Renal regulation of acid-base balance

This impossibly, ridiculously long chapter is relevant to the aims of Section H1(v) from the 2017 CICM Primary Syllabus, which expects the exam candidate to "describe the role of the kidneys in the maintenance of acid/base balance".  This has appeared in a couple of SAQs, and is an attractive topic for a viva question. Past appearance have included:

• Question 19 from the second paper of 2020
• Question 12 from the second paper of 2014
• Question 12 from the second paper of 2010

These questions have touched on separate aspects of renal acid-base regulation, specifically on the renal handling of bicarbonate, the changes in tubular fluid pH along the nephron, the role of the kidneys in eliminating nonvolatile acids and the renal acid-base adaptation to an increase in CO₂. Unfortunately, even with the absolute minimum attention to fascinating asides, this is a massive topic, and highly resistant to compression.

In the fewest words possible, 

Making a recommendation for a peer-reviewed alternative source was difficult. This topic certainly does not suffer for lack of experts, and the real trick is filtering the abundance of published material to find something suitable to your specific needs. For an exam candidate, the best reference would have to be a review article of some sort, where a knowledgeable person takes a few pages to explain the important concepts without digressing into minutae. Good examples of this are Curthoys & Moe (2014) or  Koeppen (2009) - thet latter is written very well, available for free, and targets an audience of physiology teachers, i.e. the whole ethic of the article is "how can this material be explained in the clearest possible way?" The absolute opposite track was taken by the authors of several chapters of the dauntingly massive Seldin and Giebisch's The Kidney (Fifth Edition), pp 1995-2138.  Some useful material was untangled from Ch.55 (Hamm et al), but the rest was unsalvageable, like a knot of hair with gum in it. 

Another challenge was to explain each concept in two potentially conflicting ways. One needs to keep in mind that there is a "classical" and a "quantitative physicochemical" method of explaining acid-base phenomena, and one should ideally be familiar with both. In Stewart's Textbook of Acid Base, a chapter (Ch. 23, p. 393 of the 10th edition) deals with these issues. Does it matter which approach you take, and is one of the more "correct"? The author's own bias is towards the Stewart method, which accounts for its appearance in this piece (most people don't even mention it), but in truth it does not matter, either from an exam standpoint or from a practical bedside position. The classical position is classical, and that's how exam writers write their questions, but the quantitative analysis does have some benefits, particularly in terms of its internal consistency, and can help you navigate some curly questions. For example, the excretion of "titratable acids" like citrate is treated by the classical model as a loss of acid, but realistically citrate is a precursor for bicarbonate (as it is metabolised into CO₂ and water) which means by the classical interpretation the elimination of citrate is also the loss of a base. Within the Stewart model, citrate is a strong anion, and if you get rid of it (whether by metabolism or by throwing it overboard with the urine) you increase the SID and alkalinise the body fluids. In short, it is useful to allow oneself the freedom to doublethink here.  Most intensivists have brains with enough capacity that two contradictory concepts can lurk in opposite corners without ever having to awkwardly confront each other. 

Excreting "acid"

Acid, meaning "acid" in the Brønsted-Lowry sense (i.e. protons), is generated in the process of normal metabolic function, for example as a part of the hydrolysis of ATP:

ATP^4- + H₂O → ADP^3- + HPO₄^2- + H⁺

As one might imagine, this reaction is rather popular, it being the fundamental basis of eukaryotic life, and so one might expect a large amount of H⁺ to be generated in this fashion. Virtually all textbooks and review authors will parrot the shibboleth that the human body generates about 1.0 mmol/kg/day of hydrogen ions, occasionally even giving their estimate for how many of these raw untreated hadrons are buzzing around in the body fluids  (around 2 μmoles, according to Bobulescu & Moe). Knowing that the hydrogen ion is, for the purposes of acid-base discussions, nothing more than a convenient narrative device, makes it difficult to regard these statements seriously, but the fact remains that the process of metabolising oxygen and other substrates ultimately leads to the acidification of the body fluids. Whichever way you plan to interpret the words "acid" and "base", the organism needs some sort of plan by which it can maintain a relatively normal pH. Renal elimination of acid (and retention of base) is a part of this plan. 

Now, surely you could just acidify the absolute hell out of urine, and get rid of the acid load that way. There are mechanisms for that: for example, the NHE3 sodium-hydrogen ion exchanger and ATP-powered hydrogen ion pumps can generate a 1000-fold gradient across the apical membrane of the proximal tubule. However, this would only drop the pH of the urine down to a minimum of about 4.4, because of the annoyingly high permeability of the tubule walls to H⁺.  Preisig & Alpern (1989) calculated a proton permeability coefficient of something like 0.52 cm/s for the apical membrane of a rat tubule. Beyond a pH level of around 4.4,  the leak of intratubular H⁺ back into the intracellular and interstitial fluid would match the efforts of the pumps trying to extrude it.  This would give a H⁺ concentration of only about 0.1 mmol/L, i.e. you'd be eliminating only 0.1 mmol of H⁺ for every litre of urine you produce. Thus, unless you plan to produce about 230 litres of urine per day, there needs to be some other mechanism of eliminating acid from the body. The kidneys offer three such mechanisms: the secretion of non-volatile acids, the synthesis and secretion of ammonia, and the retrieval of bicarbonate from the urine. What follows is an earnest attempt to introduce some sort of logical flow into the discussion of these mechanisms.

Bicarbonate handling in the proximal tubule

Behold, the glomerular ultrafiltrate. This, until very recently, was just blood plasma, and is now an acellular protein-poor fluid in a Gibbs-Donnan equilibrium with blood plasma. As all the anionic proteins have stayed behind in the bloodstream, the bicarbonate concentration of the glomerular ultrafiltrate will be very slightly higher, but it is otherwise of essentially identical composition, which means it has about 24 mmol/L of bicarbonate.

The 180-200L/day flow of glomerular filtrate therefore brings about 4300mmol/day of bicarbonate to the proximal tubule. Approximately 80% of it will be reabsorbed here by a mechanism which is coupled to H⁺ secretion, which is probably mostly NHE3-mediated sodium exchange and the activity of some ATP-powered proton pumps.

It is perhaps best to go through this process in a series of steps, which - on reflection - could have been presented as a neat ordered list. However, to acknowledge that the readers will vary in their appreciation for solid blocks of dense text, the author will point out that that spatial learners remember best through visual communication, mainly as a means of finding a new excuse to insult the audience with cartoonish diagrams.

Consider first a situation where there is perfect equilibrium.

Now, let us upset this equilibrium by dumping a vast amount of hydrogen ions into the tubule fluid, for some reason represented here in the form of fluorescent xenomorph blood.

When it is dumped into the lumen of the proximal tubule, the secreted H⁺  now finds itself the presence of HCO₃^-.  The balance of HCO₃^- and H⁺ is described by the following equation:

CO₂ + H₂O ⇌ H₂CO₃ ⇌ HCO₃^- + H⁺

Thus, adding H⁺ to one end will push the equilibrium in the direction of producing more H₂CO₃. But H₂CO₃ now finds itself in the presence of a whole army of carbonic anhydrase enzyme molecules, and is therefore rapidly converted into CO₂ and H₂O. Thus, the net effect of acidifying the tubule fluid is the conversion of bicarbonate into CO₂. 

The amount of CO₂ in the proximal tubule increases as the result of this, creating a concentration gradient between the tubular lumen and the cell. Fortunately, CO₂ is able to easily cross the lipid bilayer into the cell, which is exactly what it does (along a predictable concentration gradient)

In the cell, the increased concentration of CO₂ and the everpresent abundance of H₂O pushes the aforementioned equation in the direction of forming more H₂CO₃. And there is also plenty of intracellular carbonic anhydrase in the cell to metabolise this H₂CO₃ into HCO₃^- and H⁺.

This is perfect because H⁺ is recycled as substrate for NHE3. The newly created HCO₃^- is ushered out the back of the cell by the NBC1 co-transporter, which constantly works to reduce its concentration in the cell. 

The result is a situation where the constant export of acid into the tubule lumen produces a  CO₂ gradient which moves bicarbonate (in CO₂ form) into the cell and out through the basolateral membrane.

In short,  the net effect of all this hydrogen ion secretion is the titration of bicarbonate, the product of which (carbonic acid) ends up getting reabsorbed. In fact when you do the numbers you will note that every hydrogen ion which ends up being secreted is consumed in the production of H₂O and CO₂, and is therefore reabsorbed and endlessly recycled. The reader might complain that this seems to be futile (no hydrogen ions are excreted) but the net effect of this activity is the reabsorption of bicarbonate, and as one might imagine, the result of a lower bicarbonate concentration is still a drop in pH.  When you find this mentioned in textbooks they usually tend to mention an end-tubular pH of 6.8, which probably comes from studies like Bank & Aynedjian (1967). Their micropuncture experiments revealed a mean pH of 6.31, with a mean HCO₃^- of 2.7 mmol/L in the distal pars recta. 

What would Stewart say? Well: the disappearance of the negatively charged bicarbonate from the tubule lumen is surely going to decrease the total anionic charge in the fluid, and so one might expect some chloride to leak across some paracellular channels to maintain electroneutrality.

This explanation is offered in the most recent edition of Stewart's Textbook of Acid-Base (p. 416) even as the writer sabotages his own argument in the next paragraph.  Though  "it may seem very plausible from charge balancing that a reciprocal relationship between Cl^- and HCO₃^- transport should exist in the proximal tubule", the complex influence of excreted organic anions and other "strong" ions on the tubular quantitative acid-base balance is offered as an explanation as to why our physicochemical  Stewartian model for the comings and goings of chloride in the proximal tubule is more guesswork than science. To conclude on a positive note, the author attempts to build some sort of compromise between the two systems, as "there is good reason to believe that classically described transporters of acid-base molecules are necessarily linked with the transport of [SID] components".

Excretion of "titratable acids" in the renal tubule

So: the environment of the proximal convoluted tubule becomes highly acidic over a relatively short distance, and much of this acidity is titrated by the bicarbonate which is already present in the tubule, a clever method for reabsorbing said bicarbonate. However, the reabsorption of bicarbonate, even if 100% of the bicarbonate is reabsorbed, does nothing to eliminate acid from the body- all it does is maintain a status quo.  But as has already been mentioned, the normal metabolic functions of the human body are a relentless and prolific source of acid, and it needs to be removed somehow. Thus, the abovementioned ATP-powered proton pumps and NHE3 exchangers secrete more protons into the tubular fluid then what would be required to merely reabsorb the bicarbonate.

As has been already mentioned, just excreting raw protons into the tubule does not work particularly well because beyond a certain point they leak back across the highly proton-permeable apical membrane. There needs to be some other way of trapping these hydrogen ions in the tubular fluid which does not result in them becoming reabsorbed, i.e. they need to get trapped there and then excreted with the urine. This is achieved by using several different molecules which bind hydrogen ions under the sort of conditions that are prevalent in the fluid of the tubule. Of these, the most important are ammonia and a selection of weak acids which are usually referred to as "titratable acids" by the people who know such things. They are called this because in the Brønsted-Lowry definition of an acid, as a thing that donates a proton, these substances are "acidic" by the definition that they can donate a proton to alkaline urine, or accept a returned proton back from acidic urine (by this action decreasing its acidity). So, realistically, they should be called "titratable buffers", and in fact some authors refer to them as such. These molecules are phosphate, sulfate, citrate, urate, hippurate and several others (one might also recognise them as the non-volatile acids responsible for the uraemic acidosis of renal failure). The best account of this is the excellent article by Hamm & Simon (1987), which is the reference given by most textbooks when the time has come to discuss this topic.

Phosphate handling as an instrument of acid-base regulation

Another chapter deals in more practical terms with the contribution of phosphate to the so-called "uraemic acidosis". Phosphate accounts for something like 50% of the total "titratable acid". Its handling by the tubules is detailed in an excellent article by Gmaj & Murer (1986). Phosphate comes in a variety of species, but in the urine (at the end-proximal-tubule pH of 6.8) it is present in two main forms, H₂PO₄^- and HPO₄^2-. These species can both be reabsorbed by the proximal tubule using sodium-coupled co-transport, with HPO₄^2- absorption favoured at a normal or high pH  (Brunette et al, 1984)

The most important thing to note here is the critical role played by pH in the regulation of phosphate excretion.  HPO₄^2-  is the dominant species at a pH of 7.4, but at a pH of 6.8, the dominant form is H₂PO₄^- which has now bound a proton. As more inorganic phosphate ends up being present in H₂PO₄^- form, less is reabsorbed. Moreover, it appears the affinity of the cotransporters for sodium is directly affected (decreased) by an acidic pH, which means they would be much less inclined to reabsorb any phosphate species during conditions of acidosis. In short, all of these adaptations to the increased acidity of delivered urine result in the increased excretion of phosphate, taking the hydrogen ions with it. Because the proximal tubule is the only part of the nephron that does phosphate, all of this "titratable acid" is excreted (i.e there are no distal mechanisms which might frustrate this process by trying to reabsorb the phosphate again).

Logically, this primary site of phosphate management is also where regulatory hormones exert their effect. With chronic metabolic acidosis, the reabsorption of phosphate here decreases because of decreased apical membrane channel expression, apparently under the control of PTH.  With alkalosis, the reabsorption of HPO₄^2- is preferentially increased. According to the excellent article by Curthoys & Moe (2014), the intracellular phosphate which is reabsorbed by these mechanisms is  removed from the basolateral end of the membrane (because where else would it go) by a process which "still remains enigmatic".

Other "titratable acids": sulfate, urate, hippurate, citrate, creatinine, etc...

If the pH of the urine continues to drop for whatever reason, phosphate no longer acts as a reliable buffer. At a pH of 6.0, pretty much all of the phosphate in the urine ends up being H₂PO₄^-, which means it has done its job and no further hydrogen ions can be buffered by this system. At these low pH ranges, other buffer systems take over. Fortunately, the proximal tubule (especially pars recta) is able to secrete various other weak organic acids into the tubule lumen, and their pKa values are more favourable to buffering at this low pH range:

pKa values of urinary buffer molecules

Titratable acid	pKa value
Phosphate	6.8 (for HPO42- )
Sulfate	1.92
Urate	5.7
Hippurate	5.88
Citrate	5.6 (for trivalent citrate)
Creatinine	4.9
Ketones	Variable

Now, the attentive reader will be ready to point out that the pH of the pars recta is usually not expected to be low enough to take advantage of these substances, and that would be quite accurate.  In fact, the pKa of sulfate is so low that it probably never gets a chance to act as a buffer. Some of the others (eg. urate, hippurate) have a plausible pKa but never get to pitch in with the buffering process because their concentration in the tubule is never high enough to make much of a difference. According to Weiner et al (2013), there's about 4 mmol of urate excreted every day, which is a miserably small amount. Creatinine, on the other hand, has the right pKa (4.9, though it seems to vary from textbook to textbook) and is available in significant concentrations, which means under conditions of severe metabolic acidosis it can contribute as much as 20% to the total titratable acid excretion. Again, exactly how acidaemic one has to be for this effect to become important, or where the "20%" figure comes from, is impossible to determine because Weiner et al did not offer any references to support this information.

Production and excretion of ammonia in the proximal tubule

Ammonia is filtered in the glomerulus, and the proximal tubule cells can produce ammonia locally out of glutamine. It enters the cells through the basolateral membrane through SNAT-3 transport proteins, is metabolised by glutaminase and glutamate dehydrogenase, and transformed into ammonia (NH₃).

In solution, ammonia exists in an equilibrium with ammonium (NH₃ + H⁺ ↔ NH₄⁺), but the pKa of this reaction is 9.15, which means that at physiologically relevant pH virtually all ammonia exists in the form of NH₄⁺. Thus, when the relatively lipid-soluble NH₃ is secreted into the lumen of the tubule, ammonia immediately finds a proton and binds it to become ammonium (NH₄⁺), becoming trapped in the urine by its positive charge and poor lipid solubility.

Weiner et al (2011) and Weiner & Verlander (2017) report that the excretion of ammonium into the tubule is also direct, via NHE-3. This exchange pump is supposed to handle mainly hydrogen ions, but apparently, NH₄⁺ is a suitable substrate. In fact it can also pose as other cations, effectively pretending to be potassium at ROMK channels (more on that later). Unlike the polar ammonium ion,  ammonia does not seem to require any special channels, and is thought to leak straight out through the membrane of the cell. When Simon et al (1989) disabled every possible and impossible channel in the rat tubule, they found that ammonia secretion continued, albeit at 50% of the previous rate.

Why is the secretion of ammonia important? With the pKa for this ion being as high as it is, one can safely say that it will never act as a proper "titratable acid", donating protons when the urinary pH is high. Those protons are trapped. Removing ammonium from the body therefore results in the removal of H⁺.

Now, a word of caution must follow these statements, as they are probably not entirely correct. At the same time, they are repeated often enough to have entered textbooks and official-looking peer reviewed articles, which makes them correct enough for exams. The attentive reader will point out that the creation of NH_anything in the kidneys is going to generally be the creation of NH₄⁺, because nothing in the tubular cells could possibly produce enough NH₃ with its pKa of 9.15. Thus, 99% of intracellular ammonium production does not usefully bind new tubular protons, as it's already got one from the intracellular cytosol. Hamm et al (2015) correctly point out that a lot of the acid-base effects of ammonium elimination are probably the consequence of glutamine catabolism, which conceptually produces one molecule of bicarbonate for every ammonium ion produced (if you follow all the steps, you will eventually end up at the citric acid cycle, and therefore ultimately there metabolism of glucose and the production of bicarbonate in the form of CO₂ and water).

These intellectual contortions are required by the classical model of acid-base interpretation to explain how the secretion of NH₄⁺ could possibly lead to decreased total systemic acidity (whereas the physicochemical model merely requires NH₄⁺ to be excreted along with chloride to decrease the SID). It is worth knowing about this caveat, and at the same time it is worth knowing that nobody will ever be interested in such esoterica. With their focus on the end goal of passing exams, those ICU trainees who are still reading this can calmly feed this information into the shredder.

Anyway, irrespective of how you cut it, ammonium secretion is important. How much secretion takes place in the proximal tubule? Laboratory manuals inform us that the normal range is less than 50 µmol/L (usually 11 to 32 µmol/L), which means glomerular filtrate should be expected to be extremely ammonium-poor. In the process of passing through the proximal tubule, it is enriched by the concentrating effects of water reabsorption and by the active secretion of ammonium to the point in the late proximal tubule its concentration has increased up to 1.7-2.3 mmol/L, i.e a thousand-fold. That's nothing compared to how high it can get in the collecting duct, and overall the total secretion of ammonium by the whole nephron ends up being something like 40-50 mmol per day, which makes ammonium secretion the dominant force in renal acid-base management. We will come back to that later, towards the end of the chapter.

Total effect of "titratable bases" on urinary acidification

Staring blankly at the numbers which describe end-tubular ammonium concentration pH and phosphate content, one might very reasonably ask oneself, is that a little or a lot? In short, these secretory mechanisms and buffer systems we have just discussed -  how much does each of them contribute, and when do they make their contribution? In their chapter for Mount et al, Weiner Verlander and Wingo (2013) have a beautiful diagram (Fig 7.6, p. 218) that plots "buffer capacity" over urinary pH.  The same diagram, or variations thereof, appear to be reproduced without any permission or references in a variety of sources, making it difficult to prosecute any specific person for copyright infringement, and emboldening future infringers. It is not clear where the numbers come from, but they are weirdly specific (this is a diagram of daily buffer capacity in mmol/day), suggesting that somebody somewhere must have measured this directly. Without shamelessly plagiarising the original image, or replicating values without knowing where they came from, it should still be possible to reinterpret this diagram retaining whatever educational potential it was supposed to have:

In short, under normal circumstances, most of the buffering is done by phosphate, and only when the urinary pH is very low do other systems (most notably creatinine) add their two cents to the overall work of buffering the urine, because the capacity of the phosphate buffer system is exhausted with increasing urinary acidity. One must be cautioned in interpreting this graph - it describes only buffering capacity, not the total renal urinary excretion. The capacity of ammonia as a buffer is minimal (as at normal physiological urinary pH it is present mainly in the form of ammonium), but its contribution to total acid-base removal is much greater for other reasons. 

Acid-base handling in the loop of Henle

As mentioned above, the fluid entering the thin descending limb is an isotonic soup with a pH of around 6.8 and a bicarbonate concentration as low as 2-3 mmol/L. This part of the loop of Henle is impermeable to ions, and so as the tubular fluid is concentrated along its way down, one might also expect the remaining bicarbonate to also become concentrated. And as the concentration of bicarbonate increases, so the pH should increase, it logically follows. This is in fact what you see experimentally. DuBose et al (1983) performed a series of micropuncture experiments and determined that the pH at the hairpin bend of the tubule was about 7.38 on average, with a bicarbonate concentration around 20 mmol/L. 

However, it does not stay that way. Malnic et al (1972) observed that the pH of the fluid exiting the loop of Henle was not markedly different from the pH of the fluid that entered it, i.e. around 6.8, with a low bicarbonate concentration. On that basis, it is thought that some bicarbonate reabsorption probably takes place, and probably in the thick ascending limb. This was ultimately confirmed by Capasso et al (1991), who had demonstrated that this reabsorption accounts for perhaps 15% of the filtered bicarbonate (though this was based on a microperfusion study where the tubule was being filled with a relatively bicarbonate-rich fluid). The mechanism is thought to be the same as in the proximal tubule, involving the extusion of protons into the tubule lumen by pumps and exchangers, coupled to the activity of carbonic anhydrase.

Ammonium reabsorption in the thick ascending limb

As the process of passing through the concentrated circles of hell in the inner medulla causes urinary pH to become more alkaline by making the bicarbonate more concentrated, so does the urinary ammonium concentration increase. According to some micropuncture experiments by Buerkert et al (1983), the concentration of ammonium in the hairpin bend of the loop of Henle ends up increasing from 1-2 mmol/L to something like 4-5 mmol/L.

So far, so good - all of this makes logical sense. But then, at the beginning of the distal tubule, the concentration of ammonium is again only about 1.2 mmol/L. Why is this so? Good articles by Good (1990) and Good (1994) informed this section well. It appears the ammonium is reabsorbed in some way (it clearly has to be). The transporter involved is the NKCC2 transporter made famous by being the drug target of loop diuretics. In this instance, ammonium acts as an impostor. It is sufficiently physicochemically similar to potassium ions, and is able to substitute for them in this exchange protein. There are tons of these transporters in this part of the nephron, which means the upshot of this is an avid uptake of ammonium out of the lumen of the thick ascending limb. It is then exported into the medullary interstitium through the basolateral membrane - again by pretending to be potassium, but this time fooling basolateral ROMK channels and K-Cl cotransporters.

The attentive reader will have realised by this point that this process must surely result in the accumulation of ammonium in the inner medulla, as things that are reabsorbed by the thick ascending limb generally end up getting trapped there by the countercurrent exchange mechanism. This definitely appears to be the case; Good et al (1987) measured an ammonium concentration of around 2mmol/L in the medullary vasa recta, which they felt was a reasonable surrogate for medullary interstitial fluid. In acidosis, it went up as high as 6mmol/L. So why does the inner medulla want to stockpile ammonium in this way? Well: it has a role to play in distal urinary acidification. Specifically, it is used by the collecting duct, as will now be explained.

Acidification in the distal nephron

The best peer-reviewed reference for the acid-base handling role of distal nephron structures comes from Malnic et al (1994). One might summarise much of this section as "intercalated cells do everything", as the regular local cells of the distal convoluted tubule really have minimal input into acid-base regulation. 

The distal convoluted tubule receives fluid with a pH of around 6.8 and bicarbonate in the low single digits, it does basically nothing with it, and identical-looking fluid emerges out of the other end in much the same state as it entered. Only towards the end of the distal tubule, where intercalated cells begin to appear, do we see much of a change in the acid-base state of the tubular fluid. The pH drops to about 6.6 by the end of the connecting tubule and is as low as 6.13 in the upper collecting duct. Depending on the prevailing conditions, the pH of the terminal collecting duct fluid can be as low as 5.5 in conditions of chronic acidosis. 

The intercalated α cells (which contain ATP-powered H⁺ pumps) and intercalated β cells (which feature Cl^-/H⁺ exchange proteins) are responsible for four main acid-management functions.

• They secrete hydrogen ions. As is already abundantly clear from the discussion above, this has limits on what it can accomplish on its own, but also:
• They release ammonia (NH₃). By combining the hydrogen ions and the ammonia in the acidic environment of the tubule, ammonium (NH₄⁺) is formed, and trapped in the urine.
• They release chloride. Apart from its Stewartian importance (where a strong anion leaving the body is always going to exert an alkalinising influence), the secretion of chloride into the lumen has downstream effects, because:
• They recycle chloride to secrete bicarbonate.  In this way, you can dump bicarbonate into the urine if that is what's called for (for example, under conditions of systemic metabolic alkalosis). 

If channel diagrams are more your thing, then have at you:

In this way, the distal nephron contributes significantly to renal acid-base regulation. This is the last time you can make changes to the acidity of the urine, and the best time to dump a large amount of acid into it.

Ammonium elimination by the distal nephron

When tubule fluid enters the early distal tubule, the ammonium concentration is about 1.2 mmol/L. Then, something happens, and the ammonium concentration of the distal nephron increases massively. Moreover, it increases even more massively if the organism is experiencing metabolic acidosis, which strongly suggests a regulatory role.  Good et al (1987) measured a collecting duct ammonium concentration of 33.8 mmol/L, and as high as 73.6 mmol/L in rats with a chronic acidosis. 

How does this happen? Nobody actually knows, and the uncertainty is reflected in the broken arrows in the diagram above. The concentration of ammonium in the interstitial fluid of the inner medulla is quite high (about 4 mmol/L) but clearly that is not high enough to create a concentration gradient and drive the ammonium out by passive diffusion. The ammonium ion itself is positively charged, and to expect that it would cross the membranes on its own is not especially plausible, which suggests that there is some sort of transporter involved. Karim et al (2005) document the contribution of RhBG and RhCG proteins which seem to permit the entry of NH₃ into the cells, potentially explaining how it moves through the basolateral membrane. For this to happen, NH₄⁺ would need to split into NH₃ and H⁺, get transported into intercalated cells, and then get excreted separately to recombine again in the urine, as depicted in this crude diagram:

Several other mechanisms are also implicated, such as scenarios where NH₃ and NH₄⁺ plug into the function of other transporter systems, taking advantage of their resemblance to K⁺. In short, ammonium secretion clearly occurs in the distal nephron, and it's clearly both massive in scale and important from a regulatory standpoint, but exactly how it happens is still the subject of debate, fertile soil for entire fields of PhDs. 

So, in the classical interpretation of acid-base balance, ammonium and ammonia represent mechanisms for removing more hydrogen ions (and therefore acid) from the body then would otherwise be possible by simple proton pumps. Ammonium excretion also plugs into the quantitative physicochemical paradigm of Stewart's model. Sodium and potassium cations need to be retained in the body in order for the strong ion difference to favour the presence of a large amount of bicarbonate, and therefore an alkaline pH. In order to generate this sustained high SID, one needs to get rid of strong anions - specifically chloride. But chloride will not be leaving on its own - it is negatively charged, and therefore needs to be excreted along with a cation. You'd obviously not want to be excreting it along with sodium or potassium, and so this is where ammonium comes in. By excreting the positively charged ammonium ion along with chloride, one is able to maintain the electroneutrality of urine, and the more ammonium you excrete, the more chloride you can afford to dump.

The central role of ammonium in urinary acidification

To check in with the reader and summarise the tangled mess of random and seemingly unconnected statements made so far:

• Renal reabsorption of bicarbonate maintains the acid-base status quo. The insanely massive churn of bicarbonate in the proximal tubule (4000 mmol/day or whatever it is) usually contributes absolutely nothing to acid excretion.
• Elimination of acid via the urine is accomplished by the elimination of titratable acids and ammonium
• Of these, ammonium is the most important in terms of quantity and scalability.

So, titratable acids, though they contribute significantly (and you really want to get rid of them anyway), are on their own insufficient for the handling of the daily acid excretion requirements. There is unfortunately only so far that you can go with those, as the body needs some circulating phosphate and urate to carry on vital functions (i.e. you can't just decide to dump all your phosphate into the urine). This makes ammonium, which is created locally in the kidneys specifically for urinary acidification purposes, the most important adjustable factor involved in urinary acid excretion.

According to most authors (eg. Hamm et al, 2015), ammonium elimination accounts for at least 50-66% of the total daily acid-base elimination (40–50 mmol per day), and is subject to regulatory influences which can dramatically change the rate of its excretion. Specifically, ammonium synthesis in the proximal tubule is sensitive to chronic changes in acid-base balance and specifically chronic metabolic acidosis is a strong stimulus for increased ammonia production. From this, logically it follows that urinary ammonium excretion could be used to measure the effectiveness of urinary acidification. Unfortunately, it's a massive pain to measure, and usually we resort to surrogate measures, such as the urinary anion gap.

Urinary anion gap

Another chapter discusses the urinary anion gap in normal anion gap metabolic acidosis and yet another one lists the possible findings for the purpose of Part II exam preparation. In short, even though you're really interested in the urinary ammonia handling, because of rude convenience you end up measuring everything else, and extrapolating ammonia handling from that. The formula is:

Urinary anion gap = (Na⁺ + K⁺) - Cl^-

It would perhaps be easier to represent this with a Gamblegram:

What you want to have under most normal circumstances is a negative urinary anion gap. At all times, the presence of unmeasured eliminated ammonium among the cations will mean that urinary chloride is vastly higher than the sum of the measurable urinary cations, and the urinary anion gap will be negative (which, in all fairness, should really be called a "cation gap"). When urinary acidification is deficient (like, for example, in distal renal tubular acidosis), there is minimal urinary ammonium present and the urinary anion gap is positive. The classical interpretation of this is the lack of H⁺ clearance because not enough ammonia is being excreted to trap the protons; the quantitative physicochemical interpretation is the lack of proper chloride clearance, resulting in the retention of chloride in the body (which leads to a decreased strong ion difference).

So, we have discussed the various mechanisms used by the kidney to reclaim bicarbonate and extrude acids in every which way. How much, then, do these mechanisms accomplish, and how fast?

Renal response to respiratory acidosis and alkalosis

The renal compensation for chronic respiratory acid-base disturbances is described by the well-known empirical formula for compensation, which states that

For every 10 mmHg increase in PaCO₂, the HCO₃^- will rise by 4 mmol/L

We know these things because brave soldiers of science peed on command, choked, hyperventilated and ate weird things under perverse experimental conditions, all while having their arterial blood invasively sampled (eg. Adrogué et al, 1986, who locked ten puppies in a gas chamber at an FiCO₂ of 10%, or Barker et al, 1957, who somehow compelled humans to do something similar). How does this compensation happen, and what are the mechanisms? According to CICM examiner comments to Question 12 from the second paper of 2010, "for a good answer candidates were expected to mention that Hypoventilation results in an increase in arterial PCO2 that readily diffuses into tubular cells resulting in increased intracellular H2CO3 and subsequently bicarbonate, that is reabsorbed, and H+ that is secreted." The statements made by the examiners seem to come from Vander's Renal Physiology (Ch. 9, p. 176 of the 7th edition from 2009) which says:

"...because tubular membranes are quite permeable to CO₂, an increased arterial PCO₂ causes an equivalent increase in PCO₂ within the tubular cells. This, in turn, causes elevated intracellular hydrogen ion concentration by driving the reactions should in Equation 9-4 to the right [this refers to the equation describing the activity of carbonic anhydrase]. It is this change that, via a sequence of intracellular events, increases the rate of hydrogen ion secretion."

Or, in the form of art, 

This is straight from the official college textbook for renal physiology, and is by that definition the most correct answer possible, but it must be pointed out that there is no reference associated with these statements, and other experts  (Madias & Adrogué, 2003) do not mention this mechanism. Moreover, the changes in blood PCO₂ (and therefore tubular intracellular PCO₂) are very rapid (over the course of minutes given the excellent lipid diffusability of CO₂), whereas the changes in bicarbonate reabsorption are initially minimal, and take days to manifest.  However it seems to be supported by experimental data. In his excellent paper for J Nephrol, Walter Boron (2006) touches on this topic, quoting his own research where washing the basolateral membrane with CO₂-rich fluid produced an acute drop in tubular fluid pH. Boron and his colleagues were forced to admit that, 

"...as unlikely as it seems, CO2 and/or HCO3  on the basolateral side of the cell somehow must trigger the secretion of H across the membrane on the apical side."

But Boron and colleagues did not actually propose that CO₂ penetrated the tubule cells to be split two ways. Their idea was that some sort of a CO₂ sensor (perhaps a tyrosine kinase of some sort?) detects CO₂ and kicks off the (slow, protein-expression-related) process of increasing tubule acidification by increasing the activity of normal existing mechanisms. In short, it is not clear where the official textbook got this idea from, or how it became incorporated into CICM canon.

Anyway, without digressing overmuch on a controversy that is part of a much larger topic, it will suffice to give the readers a good reference and restate the facts in point form, incorporating the CICM/Vanders narrative while maintaining some attachment to other published peer-reviewed works:

• With chronic respiratory acidosis, the PaCO₂ increases.
• At the same time, there is a decrease in pH, but the increase in PaCO₂ is what drives the changes (Madias et al, 1985).
• The specific molecular signalling pathway which causes the changes in renal acid-base handling is unknown
• The changes in renal acid-base handling are triggered by the delivery of CO₂ to the basolateral membrane of proximal tubule cells
  • Initial changes are:
    • Increased acidification of tubule fluid, even acutely, by unclear mechanisms (potentially due to CO₂ entry and subsequent acidification of tubule cells producing increased apical H⁺ export)
    • NHE3 Na⁺/H⁺ transporter expression increases over the next 1-2 days
    • Renal ammonia synthesis and ammonium secretion is rapidly increased 
    • ATP-powered H⁺ pumps are distributed to the apical membrane 
  • Later:
    • Bicarbonate reabsorption in the proximal tubule is increased. When Cogan (1984) exposed rats to 10% FiCO₂, their bicarbonate reabsorption increased by 50% over the following days.
    • This adaptation takes about 3-5 days to complete
    • At the end of the process of adaptation, the increased bicarbonate reabsorption maintains a stable status quo and the renal acid excretion decreases back to a more normal level, similar to what it was before the onset of the chronic respiratory acidosis
    • In this status quo, ammonia excretion remains elevated while the excretion of other titratable acids is reduced

In short, ammoniagenesis seems to be the main early response to respiratory acid-base derangements, but as the renal bicarbonate reabsorption ramps up, renal acid secretion decreases, and in states of chronic respiratory acidosis there is no major increase in renal acid excretion beyond normal levels. Everybody who discusses this seems to reference Adrogué & Madias (1986) as the main source for this. The results of their experiment are presented here, incorporated into what one can only describe as a contemporary artwork loosely based on the original data. For the readers' interest, it is worth noting that the experimental animals were maintained at a "chronic" PaCO₂ of 80 mmHg.

It would be logical to expect that the renal compensation for chronic respiratory alkalosis is exactly the same series of changes except in reverse. This is probably true, but hard to pin down because there is so little written about this entity. Madias & Adrogué (2003) are the only authors who spend more than a page on this topic. In short, it's exactly as you would expect. 

• The respiratory alkalosis is detected by some unknown mechanism, which also appears to be triggered by the decrease in CO₂ rather than the increase in pH.
• Secretion of ammonium and titratable acids is decreased
• The reabsorption of bicarbonate is decreased
• NHE3 ion-exchange channels and ATP-powered proton pumps are retrieved from the apical membrane
• The net result is a chronically decreased bicarbonate which is sustained as long as the respiratory alkalosis persists

Additionally, where the respiratory "alkalosis" is in reality just a return to normal following a period of respiratory acidosis,  the lag in renal compensation tends to keep the plasma bicarbonate high over several days. The duration of this "post-hypercapnic metabolic alkalosis" is increased by renal failure, a deficiency in dietary chloride, or the intensivists' reluctance to use chloride-rich fluids.

What would happen if one performed a physicochemical analysis of these processes? Alfaro et al (1996) is a good representation of what that might look like. In short, through the increased elimination of ammonium, the distal nephron is able to get rid of more chloride, increasing the SID.  At the same time, the serum sodium and potassium should remain essentially unchanged. The investigators were able to demonstrate that both of these expected changes can be seen in COPD patients with chronic hypercapnia.

Renal response to metabolic acidosis and alkalosis

Hend et al (2010) explains this very well. Basically, everything here happens because of the kidney's increased metabolism of glutamine, which is both the precursor for ammonium and for bicarbonate. Squires et al (1976) determined that normally kidneys clear about 3-7% of the glutamine in the blood they are perfused with, but in conditions of acidosis the glutamine extraction ratio increases to something like 30%. From the protoncentric classical perspective, this renal compensation mechanism works in the following way:

In the proximal tubule:

• Glutamine uptake by the proximal tubule cells increases (because of a pH-induced increase in uptake protein synthesis)
• All the extra glutamine is deaminated (twice), yielding two molecules of ammonia and α-ketoglutarate. 
• The ammonia is extruded via the apical membrane and combines with H⁺ in the tubule lumen
• The α-ketoglutarate is subsequently consumed to yield glucose, and therefore bicarbonate (i.e. CO₂ and water), which are released from the cell
• Thus, the increased glutamine uptake results in both synthesis of new bicarbonate and the increased elimination of H⁺

In the distal nephron:

• The concentration of inner medullary interstitial ammonium is increased by the increased activity of apical NKCC2 transporters of the thick ascending limb
• This results in increased ammonium availability for the collecting duct, where it is excreted into the duct lumen by α-intercalated cells.
• The total rate of ammonium excretion here is increased perhaps twofold in metabolic acidosis

The Stewart physicochemical interpretation is rather less acrobatic:

• The increased ammonia production allows more ammonium to be excreted, which allows more chloride to be excreted, and this lowers the strong ion difference.

These changes obviously work in reverse during states of metabolic alkalosis, where bicarbonate is 

So, the renal compensation for metabolic acidosis involves the synthesis of new proteins.  As with the reaction to PaCO₂, the exact molecular sensor which triggers all this protein synthesis is unknown. It appears to be related to a selective increase in the stabilisation of mRNA which is specific for these proteins (Hend et al, 2010) but this really does not answer the "how" question.

Other factors which affect renal acid-base handling

There a few other peripheral matters to attend do, with regards to renal acid-base handling. As all must surely have noticed by now, the movements of sodium (as an exchange substrate) and potassium (for which ammonium is often mistaken) are key to renal acid-base balance management. And as sodium handling and potassium handling are tightly regulated by various neurohormonal actors, it stands to reason that these actors will have some indirect effect on acid-base handling as well.

• Sodium delivery to the proximal tubule:  more sodium in the lumen will act as a substrate for NHE3 exchangers and will result in greater elimination of H⁺. A Stewart cultist would point out that the increased alkalinisation of the body fluids in this scenario is due to the increased reabsorption of sodium, a strong ion, rather than any hydrogen ion movements.
• Potassium delivery to the thick ascending limb: the NKCC channel in the thick ascending limb is relatively promiscuous, and is equally happy acting as the conduit for ammonium or potassium. The presence of excess potassium in the tubule lumen produces some competition, and less ammonium ends up being reabsorbed. This limits the interstitial ammonium content of the inner medulla, and potentially produces acidaemia as the consequence of decreased ammonium excretion by the collecting duct. This hypothesis was thoroughly tested and ultimately confirmed by Harris et al (2018)
• Angiotensin II stimulates renal acidification in the proximal tubule and the distal nephron. When Henger et al (2000) fed some losartan to volunteers, their urinary ammonium concentrations decreased by about 25 mmol/day (a non-trivial amount). Ergo, ACE-inhibitors and ARBs may stimulate a metabolic acidosis, and infusions of raw untreated angiotensin may have an alkalinising effect (as was observed by some lucky people who have some clinical experience with its use).
• Aldosterone appears to have a urine acidifying effect which is mainly expressed in its activity at the intercalated cells of the collecting duct. Aldosterone levels are elevated during acidosis and pathological aldosterone excess produces metabolic alkalosis (Wagner, 2014). Conversely, the blockade of mineralocorticoid receptors produces a metabolic acidosis (Type IV renal tubular acidosis)

Changes in pH and ion concentration along the nephron

Again, its time for one of those huge diagrams of renal tubular pH, with unreadably small writing (but, if you open it in its own window, it can be zoomed to a more readable size, though this may do nothing to improve its educational content). The only reason this exists is because in Question 12 from the second paper of 2014, the college asked us to "describe... the changes in urine pH along the nephron", for 80% of the marks. So, that's what it would look like if you tried to answer with a  diagram:

If this horror has any merit, it is in demonstrating what happens with an increased bicarbonate load, i.e. a metabolic alkalosis. The proximal tubule is the main site of reabsorption, and elsewhere in the tubule the mechanisms of bicarbonate reclamation are relatively weak (Galla, 2000) and lack the capacity to make up for the added bicarbonate delivery to the distal nephron. This means the tubular pH would rapidly approach some sort of maximum value (around 8.0) and it would remain there for the length of the tubule.