The urate anion originates from purine metabolism, and the hippurate anion is a product of quinic acid metabolism (for which there are several dietary sources). These anions are responsible for some (but not a lot) of the high anion gap metabolic acidosis associated with uraemia.

Origin of the urate anion

origin of the urate anion

Urate, uric acid,  is the end product of purine metabolism. It is not very water-soluble, and at physiologic pH has a tendency to crystallize, which underlies its tendency to cause gout.  It is the end-product of the metabolism of purines, which are ground down to xanthine and hypoxanthine, so that xanthine oxidase can oxidize them into urate. All of this goes on predominantly in the liver. The rest of your body tissues have no way to metabolise urate; they merely soak in it, waiting for the gut or kidneys to excrete it.

Urate clearance

Unlike kangaroos and some rodents (who can poop out a solid urate pellet) humans must rely on renal clearance, and about 70-90% of serum urate is cleared by the kidneys. The remainder passively migrates into the gut, where intestinal bacteria feed on it.

urate clearance

There is a weird four-stage process of renal urate handling, and all of the stages occur in the proximal tubule.

  • First, the urate is filtered in the glomerulus.
  • Then, 90% of it is reabsorbed by sodium-urate cotransporter.
  • Then, 50% of the reabsorbed urate is actively secreted out by various transporters (either ATP-powered like ABCG2, or potential difference powered like SLC17A1)
  • Then, more urate is reabsorbed (post-secretory reabsorption) by an organic anion exchanger (URAT-1)
    • The URAT-1  pump  exchanges the urate in the tubular lumen for various organic anions (among them, various drugs such as beta-lactams and oseltamivir).  This the site of action of probenecid; by blocking the transport of urate out of the tubule, probenecid prevents the exchange transport of penicillin into the tubule.

In renal failure, the retention of urate begins at the end stage. One can ramp up their excretion of urate quite a lot, and at the end it is the loss of functioning nephrons which frustrates one’s ability to clear urate effectively. However, its buildup does not appear to contribute massively to the uraemic metabolic acidosis. It is merely another organic acid which the dying kidneys fail to clear.  Hyperuricaemia is frequently seen as a causative factor in renal failure (eg. high urate causing acute renal failure in tumour lysis syndrome), but it may not be the major reason for the acidosis. 

The near-complete irrelevance of the hippurate ion

hippurate molecule.

Hippuric acid is a carboxylic acid, and one of the uraemic toxins.  In humans, there is a certain normal daily rate of urinary hippurate excretion. Where is coming from? Well some berries and colourful fruits we consume provide us with certain quantities of quinic acid, which gut microflora metabolise into hippurate.  According to authoritative sources humans excrete 0.44mg/L of hippurate per day under normal dietary circumstances. Again, this is usually not an issue until the end stages of renal failure. Unless of course one is prone to unusual dietary excesses, or if one is a connoisseur of the volatile solvents.

There is one possible relevance for the hippurate ion which goes largely ignored by the adult intensive care world, and which becomes relevant in the presence of renal failure (or even slightly subnormal renal function). It is the use of sodium benzoate as an ammonium scavenger. Benzoate is given to people with weird urea cycle disorders and hepatic encephalopathy as a new pathway of removing ammonia form the body. Benzoate ends up complexed with coenzyme A to form benzoyl-Coa which is then conjugated with glycine to form hippurate. The dose of sodium benzoate is in the order of 10g/day, which (if al of it is converted) would yield about 70 mmol of hippurate. In the completely anephric patient, this substance would have nowhere to go and a severe metabolic acidosis would develop over days. 

References

Daniel Markovich Physiological Roles and Regulation of Mammalian Sulfate Transporters Physiol Rev January 10, 2001  vol. 81 no. 4 1499-1533

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.

Wallia R, Greenberg A, Piraino B, Mitro R, Puschett JB Serum electrolyte patterns in end-stage renal disease. Am J Kidney Dis. 1986;8(2):98

Hakim RM, Lazarus JM Biochemical parameters in chronic renal failure. Am J Kidney Dis. 1988;11(3):238.

Michalk, D., et al. "Plasma inorganic sulfate in children with chronic renal failure." Clinical nephrology 16.1 (1981): 8.

Stipanuk, Martha H. "Metabolism of sulfur-containing amino acids." Annual review of nutrition 6.1 (1986): 179-209.

Brosnan, John T., and Margaret E. Brosnan. "The sulfur-containing amino acids: an overview." The Journal of nutrition 136.6 (2006): 1636S-1640S.

Widmer B, Gerhardt RE, Harrington JT, Cohen JJ Serum electrolyte and acid base composition. The influence of graded degrees of chronic renal failure. Arch Intern Med. 1979;139(10):1099.

Warnock DG. Uremic acidosis. Kidney Int. 1988 Aug;34(2):278-87.

Relman, Arnold S., Edward J. Lennon, and Jacob Lemann Jr. "Endogenous production of fixed acid and the measurement of the net balance of acid in normal subjects." Journal of Clinical Investigation 40.9 (1961): 1621.

S. B. BAKER, ET AL   The Essentials of Calcium, Magnesium and Phosphate Metabolism: Part I. Physiology Critical Care and Resuscitation 2002; 4: 301-306

KDIGO clinical practice guidelines for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD) Kidney Int. 2009; 76(Suppl 113):S1.

Tonelli M, Pannu N, Manns B. Oral phosphate binders in patients with kidney failure. N Engl J Med. 2010 Apr 8;362(14):1312-24.

Sorensen, Leif B. "THE ELIMINATION OF URIC ACID IN MAN. STUDIED BY MEANS OF C $ sup 14$-LABELED URIC ACID." Scand. J. Clin. & Lab. Invest.12 (1960).

Kutzing, Melinda K., and Bonnie L. Firestein. "Altered uric acid levels and disease states." Journal of Pharmacology and Experimental Therapeutics 324.1 (2008): 1-7.

Conger JD (1990). "Acute uric acid nephropathy". Med Clin North Am 74 (4): 859–71.

Krebs HA, Wiggins D, Stubbs M (1983). "Studies on the mechanism of the antifungal action of benzoate". Biochem J 214 (3): 657–663.

Rastislav Dzúrik1, Viera Spustová1, Zora Krivoíková1 and Katarína Gazdíková1 Hippurate participates in the correction of metabolic acidosis Kidney International (2001) 59, S278–S281;

Hayden, James W., Richard G. Peterson, and James V. Bruckner. "Toxicology of toluene (methylbenzene): review of current literature." Clinical toxicology 11.5 (1977): 549-559.

Pero RW. Health consequences of catabolic synthesis of hippuric acid in humans.Curr Clin Pharmacol. 2010 Feb;5(1):67-73.

Hamadeh MJ, Hoffer LJ. (2001) Use of sulfate production as a measure of short-term amino acid catabolism in humans. Am J Physiol Endocrinol Metab 280:E857–E866.