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University of California, San Francisco UCSF/Moffitt General Clinical Research Center 1202 Moffitt Hospital, Box 00126 San Francisco, CA 94143 E-mail: sebastia{at}gcrc.ucsf.edu
Dear Sir:
In estimating net endogenous acid production (NEAP) in preagricultural humans and their hominid ancestors (1), we computed the contribution to the NEAP of the body’s total organic acid production as a function of the "unmeasured anion" content of the diet, on the basis of the following considerations. Ultimately, one must determine the contribution to the NEAP of total organic acid production as that fraction of organic acids produced whose dissociated organic anions escape into the urine, leaving behind the protons once associated with them (2). Those organic anions that do not so escape are metabolized to bicarbonate, which back-titrates the dissociated protons. As total organic acid production increases, so does the spillover of organic anions into the urine. Total organic acid production increases in response to increased bicarbonate input to the body—evidently a homeostatic response to mitigate the alkalinization (3)—and as a result the excretion rate of the dissociated organic anions increases. The increase in lactic acid and ketoacid production, and the excretion of their anions, after alkali administration exemplifies that fact (3), as does the dose-dependent increase in total organic anion excretion in response to increased dietary bicarbonate precursors (4). The dose-dependent increase in citrate excretion in response to bicarbonate administration or to dietary bicarbonate precursors also exemplifies that fact (5, 6), which is contributed to by reduced reabsorption of citrate filtered at the renal glomerulus (3).
Accordingly, organic anion excretion increases in response to increases in the so-called unmeasured anion (UA) content of the diet—computed as Na+ + K+ + Ca2+ + Mg2+ - Cl- - Pi in mEq/d—because such UAs consist of organic anions largely metabolized to bicarbonate and thus are dietary bicarbonate precursors (4). Empirically, in adults eating a wide variety of diets, organic anion excretion correlates positively and quantifiably with the UA content of the diet (4, 6). Thus, in our study (1), we computed the contribution of organic acid production to the NEAP from the UA content of the diet by using the regression equation of Kleinman and Lemann (4).
Remer and Manz prefer to estimate organic anion excretion not from dietary UA but from body surface area (BSA) independent of diet composition. This approach ignores the physiology discussed above, in that persons with a given BSA may have markedly different organic anion excretion rates depending on the content of bicarbonate precursors in the diet. The BSA approach might identify a basal component of organic anion excretion independent of diet. However, our method accounts for any such baseline effect because the organic anion excretion intercept at zero diet UA content in the regression of the former on the latter among adult diets has a positive value, which is incorporated in the calculation for organic anion excretion (4). Moreover, because the UA content of contemporary Western diets is almost an order of magnitude lower than that in preagricultural diets (1), it has little influence on organic anion excretion relative to the diet-independent basal rate. This may explain why Remer and Manz’s BSA approach works reasonably well for contemporary diets, and why their approach may be questioned for preagricultural diets.
In part for the reasons cited above, we take exception to the estimation of the positive value of NEAP for the single retrojected preagricultural diet shown in Remer and Manz’s Table 1. We consider their estimation of organic acid contribution to NEAP in the table problematic, not only because it is based on an assumed BSA and thereby ignores the effect of the diet’s content of bicarbonate precursors independent of BSA but also because it posits an arbitrary diet-dependent substantial production of a nonmetabolized organic acid, hippuric acid, which might result from eating large amounts of noncombustible hippuric acid precursors in their undissociated acid form. Although a few plant foods (eg, cranberries and plums) do contain substantial amounts of noncombustible organic acids, such foods would substantially alter interpretation of the quantitative relation between organic anion excretion and dietary UA content only if they were a regular and major component of the daily diet. Estimating NEAP as we did for a large number of preagricultural diets (n = 159), with widely differing plant food group distribution ratios, gives a more comprehensive picture of the potential range of preagricultural diet-induced NEAPs, most of which were computed as decidedly negative values (1).
Nothwithstanding their comments, Remer and Manz accept the main conclusion of our article. They end by writing, "Taken together, we also conclude that the average Paleolithic diet principally led to net base production," although they suggest that the average NEAP we reported for 159 diets, -88 mEq/d, might slightly overestimate net base production because of the presence of noncombustible organic acids in some food items. We do not necessarily disagree but doubt that the adjustment is large averaged over 159 different diets, given the small fraction of natural food items with substantial noncombustible organic acid content present in the undissociated acid form. Further limiting the effect of any such noncombustible organic acids, some fraction of those acids in a food item exist in their dissociated organic anion form, the amount depending on the acid’s pKa and the pH of the food. Because such non-bicarbonate-generating organic anions appear as UAs, they get computed both as part of the bicarbonate yield of the food and as part of its contribution to the organic anion excretion rate. Therefore, their effect on the NEAP tends to be cancelled out.
As to meat-eating sweet potato eaters, we concede that odd 2-food item combinations might yield lower estimates of net base load than our reported average for preagricultural diets. We reported several such examples in our paper, even some with net acid loads (1). It seems unlikely that ancestral hominid diets consisting predominately of such odd 2-food item combinations were habitually ingested over millions of years, and therefore it seems unlikely that they played a dominant role in conditioning the genetic makeup of humans.
We end by expressing our appreciation to Remer and Manz for their numerous contributions over many years to our knowledge of diet effects on NEAP and for their trailblazing efforts in tackling the problem of computing the NEAP from diet composition. To the extent that our findings suggest that natural selection likely has adapted human metabolic machinery and integrated organ physiology to habitual ingestion of a net base-producing diet, and not to the modern net acid-producing diet, Remer and Manz merit a share in the discovery.
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