The Continuum of Acid Stress

Abstract

Acid-related injury from chronic metabolic acidosis is recognized through growing evidence of its deleterious effects, including kidney and other organ injury. Progressive acid accumulation precedes the signature manifestation of chronic metabolic acidosis, decreased plasma bicarbonate concentration. Acid accumulation that is not enough to manifest as metabolic acidosis, known as eubicarbonatemic acidosis, also appears to cause kidney injury, with exacerbated progression of CKD. Chronic engagement of mechanisms to mitigate the acid challenge from Western-type diets also appears to cause kidney injury. Rather than considering chronic metabolic acidosis as the only acid-related condition requiring intervention to reduce kidney injury, this review supports consideration of acid-related injury as a continuum. This “acid stress” continuum has chronic metabolic acidosis at its most extreme end, and high-acid-producing diets at its less extreme, yet detrimental, end.

Growing evidence supports kidney injury from a range of acid challenges to acid-base status, including those insufficient to cause metabolic acidosis by reduced plasma bicarbonate concentration ([HCO₃ ⁻]). Acid accumulation that is insufficient to cause metabolic acidosis, known as “eubicarbonatemic acidosis” (1,2), “preclinical acidosis” (3), or “subclinical acidosis” (4), is associated with increased risk for kidney stones (5) and exacerbated progression of CKD (6,7). Acid-producing diets in general populations, including those typical of Western societies, are associated with increased risk for kidney injury (8) and incident CKD (8 –10). Indeed, individuals without known kidney disease who are given mineral acid cumulatively excrete less acid than ingested (11,12), consistent with sustained acid accumulation.

These data challenge scientific communities to consider injurious acid accumulation as a continuum of “acid stress” in which metabolic acidosis is its most severe manifestation, but includes high-acid-producing Western diets. Reframing these disorders as a continuum enables recognition of lower, yet clinically meaningful, levels of kidney injury caused by conditions earlier in the acid stress continuum. This reframing also underscores an opportunity for medical and public health professionals to address the apparent contribution of high-acid-producing diets to kidney injury, through practitioner and public health recommendations for lower-acid diets. Although these diets are associated with other organ injury to be discussed briefly, this review will focus primarily on their associated kidney injury.

What Is “Normal” Plasma Bicarbonate Concentration?

The normal range of plasma [HCO₃ ⁻] varies widely among clinical laboratories, with low ends as low as ≥18 mmol/L and high ends as high as ≤36 mmol/L (13), lending uncertainty as to a “low” plasma [HCO₃ ⁻] that is consistent with metabolic acidosis. In a large US database of apparently healthy individuals who were presumably eating typical Western diets, 91% of plasma [HCO₃ ⁻] determinations were between 23 and 30 mmol/L (13), supporting this narrower range for normal. These data also align with expert opinion of current guidelines that define metabolic acidosis in populations eating Western diets as plasma [HCO₃ ⁻] <22 mmol/L in the absence of respiratory alkalosis (14). Whether lower ends of this normal range include individuals with injurious acid accumulation needing treatment, and whether it would be higher in populations eating a non-Western, less acid-producing diet, awaits further study.

The Daily Acid Challenge to Acid-Base Status

Our “fixed” acid challenge derives from endogenous metabolism and metabolism of dietary proteins, phospholipids, nucleic acids, and incomplete oxidation of carbohydrates (15), and is approximately 0.7–1.0 mmol/kg body wt per day in healthy adults eating Western diets (16,17). These diets are acid-producing because of the preponderance of acid-producing meats and refined grains compared with base-producing fruits and vegetables (18). Animal-sourced compared with plant-sourced foods have more protein per mass and more sulfur-containing amino acids (e.g., methionine, cysteine) that yield acid when metabolized, than plant-sourced foods. Even fresh animal-sourced foods have various amounts of sodium chloride (NaCl) that increase acid production (19,20), and processed foods—an increasing proportion of Western diets—typically have added NaCl. Most fresh plant-sourced foods are very low in NaCl, and many have potassium and magnesium salts of organic acids (e.g., citrate) that metabolize to yield HCO₃ ⁻.

The acid-producing capacity of a diet can be estimated by calculating its potential renal acid load (PRAL) through tabulation of the type and quantity of its foods, and assigning the amount of acid (positive value) or base (negative value) produced when metabolized (15). This calculation excludes an estimate of organic acid excretion, about 40 mmol in average adults, that, combined with PRAL, estimates urine net acid excretion (NAE) (15). Table 1 lists PRAL of various food groups and composite PRALs for indicated diets calculated by the author, applying PRAL for various foods (15) to the types and food amounts in published diets (21,22). The table shows that the average US diet (21) has higher PRAL than the diet recommended by US Department of Agriculture (22), supporting that typical Western diets are highly acid-producing (18). Table 1 shows even higher PRAL for diets of study participants from a low-income, “food desert” community in the United States (23), which was reduced to lower dietary acid for participants given fresh fruits and vegetables. Sample Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and vegan diets, each of which is associated with reduced CKD risk (24 –26), had lower PRAL. Overall, Table 1 shows that typical US diets are acid-producing, more so in food desert communities who appear to be at very high CKD risk (27), and that recommended healthy diets are comparatively low acid. Unfortunately, there are no published guidelines regarding a healthy dietary acid content.

Table 1.

Calculated potential renal acid load of selected relevant diets

Food	USDA Recommended	Average Intake in the United States	Study Participants	Study Participants Given F+V	Mediterranean Diet	DASH Diet	Vegan Diet
Meat/seafood	13.61	22.55	27.45	25.21	6.03	22.83	0
Vegetables	−24.91	−12.46	−5.75	−13.96	−22.63	−20.19	−6.52
Fruit	−1.81	−0.91	6.23	−18.68	−10.04	−5.91	−13.72
Grains	6.34	6.43	10.64	9.57	18.26	8.15	27.6
Dairy	10.16	11.21	23.31	23.31	7.99	5.77	0
Oils	0.01	0.01	0.01	0.01	0.01	0.01	0
Total	3.4	26.83	61.89	25.46	−0.39	10.63	7.36

All values are shown in millimoles per day. USDA, United States Department of Agriculture; F+V, fruits and vegetables; DASH, dietary approaches to stop hypertension.

Chronic Engagement of Mechanisms to Mitigate Acid Accumulation can Cause Organ Injury

Figure 1 outlines mechanisms that help maintain plasma [HCO₃ ⁻] such that even large increases in dietary acid elicit quantitatively small increases in plasma hydrogen ion concentration ([H⁺]) (expressed clinically as pH) and quantitatively small decreases in plasma [HCO₃ ⁻] (approximated clinically by total carbon dioxide [total CO₂]), within normal ranges for each (28). Accordingly, plasma [H⁺]/[HCO₃ ⁻] yield inadequate insight for acid accumulation that is not enough to cause metabolic acidosis, yet is enough to cause injury. These data highlight the clinical challenge of using plasma acid-base parameters to detect potentially injurious levels of chronic acid accumulation that are earlier in the continuum of acid stress than metabolic acidosis.

Figure 1.

The body has multiple strategies to mitigatethe potential untowardeffects of added acid (H⁺). Alb⁻, albumin; AlbH, protonated albumin; Buf⁻, buffer; Ca⁺⁺, calcium; CO₃ ²⁻, carbonate; CO₂, carbon dioxide gas; ECF, extracellular fluid; H⁺, hydrogen; H₂CO₃, carbonic acid; Hb⁻, hemoglobin; HbH, protonated hemoglobin; HCO₃ ⁻, bicarbonate; HPO₄ ⁼/H₂PO₄ ⁻, phosphate; ICF, intracellular fluid; K⁺, potassium; Na⁺, sodium; NAD⁺/NADH, nicotinamide adenine dinucleotide; NH₄ ⁺, ammonium; PCO₂, partial pressure of carbon dioxide; PO₄ ³⁻, phosphate.

Acid Sequestration

Most (60%–75%) of H⁺ added to plasma is sequestered intracellularly (29) and buffered by anionic proteins, phosphate (HPO₄ ⁼), and HCO₃ ⁻, limiting the proportion of “free” H⁺ (30). Sequestered H⁺ from plasma into cells and bone yields the benefit of reduced H⁺ exposure to tissues that interface with plasma, but increased intracellular acidity yields the detriment of released iron, previously bound to intracellular protein, causing tissue-damaging oxidative stress (31).

Acid Buffering

HCO₃/H₂CO₃ Buffer System.

Adding H⁺ to body fluids containing HCO₃ leads to the following equation: H⁺ + HCO₃ ⁻ → H₂CO₃ → H₂O + CO₂ ↑ (lungs excrete CO₂ gas).

This response removes H⁺ from plasma as CO₂ gas that would yield H⁺ (reversal of the above equation) were it to accumulate. The price paid is reduced plasma [HCO₃ ⁻], which kidneys must regenerate through NAE, while suffering potential detrimental effects from sustained engagement of kidney H⁺ excretory mechanisms (see Enhanced Urine Acid Excretion).

Non-bicarbonate Buffers.

Increased dietary acid in animals augmented H⁺ titration of extracellular non-HCO₃ buffers (32). Bone calcium carbonate and dibasic HPO₄ ⁼ chronically buffer increased net endogenous acid production (NEAP), which progressively reduces bone mineral content (12).

Endogenous Acid Neutralization

The pH-sensitive metabolite citrate is the most abundant urine organic base-equivalent, and proximal tubule reabsorption determines its urine excretion (33). Proximal tubule cell secreted H⁺ into luminal fluid partially titrates citrate³⁻ to H-citrate²⁻, the latter being preferred substrate for reabsorption by the apical Na⁺ dicarboxylate cotransporter NaDC-1 (34,35), with NAD⁺ conversion to NADH. Metabolism of retained citrate yields HCO₃ ⁻, so its reabsorption is base gain, but its excretion is base loss (36). pKa of the three citrate valences (6.40, 4.76, and 3.14 for its ⁻3, ⁻2, and ⁻1 valences, respectively) makes it mostly dissociated at typical urine pH, limiting H⁺ binding, making its urine excretion yield little H⁺ excretion. Citrate metabolism to HCO₃ ⁻ yields benefit by replacing HCO₃ ⁻ titrated by accumulated H⁺, but yields detriment by reducing body H⁺ buffering capacity and increased kidney stone risk through reduced urine citrate excretion (37). Individuals with eubicarbonatemic acidosis have reduced urine citrate excretion (7,38) that can be increased by adding dietary fruits and vegetables (38).

Reduced Net Endogenous Acid Production

Individuals with increased NEAP, as with starvation-induced ketoacidosis, reduce NEAP in response to an increment in dietary acid given as ammonium chloride (39). By contrast, they maintain higher NEAP when given sodium bicarbonate or NaCl (39), supporting the idea that individuals with high baseline NEAP can reduce NEAP in response to high dietary acid.

Enhanced Urine Acid Excretion

Importance of Ammonium.

Ammonium (NH₄ ⁺) increases in response to augmented dietary acid (18,40), forming from H⁺ titration of ammonia (NH₃ + H⁺ → NH₄ ⁺) after metabolism of the amino acid glutamine that also yields α-ketoglutarate. Urine acid excretion as NH₄ ⁺, along with α-ketoglutarate metabolism to yield HCO₃ ⁻, constitutes NAE, with regeneration of HCO₃ ⁻ to replace that titrated by accumulated acid (Figure 1). Dietary acid in animals stimulated kidney NH₄ ⁺ production, enhancing complement deposition in kidney tissue (41). Complement could be a marker of an inflammatory response to NH₄ ⁺ that contributes to kidney injury and mediates progressive kidney function decline in response to dietary acid (41). Furthermore, patient studies showed an association between urine NH₄ ⁺ and the profibrotic marker TGF-β1, supporting a potential role for NH₄ ⁺ in progressive kidney injury in patients (42,43). The data support that increased urine NH₄ ⁺ production, and excretion in response to increased dietary acid, yields the benefit of increased NAE but the possible detriment of kidney injury, with progressive kidney function decline.

Increased Kidney Tubule Acidification.

Increasing dietary acid with mineral acid (44) or acid-producing dietary protein (45,46) increased kidney angiotensin II (47,48), aldosterone (49), and endothelin-1 (ET-1) (44,49) in animals. Higher kidney levels contributed short-term benefit of enhanced kidney acidification with increased urine NAE (44 –47), but long-term detriment of increased kidney interstitial fibrosis (50 –52), a component of progressive nephropathy (53). By contrast, dietary base as oral mineral alkali (47 –49,54) or base-producing dietary components (45,46,55) decreased their urine excretion. Furthermore, mineral alkali reduced these levels in patients with eubicarbonatemic acidosis (56). These data support that sustained engagement of H⁺ excretory mechanisms in response to dietary acid has long-term detrimental kidney consequences that can be ameliorated by reducing dietary acid and/or neutralizing accumulated acid of eubicarbonatemic acidosis.

Influence of Glomerular Filtration Rate on Acid Accumulation in Response to Dietary Acid

Animals with normal GFR given high compared with lower dietary acid that increases urine NAE but with normal plasma [HCO₃ ⁻] nevertheless had acid accumulation by microdialysis (32). Acid accumulation that was insufficient to reduce plasma [HCO₃ ⁻] below normal, and so not manifest as metabolic acidosis, was greater in animals with reduced than normal GFR (54,57). Likewise, patients with reduced compared with normal eGFR and a high-acid diet had greater acid accumulation despite normal plasma [HCO₃ ⁻] (38,58). Higher acid diets directly associated with higher anion gap in individuals with CKD, and the anion gap was higher in those with eGFR 30–59 ml/min per 1.73 m² than with eGFR >60 ml/min per 1.73 m², including individuals with plasma [HCO₃ ⁻] within normal ranges (59). Furthermore, acid accumulation in individuals with reduced eGFR and eubicarbonatemic acidosis increased as eGFR further declined over time (58), and increased accumulated acid directly associated with increased plasma anion gap despite maintenance of plasma [HCO₃ ⁻] with the normal range (9).

Whether diet-induced acid accumulation manifests as metabolic acidosis depends, in part, on the level of remaining eGFR and the level of dietary acid. Indeed, individuals with CKD and reduced eGFR had greater increases in plasma [H⁺] and greater decreases in plasma [HCO₃ ⁻], even developing metabolic acidosis, at dietary acid levels that did not cause metabolic acidosis in those with higher eGFR (60). The data support that individuals with normal eGFR more completely excrete the acid of Western diets, but do so less with declining eGFR. With high dietary acid, progressive eGFR decline leads to acid accumulation, and eventually to metabolic acidosis, as in Figure 2.

Figure 2.

In the setting of a high acid-producing diet, progressive decreases in glomerular filtration rate are associated with progressively increasing acid accumulation that initially decreases plasma bicarbonate concentration (HCO₃⁻]) within normal ranges but eventually decreases it below normal to manifest as metabolic acidosis. The top horizontal line of the boxes characterizes progressively decreasing levels GFR combined with either low or high dietary acid intake. The middle horizontal portion figuratively compares plasma bicarbonate concentration ([HCO₃ ⁻]) either within the brackets of the normal range or below it. The bottom horizontal figuratively compares H⁺ retention among the four stages. Adapted from ref. 86, with permission.

Acid Accumulation and Organ Injury

Table 2 lists untoward systemic and organ injury of high dietary acid. High-acid diets associate with increased mortality (61,62), insulin resistance (63,64), increased risk for type 2 diabetes (65,66) and hypertension (67,68), and increased glucocorticoid activity (20). These diets also associate with decreased bone health (69,70) and increased catabolism that decreases muscle mass (71,72). Table 3 lists untoward effects associated with reduced GFR/eGFR and eubicarbonatemic acidosis. These effects include vascular endothelial inflammation (73), increased oxidative stress (31), and tissue inflammation and fibrosis (74). Also, patients with CKD and progressively decreasing eGFR developed signs of disturbed Ca/HPO₄ ⁼ metabolism before the onset of metabolic acidosis manifest by reduced plasma [HCO₃ ⁻] (75). Furthermore, patients with eubicarbonatemic acidosis had an increased catabolic state, with augmented protein catabolism (76).

Table 2.

Systemic/organ injury associated with increased dietary acid in individuals/animals without reduced GFR and, presumably, initial normal acid-base status

Systemic/overall effects

Increased mortality (61,62)

Insulin resistance (63,64)

Type 2 diabetes (65,66)

Hypertension (67,68)

Increased glucocorticoid activity (20)

Decreased bone health (69,70)

Muscle: increased catabolic state with decreased muscle mass (71,72)

Kidney

Increased CKD risk (8 –10)

Increased chronic tubulointerstitial injury (52) and increased urine markers of tubulointerstitial injury (57) in animals with normal GFR

Increased risk for kidney stones (5,37)

Table 3.

Systemic/organ injury associated with individuals/animals with reduced GFR and eubicarbonatemic acidosis

Systemic/overall effects

Vascular endothelial cell inflammation (73)

Oxidative stress (31)

Tissue inflammation and fibrosis (74)

Disturbed CKD calcium/phosphate metabolism before metabolic acidosis onset (75)

Increased catabolic state with protein catabolism (76)

Kidney

Decreased urine citrate with increased kidney stone risk (2)

Increased kidney production of angiotensin II, aldosterone, and endothelin-1, with increased risk for kidney interstitial inflammation (44 –49,77)

Complement activation with increased risk for kidney injury (41,43)

Increased risk for progression of established CKD to ESKD (6,7,80)

Although patients with CKD-related metabolic acidosis have kidney injury (77) and CKD progression (23,77,78,79), acid-induced kidney injury with CKD progression is not limited to those with reduced GFR and reduced plasma [HCO₃ ⁻] (Table 2). Chronic high-acid diets in animals with normal GFR and normal plasma [HCO₃ ⁻] caused long-term tubulointerstitial injury (52). Switching to a high-acid diet increased a urine marker of tubulointerstitial injury in animals with normal GFR and normal plasma [HCO₃ ⁻] (57). High-acid diets in the general population increase the plasma anion gap (59), consistent with acid accumulation, and this is associated with increased CKD risk (9) and increased risk for progression of prevalent CKD to ESKD (80). Also, chronic oral NaHCO₃ in patients with CKD, normal GFR, and normal plasma [HCO₃ ⁻] reduced urine excretion of endothelin and aldosterone (56), substances associated with CKD progression (50,51). These data support the physiologic construct in Figure 2, in which harmful acid accumulation occurs with transition from a low- to high-acid diet, constituting the earliest stage of the acid stress continuum.

Acid accumulation remained unchanged in participants with declining eGFR who receive chronic oral alkali, but increased in those who do not receive it, showing long-term benefit of chronic oral alkali (5 years) to reduce acid accumulation in eubicarbonatemic acidosis (58), in addition to its shorter-term (30 days) benefit to do so (56). Such treatment in patients fitting these criteria reduced urine indices of kidney injury (6,81) and slowed eGFR decline (6), supporting that eubicarbonatemic acidosis caused kidney injury and exacerbated eGFR decline (Table 3). These data support the progressive course of acid stress in Figure 2 in individuals with reduced eGFR who eat high-acid diets and suffer from kidney toxic acid accumulation before it accrues to reduce plasma [HCO₃ ⁻], when current guidelines recommend treatment (14).

Strategies to Detect Acid Stress in Individuals without Metabolic Acidosis

As noted earlier and depicted in Figure 2, steady-state eubicarbonatemic acidosis more likely occurs in individuals with CKD, reduced eGFR, and those who eat high-acid diets. Those without metabolic acidosis appear to be appropriate for investigation to determine their candidacy for interventions to reduce dietary acid and/or treatment with Na⁺-based alkali. Reducing dietary acid by adding base-producing food components appears to be an effective initial step to decrease identified acid accumulation (38).

Microdialysis can detect acid accumulation insufficient to significantly reduce plasma [HCO₃ ⁻] in animals (32,49,54,57,82), and indirect techniques do so in patients with plasma [HCO₃ ⁻] within normal ranges (38,56,58,83). Acid accumulation can be estimated in patients with plasma [HCO₃ ⁻] within normal ranges by comparing the observed to expected plasma [HCO₃ ⁻] increase in response to retained HCO₃ ⁻ (administered minus excreted) after an oral NaHCO₃ bolus (0.5 mmol/kg body wt), assuming 50% body wt HCO₃ apparent space of distribution (38,83). This procedure is invasive and time-consuming, making it unsuitable for clinical settings.

Rather than measuring acid accumulation directly, identifying its surrogates appears to be a more attractive option. Compromised urine NAE in the setting of high-acid diets might indicate increase risk for acid accumulation, particularly in patients with reduced eGFR. Low urine NH₄ ⁺ excretion in patients with CKD and reduced eGFR, possibly a reflection of suboptimal urine NAE, is associated with adverse kidney outcomes (42,84), and so its measurement might identify patients at risk for eubicarbonatemic acidosis. Although currently not routinely available in clinical laboratories, advances in urine NH₄ ⁺ measurement might identify individuals with low NAE in the setting of reduced eGFR with normal plasma [HCO₃ ⁻] that increases risk for acid accumulation. On the other hand, clinicians might identify underlying acid accumulation by assessing compensatory mechanisms that help maintain acid-base status, including urine citrate excretion (85). Low levels of timed urine citrate excretion indicated eubicarbonatemic acidosis in patients with CKD (7,38), their response to treatment with either mineral alkali (7) or base-producing food components (38), and indicated changes in acid accumulation over time (7). Other studies support the utility of the more clinically practical citrate-to-creatinine ratio in a “spot” urine specimen to identify patients with underlying acid accumulation despite having normal plasma [HCO₃ ⁻] (85). Further studies will determine clinically useful indicators to identify individuals with eubicarbonatemic acidosis.

Future Research Considerations

Data supporting the contribution of high-acid Western diets to kidney and other organ injury highlight the need for noninvasive methods to detect lower, yet injurious, levels of acid accumulation that are earlier in the acid stress continuum than metabolic acidosis. Ongoing research will help develop noninvasive surrogates to identify patients with CKD and compromised NAE, possibly through reduced urine NH₄ ⁺, indicating increased risk for injurious acid accumulation. Research to assess engagement of compensatory mechanisms to protect against acid accumulation, like reduced urine citrate excretion, will help determine if this strategy reliably identifies patients with injurious acid accumulation not evident by plasma acid-base parameters. Such diagnostic tools will facilitate large-scale interventional studies to determine if treatment of earlier stages of the acid stress continuum, by practitioner-recommended reductions of dietary acid and/or neutralization of accumulated acid, is kidney- and other organ-protective. Such studies will also help to determine the population benefit(s) of public health strategies to implement lower-acid diets.

Disclosures

D.E. Wesson reports employment with Baylor Scott and White Health; serving as a paid consultant of Tricida, Inc.; serving on the American Journal of Nephrology Editorial Board, CJASN Editorial Board, Journal of Renal Nutrition Editorial Board, and Kidney International Editorial Board; and serving as a Deputy Editor of JASN.

Funding

This work was supported in part by the National Institutes of Health grant R21DK113440 (D.E. Wesson, Principal Investigator).