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Clinical nutrition, enteral and parenteral nutrition

Established dietary estimates of net acid production do not predict measured net acid excretion in patients with Type 2 diabetes on Paleolithic–Hunter–Gatherer-type diets



Formulas developed to estimate diet-dependent net acid excretion (NAE) generally agree with measured values for typical Western diets. Whether they can also appropriately predict NAE for ‘Paleolithic-type’ (Paleo) diets—which contain very high amounts of fruits and vegetables (F&V) and concurrent high amounts of protein is unknown. Here, we compare measured NAEs with established NAE estimates in subjects with Type 2 diabetes (T2D).


Thirteen subjects with well-controlled T2D were randomized to either a Paleo or American Diabetes Association (ADA) diet for 14 days. Twenty-four hour urine collections were performed at baseline and end of the diet period, and analyzed for titratable acid, bicarbonate and ammonium to calculate measured NAE. Three formulas for estimating NAE from dietary intake were used; two (NAE_diet R or L) that include dietary mineral intake and sulfate- and organic acid (OA) production, and one that is empirically derived (NAE_diet F) only considering potassium and protein intake.


Measured NAE on the Paleo diet was significantly lower than on the ADA-diet (+31±22 vs 112±52 mEq/day, P=0.002). Although all formula estimates showed similar and reasonable correlations (r=0.52–0.76) with measured NAE, each one underestimated measured values. The formula with the best correlation did not contain an estimate of dietary OA production.


Paleo-diets are lower in NAE than typical Western diets. However, commonly used formulas clearly underestimate NAE, especially for diets with very high F&V (as the Paleo diet), and in subjects with T2D. This may be due to an inappropriate estimation of proton loads stemming from OAs, underlining the necessity for improved measures of OA-related proton sources.

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  1. Eaton SB, Konner M . Paleolithic nutrition. A consideration of its nature and current implications. N Engl J Med 1985; 312: 283–289.

    Article  CAS  Google Scholar 

  2. Eaton SB, Konner M, Shostak M . Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective. Am J Med 1988; 84: 739–749.

    Article  CAS  Google Scholar 

  3. Eaton SB, Cordain L . Evolutionary aspects of diet: old genes, new fuels. Nutritional changes since agriculture. World Rev Nutr Diet 1997; 81: 26–37.

    CAS  PubMed  Google Scholar 

  4. Frassetto LA, Schloetter M, Mietus-Synder M, Morris RC Jr, Sebastian A . Metabolic and physiologic improvements from consuming a paleolithic, hunter-gatherer type diet. Eur J Clin Nutr 2009; 63: 947–955.

    Article  CAS  Google Scholar 

  5. Frassetto LA, Morris RC Jr., Sebastian A . Dietary sodium chloride intake independently predicts the degree of hyperchloremic metabolic acidosis in healthy humans consuming a net acid-producing diet. Am J Physiol Renal Physiol 2007; 293: F521–F525.

    Article  CAS  Google Scholar 

  6. Rylander R, Remer T, Berkemeyer S, Vormann J . Acid-base status affects renal magnesium losses in healthy, elderly persons. J Nutr 2006; 136: 2374–2377.

    Article  CAS  Google Scholar 

  7. Remer T, Manz F . Paleolithic diet, sweet potato eaters, and potential renal acid load. Am J Clin Nutr 2003; 78: 802–803. 03-4.

    Article  CAS  Google Scholar 

  8. Remer T, Manz F . Estimation of the renal net acid excretion by adults consuming diets containing variable amounts of protein. Am J Clin Nutr 1994; 59: 1356–1361.

    Article  CAS  Google Scholar 

  9. Ausman LM, Oliver LM, Goldin BR, Woods MN, Gorbach SL, Dwyer JT . Estimated net acid excretion inversely correlates with urine pH in vegans, lacto-ovo vegetarians, and omnivores. J Ren Nutr 2008; 18: 456–465.

    Article  Google Scholar 

  10. Lemann J Jr. . Relationship between urinary calcium and net acid excretion as determined by dietary protein and potassium: a review. Nephron 1999; 81 (Suppl 1), 18–25.

    Article  CAS  Google Scholar 

  11. Sebastian A, Frassetto LA, Sellmeyer DE, Merriam RL, Morris RC Jr. . Estimation of the net acid load of the diet of ancestral preagricultural Homo sapiens and their hominid ancestors. Am J Clin Nutr 2002; 76: 1308–1316.

    Article  CAS  Google Scholar 

  12. Frassetto LA, Lanham-New SA, Macdonald HM, Remer T, Sebastian A, Tucker K et al. Standardizing terminology for estimating the diet-dependent net acid load to the metabolic system. J Nutr 2007; 137: 1491–1492.

    Article  CAS  Google Scholar 

  13. Remer T, Manz F . Potential renal acid load of foods and its influence on urine pH. J Am Diet Assoc 1995; 95: 791–797.

    Article  CAS  Google Scholar 

  14. van den Berg E, Engberink MF, Brink EJ, van Baak MA, Joosten MM, Gans RO et al. Dietary acid load and metabolic acidosis in renal transplant recipients. Clin J Am Soc Nephrol 2012; 7: 1811–1818.

    Article  CAS  Google Scholar 

  15. Macdonald HM, New SA, Fraser WD, Campbell MK, Reid DM . Low dietary potassium intakes and high dietary estimates of net endogenous acid production are associated with low bone mineral density in premenopausal women and increased markers of bone resorption in postmenopausal women. Am J Clin Nutr 2005; 81: 923–933.

    Article  CAS  Google Scholar 

  16. Remer T, Berkemeyer S, Manz F . Acid base considerations in Stone-Age farming Sweet potato eaters, modern-day sweet potato eaters, and high-protein consumers. Open Nutr J 2008; 2: 23–28.

    Article  CAS  Google Scholar 

  17. Maalouf NM, Cameron MA, Moe OW, Sakhaee K . Metabolic basis for low urine pH in type 2 diabetes. Clin J Am Soc Nephrol 2010; 5: 1277–1281.

    Article  CAS  Google Scholar 

  18. Litkowski LJ, Wilson TL . Effect of protein on titrimetry of bicarbonate, titratable acid and ammonium in urine. Clin Chem 25: 362–365.

  19. Frassetto LA, Todd KM, Morris RC Jr, Sebastian A . Estimation of net endogenous noncarbonic acid production in humans from diet potassium and protein contents. Am J Clin Nutr 1998; 68: 576–583.

    Article  CAS  Google Scholar 

  20. Cameron MA, Maalouf NM, Adams-Huet B, Moe OW, Sakhaee K . Urine composition in type 2 diabetes: predisposition to uric acid nephrolithiasis. J Am Soc Nephrol 2006; 17: 1422–1428.

    Article  CAS  Google Scholar 

  21. Hood VL, Tannen RL . Protection of acid-base balance by pH regulation of acid production. N Engl J Med 1998; 339: 819–826.

    Article  CAS  Google Scholar 

  22. Tai ES, Tan ML, Stevens RD, Low YL, Muehlbauer MJ, Goh DL et al. Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men. Diabetologia 2010; 53: 757–767.

    Article  CAS  Google Scholar 

  23. Van Slyke DD, Palmer WW . The titration of organic acids in urine. J Biol Chem 1920; 16: 567.

    Google Scholar 

  24. Blatherwick NR, Long Louisa M . Studies of urianry acidity. II The increased acidity produced by eating prunes and cranberries. J Biol Chem 1923; 57: 815–818.

    CAS  Google Scholar 

  25. Krupp D, Doberstein N, Shi L, Remer T . Hippuric acid in 24-h urine collections is a potential biomarker for fruit and vegetable consumption in healthy children and adolescents. J Nutr 2012; 142: 1314–1320.

    Article  CAS  Google Scholar 

  26. Kessler T, Jansen B, Hesse A . Effect of blackcurrant-, cranberry- and plum juice consumption on risk factors associated with kidney stone formation. Eur J Clin Nutr 2002; 56: 1020–1023.

    Article  CAS  Google Scholar 

  27. Manz F, Remer T, Decher-Spliethoff E, Höhler M, Kersting M, Kunz C et al. Effects of a high protein intake on renal acid excretion in bodybuilders. Z Ernahrungswiss 1995; 34: 10–15.

    Article  CAS  Google Scholar 

  28. Remer T, Manz F, Alexy U, Schoenau E, Wudy SA, Shi L . Long-term high urinary potential renal acid load and low nitrogen excretion predict reduced diaphyseal bone mass and bone size in children. J Clin Endocrinol Metab 2011; 96: 2861–1868.

    Article  CAS  Google Scholar 

  29. Macdonald HM, Black AJ, Aucott L, Duthie G, Duthie S, Sandison R et al. Effect of potassium citrate supplementation or increased fruit and vegetable intake on bone metabolism in healthy postmenopausal women: a randomized controlled trial. Am J Clin Nutr 2008; 88: 465–474.

    Article  CAS  Google Scholar 

  30. Remer T, Dimitriou T, Manz F . Dietary potential renal acid load and renal net acid excretion in healthy, free-living children and adolescents. Am J Clin Nutr 2003; 77: 1255–1260.

    Article  CAS  Google Scholar 

  31. Remer T, Libuda L . Bone-anabolic impact of dietary high protein intake compared with the effects of low potential renal acid load, endogenous steroid hormones, and muscularity in children. In: Burckhardt P, Dawson-Hughes B, Weaver CM (eds). Nutritional Influences on Bone Health. Springer: London. pp 187–196, 2010.

    Google Scholar 

  32. Wynn E, Krieg MA, Aeschlimann JM, Burckhardt P . Alkaline mineral water lowers bone resorption even in calcium sufficiency: alkaline mineral water and bone metabolism. Bone 2009; 44: 120–124.

    Article  CAS  Google Scholar 

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We wish to acknowledge the staff of the University of California Clinical Research Center, without whose support this study could not have been done. We also wish to acknowledge Donald Wesson MD and Jan Simoni PhD, for their help in measuring net acid excretion parameters. The Grant support was provided by CTSI CRC center grant UL1 TR000004.

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Correspondence to L A Frassetto.

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Frassetto, L., Shi, L., Schloetter, M. et al. Established dietary estimates of net acid production do not predict measured net acid excretion in patients with Type 2 diabetes on Paleolithic–Hunter–Gatherer-type diets. Eur J Clin Nutr 67, 899–903 (2013).

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