alberti (1983) do this accounting much better, and the reader who is interested in the details of the chemistry is pitched their excellent article to distract them from the following oversimplification. But briefly, one mole of glucose yields 38 mol of ATP, and one mole of triglyceride yields about 409 mol of ATP; and the synthesis of each ATP molecule requires effectively three H⁺ to complete (well, two H⁺ and the loss of one OH^-). Plus there is the NADH and FADH₂ oxidised in the process of glucose metabolism. In total, the average adult will metabolise about 1 mole of glucose and about 0.2 mol of triglycerides per day, yielding a total of about 120 mol ATP, and therefore 120 mol H⁺, which is accompanied by about 80 mol of H⁺ from the various NADH/FADH oxidation reactions and 360 mol of H⁺ cycling endlessly between the mitochondrial membranes. In short, the total H⁺ traffic around the cells of a normal resting body may be something in the vicinity of 560 mol per day, equivalent to about 20.5 kg of HCl, or 30L of concentrated sulfuric acid.

At this stage, even the most patient reader would object that none of this makes any difference because all these hundreds of moles of H⁺ are confined to the cell, and we never get to see or measure it. That may be correct under normal circumstances, but under conditions of stress, there may be "spillover" of H⁺; or rather, the acidification of the extracellular fluid as well as intracellular. Specifically, this occurs when the rate of ATP hydrolysis exceeds the rate of aerobic ATP synthesis. The hydrolysis liberates H⁺ but if there is not enough oxygen to create ATP in the conventional way, via ATP synthase, which would normally consume H⁺:

ADP + P_i + 2H⁺_out ⇌ ATP + H₂O + 2H

Instead, ATP is produced in the process of glycolysis, which generates lactate, and which does not consume H⁺:

C₆H₁₂O₆ + 2ADP^3- + 2HPO₄^2- →  2CH₃CHOH COO^- + 2ATP^4- + 2H₂O

Moreover in metabolically active stressed tissues the rapid consumption of inorganic phosphate prevents it from playing a normal intracellular buffer role, as it is immediately conscripted back into the glycolytic synthesis of ATP. All this extra H⁺ in the cell is then exported into the extracellular water, whether directly by leaking though the lipid bilayer or by the activity of various Na⁺/H⁺ exchange pumps.  The result, according to Robergs et al (2004) and Zilva (1978), is the systemic metabolic acidosis seen in association with hyperlactataemia, for which lactate is unfairly blamed. Thankfully, this finally leads us to the discussion of measurable organic acids, which have a clinical relevance most people would recognise.

Nonvolatile acids produced by metabolism

These "fixed" acids cannot be eliminated using any sort of powerful open buffer system, and need to be disposed of in other ways. The most important quantitatively are the following:

• Lactic acid produced by glycolysis 
• Ketoacids produced by lipolysis (​​​​​​acetoacetate and β-hydroxybutyrate)
• Free fatty acids produced by lipolysis (mostly palmitate)
• Acid produced in the metabolism of proteins (sulphate)
• Acid produced in the metabolism of bone and phospholipids (phosphate)
• Acid produced in the metabolism of purines (urate and hippurate)

Each of these is discussed elsewhere in some considerable detail, and so only a brief summary of their contribution to acidosis is revisited here:

Lactate as a nonvolatile acid in acid-base balance

Lactate is a weak acid with a pKa of something like 4.0, which should be fully dissociated at normal body fluid pH. When TJ Morgan and Hall (1999) titrated Morgan's own donated blood with lactate, they managed to drop the SBE from +4 to -3 at a lactate concentration of about 10 mmol/L.  The normal concentration of lactate in the blood is of course much lower, and though a huge amount of is is normally created by the tissues (1500 mmol/day, or 0.8 mmol/kg/hr) it usually does not contribute very much to the acid-base state of the body, as it is  consumed at the same rate in the liver, in a series of reactions that consume H⁺ and produce glucose. The Cori cycle is therefore proton-neutral. 

Ketoacids as a nonvolatile acids in acid-base balance

The ketone bodies produced in the human organism are acetone, acetoacetate and β-hydroxybutyrate. Of these, acetone is a non-contributor, as it will not dissociate into any sort of ions no matter how you spin it, which means acetoacetate and β-hydroxybutyrate are the main players. Acetoacetate has a pKa of 3.77 and β-hydroxybutyrate has a pKa of 4.70, which means they are also fully ionised at a pH of 7.4, and are therefore capable of acidifying the extracellular fluid. Their synthesis produces H⁺:

CH₃CO . CH₂CO . SCoA + H₂O → CH₃CO. CH₂COO^- + HSCoA + H⁺

However their consumption (acetoacteate oxidation)  in the tissues consumes H⁺: 

CH₃CO. CH²COO^- + H⁺ + 4O₂  → 4CO₂ + 3H₂O

Which means the net effect of ketoacids should usually be neutral. And that is what it probably is under normal circumstances. How much of this is constantly going on?  "The liver is capable of producing up to 185 g of ketone bodies per day", stated Laffel (2000) without offering a reference or any context. "The human liver produces up to 300 g of ketone bodies per day", reported Puchalska & Crawford (2018). It probably depends on the liver. Balasse & Féry (1989) are probably the definitive answer, as they summarise the findings of actual isotope-labelled experiments to determine the rates of ketone synthesis in fasted, diabetic and ketoacidotic subjects.

• During an overnight fast, i.e. between dinner and breakfast, a healthy non-diabetic human produced about 0.25mmol/min of ketones, producing about 36g of ketones over 24 hours and generating a concentration of around 0.18 mmol/L (of which the majority was β-hydroxybutyrate).
• Longer periods of fasting produced the normal spectrum of physiological adaptations to prolonged starvation, with ketone synthesis ramping up to 1-2mmol/min, and a total of 140-280 g of ketones being produced in this manner, rasing the blood levels to a total of 7.5 mmol/L (with 6.0mmol/L of β-hydroxybutyrate).   
• The subject with diabetic acidosis can produce ketoacids at a rate of 3mmol/min, reaching blood levels of up to 15-25 mmol/L, and producing 430g/day of ketones in total.

Only the latter is usually associated with acidosis, as in short and long term fasting the rate of production and the rate of consumption are generally balanced, leading to no net gain of H⁺. In diabetic ketoacidosis, on the other hand, the rate of ketone synthesis exceeds the rate of peripheral consumption, which means the extra H⁺ is not removed. Owen et al (1969) measured a ketone production rate of approximately 1500mmol/day in the starving non-diabtic human, of which apparently about 800mmol end up being oxidised by the brain; and this probably represents some sort of maximum for ketone utilisation. Any more than that, and you meet a bottleneck, apparently at the level of ketone transport into skeletal muscle, which Laffel (2000) describes as a saturable process.

 It is hard to argue with the fact that acidosis ensues; though it is not clear whether this is because they are acidic and produces acidosis by dissociating, or whether there is a H⁺ excess generated by their synthesis, or some combination of the two. Theoretically, if the dissociation was responsible, then exogenous β-hydroxybutyrate should produce an equimolar increase in H⁺, and to be sure this is probably what it does in vitro,  but it did not cause any acidosis when Nielsen et al (2019) infused it into heart failure patients, raising the plasma level to 3.3 mmol/L. In fact when Balasse & Ooms (1968)  infused their healthy volunteers with a huge dose of β-hydroxybutyrate (5mmol/kg/hr), the consumption of the ketones consumed enough protons to produce a substantial alkalosis (pH around 7.49). There does not appear to be a recorded experiment where somebody titrated their own blood with ketones to see the change in pH, but perhaps this is because the author did not do a very thorough literature review.

 Free fatty acids as nonvolatile acids in acid-base balance

The contribution of free fatty acids to total body acid base balance is probably minimal, even though H⁺ is liberated in the course of their synthesis, as three protons are produced each time triglycerides are hydrolised by hormone-sensitive lipase:

Tripalmitoyl glycerol + 3H₂O → Glycerol + 3 Palmitate- + 3H⁺

However, the palmitate is then immediately oxidised, and the hydrogen ions are consumed. Free fatty acids that end up in the circulation also end up consumed rather radily (the plasma half-life is about 2 minutes), maintaining the neutral account of H⁺.  Normal free fatty acid levels are not especially high (Frayne, 2005, gives a range of 0.1 to 1.0 mmol/L),  and this low concentration makes them a minor player on the scene of total body acid-base equilibrium. Moreover, for many of these molecules, the pKa is too high for the acid to be dissociated at physiological pH (depending on the chain length these may range from a pKa of 6.0 to a pKa of 10.5). In short, it probably wasn't worth even mention them. 

 

Urate and hippurate as a nonvolatile acids in acid-base balance

The urate anion originates from purine metabolism, and the hippurate anion is a product of quinic acid metabolism. Their pKas are 5.7 and 5.8, respectively. These anions are considered "titratable acids" and are eliminated by active transport in the proximal tubule. As the total daily production is relatively low (about 300-400mg/day for urate), these are not seen as major players in the total acid-base balance.

Sulphate produced in the course of protein metabolism

The sulphate anion is SO₄^2- and it originates from the metabolism of sulphur-containing amino acids methionine, homocysteine, cysteine and taurine. A normal human produces about 10-25 mmol of this stuff every day (Hamadeh et al, 2001), mostly in the liver. The pKa for it is 1.92, meaning that it is fully dissociated at normal physiological pH.  Ring et al (2023) discuss the interpretation of sulphate through the lens of quantitative chemistry and conclude that it is indeed a contributor to the acid-base balance, as titratable acidity increases exactly with the molar equivalents of sulphate. In states of metabolic acidosis the renal reabsorption of sulphate is decreased, i.e. an effort is made to excrete more of this material in order to protect the pH of the extracellular fluid.

Phosphate produced in the course of phosphoprotein and phospholipid metabolism

Phosphate, HPO₄^2- is generally regarded as a buffer, given the pKa of phosphoric acid is 6.8, which is conveniently close to the pH inside cells. Under normal circumstances it can bind a proton and become H₂PO₄^-, and the system is open at one end, as phosphate is also eliminated in the urine and accounts for 50% of the total renal acid excretion. Under circumstances of phosphate accumulation due to renal failure this relationship is obviously a lot less productive, and phosphoric acid becomes a contributor to the high anion gap metabolic acidosis observed in uraemia. The contribution is usually minor because the concentration is usually sensible, no higher than 4.0 mmol/L even in the worst of the cases. Only the most extreme phosphate levels truly reveal its acidifying potential. Kirschbaum (1998) reported a case of an elderly woman who drank a Fleet enema, full of sodium phosphate, and developed a severe metabolic acidosis with an anion gap of 56, pH of 7.14 and a peak plasma phosphate level of 20.6 mmol/L. 

Role of buffers in acid-base balance

It requires a thoughtful pause to decide whether the buffer systems deserve a mention here. On one hand, the buffer molecule does not actually do anything to the total number of the offending hydrogen ions; they merely rearrange them by absorbing or surrendering them. The result, however, is still a decrease in the concentration and activity of hydrogen ions, which is what pH is; i.e. the pH is returned towards normality; the change in pH due to the gain of acid is resisted. And "open systems" such as the bicarbonate buffer system can remove acid by cheating, through the removal of CO_2. . In fact all mechanisms of acid elimination seem to require the participation of a disposable buffer. All things considered, buffering needs to be mentioned as a part of the overall acid-base balance. The buffers are explained in detail elsewhere, which saves some space in this already bloated chapter. 

Elimination of acid

Apart of just absentmindedly protonating all your imidazoles, you've really got to have some mechanism of removing acid from the body fluids, as buffer system capacity is finite. Fortunately, much of this has already been discussed above, which means the following summary will suffice:

• Elimination of CO₂ by ventilation matches production, and is approximately 15 moles/day
• Elimination of renally excreted non-volatile acids is largely achieved by the kidneys by means of anion excretion, and can ramp up to a total of 400 mmol/day in times of increased acid load (Satorius et al, 1949). But normally:
  • Ammonium (40-50 mmol per day)
  • Phosphate (20-40 mmol per day)
  • Sulphate (10-25 mmol/day)
  • Urate (less than 4 mmol/day)