One may recall that the kidneys are responsible for excreting strong anions and retaining bicarbonate; both of these processes can break down in renal failure.There are three main features of renal failure which promote acidosis:
There is an excellent article on this from 1988, which is presently available as a free pdf onwww.nature.com. It is essentially the transcription of a case presentation and a forum discussion on uremic acidosis between several nephrologists (Wernock, et al), who carry on about it for several pages, quoting Lavoisier and whatnot. Uremic acidosis is discussed in better detail than I can manage here; and I hope this file remains available to the public.
Most of the filtered bicarbonate is reabsorbed in the proximal tubule. It is generally held that any bicarbonate load over 26 will be excreted quite rapidly, as 26mmol/L is the upper limit of renal bicarbonate reabsorption. The process which is responsible for this is a carbonic anhydrase mediated conversion of bicarbonate into a nicely lipid-soluble CO2, and then back into bicarbonate, which is then pumped actively out of the proximal tubules cells.
Imagine, then, if the limit of renal bicarbonate resorption was significantly lower for some reason? For instance, if anything over 10mmol/L was excreted? The loss of bicarbonate would need to be offset by the gain of a strong ion, such as chloride. Obviously you cant be dumping your only strong anion into the urine when the weak anion is leaking out as well- the neutrality of charge must be maintained.This would lead to a normal anion gap metabolic acidosis; more specifically, this would be a Type 2 (proximal) renal tubular acidosis, one characterized by an inappropriately alkaline urine. This is discussed in greater detail elsewhere.
In fact, the typical picture of high anion gap metabolic acidosis (with normal chloride) is only found in a minority of uremic patients with acidosis. According to one study, 46% had a normal anion gap and were hyperchloraemic.
But this is a digression. Presently, we are discussing uraemic acidosis, which is being classified as a high anion gap metabolic acidosis. And indeed, there is occasionally a high anion gap. The loss of bicarbonate resoprtion mechanisms does not appear to play a major role in the pathogenesis of acidosis due to renal failure. Indeed, many of these patients have no evidence of bicarbonate wasting. The failure to acidify urine (particularly at the distal tubule) is much more important at the early stages of renal failure.
There is an amazing capacity with each nephron to increase its individual ammonium secretion. As glomerular filtration decreases due to the loss of more and more functioning nephrons, each remaining nephron increases its rate of ammonium secretion. It seems that this happens up to the point of GFR around 40ml/min; at that stage each remaining nephron is secreting 3-4 times the normal amount of ammonium ions. The metabolic acidosis due to a failure to acidify the urine therefore happens due to the loss of nephrons, rather than due to the decrease in the function of tubules.
As Peter Stewart explains, the kidney handles the acid-base balance of the body by excreting chloride, which increases the strong ion difference. When there is less strong anion (Cl-) but strong cations (Na+ and K+) are retained, the equilibrium favours a decrease in the amount of weak cations (which are mainly H+) and an increase in the amount of weak anions (mainly HCO3-). The whole focus on ammonium excretion is probably wrong – ammonium is merely a weak cation which is co-excreted with chloride to maintain the electrical charge neutrality of the tubular fluid. However, this is still an important role to play. Thus, a failure of ammonia excretion reduced the capacity for chloride excretion, and the “trapped” chloride in the body fluids decreases the strong ion difference, resulting in acidosis. And this is typically a normal anion gap acidosis, as the retention of chloride is to blame for the decrease in the bicarbonate and decrease in body fluid pH.
The alternative way to become acidotic due to a malfunction of urinary acidification is of course the Type 2 (distal) renal tubular acidosis, which is not related to uraemia, and is discussed elsewhere. Here, it does not matter how many nephrons you have left -indeed you probably have all your nephrons with you- but none of the distal tubules are doing their job. This is the major distinction.
Its all fine and well when you have kidneys which secrete some ammonium, and which can retain some bicarbonate. Of course, once they are gone, there is no mechanism left to clear the accumulating acidic by-products of metabolism. This is the “end” stage of renal failure, with a GFR below 20% of normal. At this stage, on top of a failure to normally clear hydrogen ions, one runs into a problem of sulfate, phosphate, urate and hippurate retention. The levels of these hidden anions progressively increase as glomerular filtration decreases, and in some studies this is observed as a progressively increasing anion gap during the historical course of renal failure.
Let us dwell briefly on these retained molecules. Some of the papers which discuss them are quite old, but still have relevance. Each anion is interesting on its own, and merits a brief discussion, which would be a digression from the topic of uraemic acidosis.
Goodman, A. David, et al. "Production, excretion, and net balance of fixed acid in patients with renal acidosis." Journal of Clinical Investigation 44.4 (1965): 495.
Eliahou, H. E., et al. "Acetate and bicarbonate in the correction of uraemic acidosis." British medical journal 4.5732 (1970): 399.
Briggs, A. P., et al. "Pathogenesis of uremic acidosis as indicated by urinary acidification on a controlled diet." Metabolism: clinical and experimental 10 (1961): 749.
Kraut, Jeffrey A., and Ira Kurtz. "Metabolic acidosis of CKD: diagnosis, clinical characteristics, and treatment." American journal of kidney diseases: the official journal of the National Kidney Foundation 45.6 (2005): 978.
Schwartz, William B., and Philip W. Hall. "On the mechanism of acidosis in chronic renal disease." Journal of Clinical Investigation 38.1 Pt 1-2 (1959): 39.
Tomas Welbourne, Michael Weber, and Norman Bank The effect of glutamine administration on urinary ammonium excretion in normal subjects and patients with renal disease. J Clin Invest. 1972 July; 51(7): 1852–1860.
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