Am J Physiol Renal Physiol 314: F985–F991, 2018.

First published January 3, 2018; doi:10.1152/ajprenal.00463.2017.

RESEARCH ARTICLE

Acid retention in chronic kidney disease is inversely related to GFR

Nimrit Goraya,1,2 Jan Simoni,3 Lauren N. Sager,4 Jessica Pruszynski,5 and Donald E. Wesson6,7
1
Department of Internal Medicine, Texas A&M College of Medicine, Temple, Texas; 2Department of Internal Medicine,
Baylor Scott & White Health, Temple, Texas; 3Department of Surgery, Texas Tech University Health Sciences Center,
Lubbock, Texas; 4Department of Biostatistics, Baylor Scott & White Health, Temple, Texas; 5Department of Cardiovascular
and Thoracic Surgery, University of Texas Southwestern, Dallas, Texas; 6Department of Internal Medicine, Texas A&M
Health Sciences Center College of Medicine, Dallas, Texas; and 7Baylor Scott & White Health and Wellness Center,
Dallas, Texas
Submitted 18 September 2017; accepted in final form 26 December 2017

Goraya N, Simoni J, Sager LN, Pruszynski J, Wesson DE. Acid
retention in chronic kidney disease is inversely related to GFR. Am J
Physiol Renal Physiol 314: F985–F991, 2018. First published January
3, 2018; doi:10.1152/ajprenal.00463.2017.—Greater H⫹ retention in
animal models of chronic kidney disease (CKD) mediates faster
glomerular filtration rate (GFR) decline and dietary H⫹ reduction
slows eGFR decline in CKD patients with reduced eGFR and H⫹
retention due to the high acid (H⫹) diets of developed societies. We
examined if H⫹ retention in CKD is inversely associated with esti-
mated GFR (eGFR) using cross-sectional and longitudinal analysis of
individuals with CKD stage 1 (⬎90 ml·min⫺ 1·1.73 m⫺2), CKD stage
2 (60 – 89 ml/min per 1.73 m2), and CKD stage 3 (30 –59 ml·min⫺ 1·
1.73 m⫺2) eGFR. H⫹ retention was assessed using the difference
between observed and expected plasma total CO2 2 h after 0.5 meq/kg
body wt oral NaHCO3. H⫹ retention was higher in CKD 2 vs. CKD
1 (P ⬍ 0.01) and in CKD 3 vs. CKD 2 (P ⬍ 0.02) at baseline and 5
yr, and was higher in CKD 2 vs. CKD 1 (P ⬍ 0.01) at 10 yr. All
groups had lower eGFR at subsequent time points (P ⬍ 0.01) but H⫹
retention was not different among the three time points for CKD 1. By
contrast, eGFR decrease was associated with higher H⫹ retention in
CKD 2 at 5 yr (P ⫽ 0.04) and 10 yr (P ⬍ 0.01) and with higher H⫹
retention in CKD 3 at 5 yr (P ⬍ 0.01). Yearly eGFR decline rate was
faster in CKD 2 vs. CKD 1 (P ⬍ 0.01) and in CKD 3 vs. CKD 2 (P ⬍
0.01). The data show that H⫹ retention is inversely associated with
eGFR, with faster eGFR decline, and support the need for greater
dietary H⫹ reduction therapy for CKD individuals with lower eGFR.
acidosis; bicarbonate; chronic kidney disease; diet; GFR
INTRODUCTION
Individuals without known kidney disease given dietary acid
(H⫹) or dietary components which increase net endogenous
acid production eventually achieve steady-state urine H⫹ ex-
cretion sufficient to avoid progressive metabolic acidosis (19,
20, 22) but cumulatively excrete less H⫹ than ingested, con-
sisted with H⫹ retention (20, 22). Animal models of this
scenario show tissue H⫹ retention which resolves when the
increment in dietary H⫹ is discontinued (33, 41). Dietary
protocols that cause H⫹ retention in animals with normal GFR
are associated with acute increases in urine parameters of
kidney injury (41) and with long-term tubulointerstitial injury
Address for reprint requests and other correspondence: D. E. Wesson,
Baylor Scott & White Health and Wellness Center, 4500 Spring Ave., Dallas,
TX 75210 (e-mail: Donald.Wesson@BSWH.org).
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(35), supporting that H⫹ retention is injurious to kidneys.
Recognition that diets in developed societies are typically
H⫹-producing (28), and epidemiologic data showing that
high-H⫹ diets are associated with increased risk for chronic
kidney disease (CKD) (3), supports a potential contributory
role for H⫹ retention to the CKD burden in developed societ-
ies.
Although overall US CKD incidence appears not to have
increased in the most recent analyses, the incidence of preva-
lent CKD progressing to its more advanced stages has never-
theless increased (29). The observation that higher end-stage
renal disease (ESRD) incidence in groups at comparatively
greater CKD risk is due more to faster progression of prevalent
CKD to ESRD than to greater incidence of CKD (14) high-
lights the importance of identifying modifiable factors for CKD
progression to ESRD. Animal CKD models show that H⫹
retention in response to an H⫹-producing diet is greater with
reduced compared with normal GFR (36, 37, 40, 41), as is the
associated kidney injury (41). Acid retention in animals with
reduced GFR mediates progressive GFR decline (36, 37, 40)
that is ameliorated by dietary alkali or by base-producing diets
(36, 37, 40). Patients with reduced eGFR also have H⫹ reten-
tion (30, 38, 39), even in the absence of metabolic acidosis (30,
38), and their H⫹ retention is ameliorated by dietary alkali
(38). Furthermore, chronic oral alkali treatment of individuals
with reduced eGFR and no metabolic acidosis slowed eGFR
decline (24), consistent with a contribution of underlying H⫹
retention to eGFR decline.
High-H⫹ diets are associated with increased risk for CKD
progression to ESRD (4) and so higher H⫹ retention induced
by such diets in individuals with reduced GFR might mediate
faster GFR decline. If the degree of H⫹ retention is indeed
inversely associated with eGFR, then greater dietary H⫹ re-
duction than is currently recommended (16) might be needed to
correct H⫹ retention and thereby limit its untoward effects in
individuals with reduced GFR. In support of this concern,
modest alkali therapy in individuals with reduced eGFR and
H⫹ retention incompletely corrected H⫹ retention (38) and
slowed but did not stop eGFR decline (24). Consequently, the
present studies used cross-sectional and longitudinal analyses
to examine the association of reduced eGFR with the degree of
H⫹ retention in individuals with CKD and progressively lower
eGFR stages, as well as the association of H⫹ retention with
the rate of eGFR decline.
F985
F986 ACID RETENTION AND GFR REDUCTION
MATERIALS AND METHODS
This study used cross-sectional and longitudinal analyses to exam-
ine the contribution of reduced cystatin C-calculated eGFR to acid
(H⫹) retention, a phenomenon detected in experimental CKD models
(36, 37, 40, 41) and some CKD patients (30, 38, 39). We recruited 102
macroalbuminuric, hypertensive, and nondiabetic participants of three
different eGFR stages and without clinical evidence of glomerulone-
phritis or evidence of a systemic disease associated with glomerulo-
nephritis. These patient studies translated from our basic science
studies in which we originally studied patients with so-called hyper-
tension-associated, nondiabetic nephropathy to approximate the pa-
thology and presumably pathophysiology of our subtotal nephrectomy
animal model of CKD. Our strategy for selecting these patients and
not those with other causes of CKD like diabetes was to optimize the
chance for true-testing of our hypothesis that dietary acid reduction is
kidney-protective in patients (7, 11–13, 25) as was shown in these
animal models (35–37, 40). We chose macroalbuminuric participants
because they are at higher risk of eGFR progression despite recom-
mended kidney-protective interventions than those with lower levels
of albuminuria (31) to include participants whose eGFR would likely
decrease during follow-up so as to examine the effect of eGFR
reduction on H⫹ retention. We followed all three groups for 5 years
and followed CKD 2 and CKD 1 groups an additional 5 years for a
total of 10 yr follow-up. Five-year eGFR decline rate was calculated
by subtracting eGFR at 5 years from the baseline value and dividing
by 5. We measured H⫹ retention indirectly as “unaccounted HCO3” at
baseline and at 5 and 10 yr by comparing the observed to the expected
change in plasma total CO2 (PTCO2) in response to retained HCO3
(dose minus excretion) 2 h after an oral bolus of 0.5 meq/kg body wt
bolus of NaHCO3: H⫹ retention ⫽ [(retained HCO3/0.5 ⫻ body wt) –
observed increase in plasma HCO3] ⫻ 0.5 body wt, assuming 50% body
weight space distribution for HCO3 (2).
We performed these determinations for CKD 2 and CKD 1 patients
at 6 h after the oral NaHCO3 bolus in previous studies (38, 39), but
PTCO2 at this time point in CKD 3 patients was not different from
baseline, possibly because higher H⫹ retention in these patients
titrated the administered NaHCO3 faster. Our technique for “unac-
counted HCO3” requires a higher post-dose vs. baseline PTCO2.
Further studies showed higher than baseline PTCO2 at 2 h in CKD 3
patients and so this time period was selected for CKD 2 and CKD 1
patients as well. Our calculations assume similar buffering among the
three groups.
Participants with three eGFR stages of CKD were studied: 1) 26
CKD 1 (eGFR ⬎ 90 ml·min⫺ 1·1.73 m⫺2); 2) 40 CKD 2 (eGFR
⫺ 1
60 – 89 ⫺ ml·min
1
·1.73 m⫺2); and 3) 36 CKD 3 (eGFR 30 –59
⫺2
ml·min ·1.73 m ). Other inclusion criteria were 1) nonmalignant
hypertension; 2) ⱖ2 primary care physician visits in the preceding
year, showing compliance with clinic visits; 3) age ⱖ 18 yr and able
to give consent. Exclusion criteria were 1) primary kidney disease or
findings consistent thereof such as ⱖ 3 red blood cells per high-
powered field of urine or urine cellular casts; 2) history of diabetes or
fasting blood glucose ⱖ 110 mg/dl; 3) history of malignancies,
chronic infections, pregnancy, or clinical evidence of cardiovascular
disease; and 4) peripheral edema or diagnoses associated with edema
such as heart/liver failure or nephrotic syndrome; and 5) unable to
tolerate angiotensin-converting enzyme inhibition because extant
guidelines at the start of the study recommended this therapy for
patients with macroalbuminuria (5). None of the participants had a
kidney biopsy to exclude other CKD causes. Secondary causes of
hypertension such as renal artery stenosis and hyperaldosteronism
were excluded clinically. Kidney Doppler studies and plasma aldo-
sterone-to-renin ratios were not done. These noninvasive measures to
exclude patients with causes other than hypertension-associated, non-
diabetic CKD nevertheless allow for a low but not zero likelihood of
including patients with CKD of other causes. Most participants were
recruited from those referred to our academic nephrology clinic for
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management of their hypertension and/or evaluation of their reduced
kidney function. Participant systolic blood pressure was reduced
pharmacologically toward a goal of ⬍130 mmHg as recommended by
extant guidelines for those with albuminuria (5). Eight-hour urine net
acid excretion (8-h NAE) was measured and calculated from urine
titratable acidity (TA), ammonium (NH4⫹), and HCO3 ([NH4⫹] ⫹
[TA] – [HCO3]) (38). Although the CKD 3 patient data are newly
presented, baseline data for the same CKD 2 and CKD 1 patients were
reported in earlier publications from this laboratory (38, 39). Because
CKD 3 patients were recruited more recently, the present studies
compare parameters among CKD 3, CKD 2, and CKD 1 patients
cross-sectionally, then longitudinally, for all three groups at 5 yr and
between CKD 2 and CKD 1 at 10 yr.
We assessed steady-state H⫹ retention by measuring 2-h NAE and
venous PTCO2 in the three CKD groups after an oral 0.5 meq/kg lean
body wt bolus of NaHCO3. Subjects were told to remain NPO after
midnight except for medications before reporting, after which they
voided to empty, had venous blood drawn for pH, PCO2, and total
CO2, and had venous access established. They were given the
NaHCO3 bolus at 8:00 AM, had urine collected for NAE and venous
blood drawn for acid-base parameters at 10:00 AM. They received 8
ounces of chilled distilled H2O, but no other intake, every 2 h to
promote urine output. Our assessment of H⫹ retention assumed that
higher H⫹ retention would manifest by greater H⫹ titration of the
administered HCO3 reflected by a smaller observed compared with
expected increase in PTCO2 (assuming 50% HCO3 space of distribu-
tion) (2) and/or by less urine HCO3 excretion. This method also
assumes similar buffering capacity among the CKD stages, an as-
sumption supported by no differences in levels of the major contrib-
utors to whole blood buffer base capacity reported in previous studies
(38). Because measured parameters did not permit comparison of
intracellular buffering capacity, we assumed this parameter to be
similar among CKD groups.
Our local IRB approved the study protocols.
Analytical methods. Plasma and urine creatinine and urine albu-
min were measured using the Sigma Diagnostics Creatinine Kit
(Procedure No. 555, Sigma Diagnostics) (26). The IRMA SL
Series 2000 blood analysis system (Edison, NJ) measured venous
plasma/blood pH and PCO2. Urine and plasma total CO2 were
measured using ultrafluorimetry (32). Urine TA was measured by
correction to the ambient plasma pH by NaOH addition, and NH4⫹
by the Formalin titrametric (to ambient plasma pH) method (6).
Potential renal acid load (PRAL) was measured using a 3-day diary
assessment of the type and amount of foods ingested and scoring
them as to their H⫹ or base content as described (27) and as done
previously (38).
Statistical methods. Characteristics of the sample are described
using descriptive statistics. Frequencies and percentages are used to
describe categorical variables. Means and SDs are used to describe
continuous variables. Group comparisons are made using a one-way
analysis of variance model. A repeated-measures analysis of variance
model is used to evaluate the change in H⫹ retention, as measured by
unaccounted HCO3, from baseline to 5 yr and from baseline to 10 yr.
Similar models are used to evaluate changes from baseline for cystatin
C-calculated estimated GFR and plasma total CO2. Statistical signif-
icance level was set to 0.05.
RESULTS
Figure 1 outlines the protocol for the 102 CKD 1, CKD 2,
and CKD 3 participants followed with the indicated measure-
ments at baseline, at 5, then 10 yr, the latter time data being
available for the CKD 1 and CKD 2 participants only. Table 1
shows no difference in sex, age, body weight, 8-h urine net
acid excretion among groups, but white subjects were under-
represented among CKD 2 and CKD 3 participants. Table 2
shows no difference in potential renal acid load (PRAL) among
 ACID RETENTION AND GFR REDUCTION F987

Study Protocol

102 CKD
subjects
Fig. 1. Outline of protocol to assess cross-
sectional and longitudinal differences in H⫹
26 CKD 1 40 CKD 2 36 CKD 3 retention among chronic kidney disease stage
0 years cys C eGFR cys C eGFR cys C eGFR 0 years 1 (CKD 1) [estimated glomerular filtration
H+ retention H+ retention H+ retention rate (eGFR) ⬎ 90 ml·min⫺ 1·1.73 m⫺2), CKD
stage 2 (eGFR ⫽ 60 – 89 ml·min⫺ 1·1.73
• 1 moved • 2 moved • 2 lost to f/u m⫺2), and CKD stage 3 (eGFR ⫽ 30 –59
⫺ 1
• 1 lost to f/u • 4 lost to f/u • 1 died ml·min ·1.73 m⫺2) subjects at baseline and
24 CKD 1 34 CKD 2 33 CKD 3 at follow-up years 5 and 10. Reasons for
5 years cys C eGFR cys C eGFR cys C eGFR 5 years subject drop out are shown. f/u, follow-up;
H+ retention H+ retention H+ retention cys C, cystatin C.

• 1 moved • 1 died
• 2 lost to f/u

21 CKD 1 33 CKD 2 No
10 years cys C eGFR cys C eGFR 10 year 10 years
H+ retention H+ retention Follow up

groups at any time point and no difference in PRAL among
time points within any of the three groups. Figure 2 shows no
difference in systolic blood pressure among groups at any time
point and was lower than baseline in follow-up years for each
group (P ⬍ 0.01), reflecting antihypertensive drug interven-
tion.
Figure 3 shows that baseline plasma total CO2 (PTCO2) was
lower in CKD 2 than CKD 1 (25.9 ⫾ 0.7 vs. 26.4 ⫾ 0.8 mM,
P ⬍ 0.01) and was lower in CKD 3 (20.8 ⫾ 0.9 mM) than
CKD 2 (P ⬍ 0.01). PTCO2 in CKD 1 was not different from
baseline at either 5 (26.4 ⫾ 0.7 mM, P ⫽ 0.92) or 10 (26.4 ⫾
0.7 mM, P ⫽ 0.84) years. Although 5-yr PTCO2 for CKD 2
(25.8 ⫾ 0.7 mM) was not different from baseline (P ⬍ 0.25),
the 10-yr value (25.3 ⫾ 0.5) was lower than baseline (P ⬍
0.01). Year 5 PTCO2 for CKD 3 (22.3 ⫾ 0.8) was higher than
at baseline (P ⬍ 0.01) because they were treated with Na⫹-
based alkali to increase PTCO2 “into the normal range” as
recommended by extant guidelines (16).
Figure 4 shows that cystatin C-calculated estimated GFR
(eGFR) was lower at each subsequent time point for each of the
three groups (P ⬍ 0.01). As per design, eGFR was lower in
CKD 2 than CKD 1 (73.5 ⫾ 6.1 vs. 97.4 ⫾ 7.7 ml·min⫺ 1·1.73
m⫺2, respectively, P ⬍ 0.01) and lower in CKD 3 (39.5 ⫾ 6.9
ml·min⫺ 1·1.73 m⫺2) than CKD 2 (P ⬍ 0.01) at baseline.
This pattern maintained at 5 yr with eGFR for CKD 2 being
lower than CKD 1 (64.0 ⫾ 6.1 vs. 91.6 ⫾ 8.3 ml·min⫺ 1·
1.73 m⫺2, respectively, P ⬍ 0.01) and lower in CKD 3
(20.5 ⫾ 6.2 ml·min⫺ 1·1.73 m⫺2) than CKD 2 (P ⬍ 0.01). In
addition, eGFR remained lower at 10 yr in CKD 2 than CKD
1 (51.4 ⫾ 4.4 vs. 84.2 ⫾ 9.1 ml·min⫺ 1·1.73 m⫺2, respec-
tively, P ⬍ 0.01). At 5 yr, the yearly rate of eGFR decline,
expressed as ml·min⫺ 1·1.73 m⫺2 per year, was faster in
CKD 2 vs. CKD 1 (2.32 ⫾ 0.14 vs. 1.16 ⫾ 0.16, respec-
tively, P ⬍ 0.01) and was faster in CKD 3 (3.77 ⫾ 0.15)
than CKD 2 (P ⬍ 0.01).
Figure 5 shows in cross-sectional comparisons that acid
(H⫹) retention was higher in CKD 2 than CKD 1 (17.4 ⫾ 9.9
vs. 3.0 ⫾ 14.0 mmol, P ⬍ 0.01) and was higher in CKD 3
(24.9 ⫾ 15.4 mmol) than CKD 2 (P ⬍ 0.02) at baseline. Figure
5 also shows that H⫹ retention was higher in CKD 2 than CKD
1 (19.2 ⫾ 10.3 vs. 3.1 ⫾ 15.1 mmol, P ⬍ 0.01) and was higher
in CKD 3 (28.3 ⫾ 14.7 mmol) than CKD 2 (P ⬍ 0.01) at 5 yr,
and was higher in CKD 2 than CKD 1 (22.1 ⫾ 11.2 vs. 3.7 ⫾
13.4 mmol, P ⬍ 0.01) at 10 yr. Although H⫹ retention in CKD
1 was not different from baseline at either 5 (P ⫽ 0.97) or 10
yr (P ⫽ 0.36) follow-up, longitudinal comparison showed
higher H⫹ retention than baseline for CKD 2 at both 5 (P ⫽
0.04) and 10 yr (P ⬍ 0.01) and for CKD 3 at 5 yr (P ⬍ 0.01).
Not indicated on the figure, the longitudinal comparison
showed that H⫹ retention was higher for CKD 2 at 10 yr than
at 5 yr (P ⬍ 0.03).

Table 1. General subject characteristics

CKD 1 (eGFR ⬎ 90 ml/min) (n ⫽ 26) CKD 2 (eGFR 60–89 ml/min) (n ⫽ 40) CKD 3 (eGFR 30–59 ml/min) (n ⫽ 36) P Value

% Males 46 48 44 0.97
% Black 35 63 53
% Hispanic 19 25 33
% White 46 13 14 ⬍0.01
Age, yr 49.4 ⫾ 9.6 51.3 ⫾ 8.5 53.9 ⫾ 4.8 0.08
Body wt, kg 84.2 ⫾ 3.8 84.1 ⫾ 4.5 83.5 ⫾ 5.4 0.78
8 h NAE, meq 24.7 ⫾ 2.9 24.6 ⫾ 5.0 26.4 ⫾ 3.2 0.11
Values for age, body weight, and 8-h net acid excretion (NAE) are means ⫾ SD. CKD, chronic kidney disease; the numbers which follow denote the estimated
glomerular filtration rate (eGFR) stage 1, 2, or 3 which fall within the indicated ranges; 8 h NAE, urine 8-h net acid excretion.

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F988 ACID RETENTION AND GFR REDUCTION

Table 2. Dietary potential renal acid load

Potential Renal Acid Load, mmol/day

CKD 1 (eGFR ⬎ 90 ml/min) (n ⫽ 26) CKD 2 (eGFR 60–89 ml/min) (n ⫽ 40) CKD 3 (eGFR 30–59 ml/min) (n ⫽ 36) P Value

Year 0 62.9 ⫾ 14.5 60.4 ⫾ 19.4 64.1 ⫾ 6.9 0.54

Year 5 62.2 ⫾ 14.3 61.0 ⫾ 18.0 63.2 ⫾ 6.3 0.80
Year 10 61.1 ⫾ 12.1 64.3 ⫾ 17.7 0.44
Values are means ⫾ (SD). CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate.

DISCUSSION Although recent data showing that overall CKD incidence

⫹ has not increased is welcome news, the incidence of CKD
The present studies show in cross-sectional analyses that H
patients with reduced GFR progressing to more advanced
retention was greater in CKD 2 than CKD 1 and was greater in
stages has increased (29). Amelioration of metabolic acidosis
CKD 3 than CKD 2. Because CKD 3 patients met criteria (16)
in CKD patients with reduced eGFR and PTCO2 ⬍ 22 mM as
for treatment of their metabolic acidosis with Na⫹-based alkali
recommended by current guidelines (16) slows the rate of
and were so treated, their H⫹ retention might have been even
decline of creatinine clearance (7) and eGFR (25) in individ-
greater and their differences from CKD 2 patients might have
uals with very low GFR. In addition, correction of metabolic
been greater without this treatment. Longitudinal analyses
acidosis that is less severe than that for which current guide-
show that H⫹ retention increased in CKD 2 and CKD 3
lines recommend treatment (i.e., PTCO2 ⫽ 22–24 mM) also
participants as their eGFR decreased over 5 yr and further
slows eGFR decline (13). Furthermore, alkali treatment of
increased in CKD 2 participants as eGFR additionally de-
individuals with reduced eGFR without metabolic acidosis but
creased at 10 yr. Notably, the dramatic quantitative differences
fitting parameters of those who have H⫹ retention slows eGFR
in H⫹ retention between CKD 2 and CKD 1 participants, with
decline (24). Together, these studies support that treatment of
neither group having metabolic acidosis by plasma acid-base
the full spectrum of “H⫹ stress” that ranges from reduced
parameters, were associated with only slight PTCO2 differ-
eGFR without metabolic acidosis yet with H⫹ retention, to
ences which were well within the normal range for clinical
individuals with very low eGFR and metabolic acidosis by
laboratories. This indicates that plasma acid-base parameters
plasma acid-base parameters, is kidney protective. Modest
alone will not permit clinicians to identify individuals with H⫹
dietary H⫹ reduction incompletely corrected underlying H⫹
retention. The 5-yr data show that that greater H⫹ retention in
retention (38) and slowed, but did not stop, eGFR decline (24).
CKD was associated with a faster rate of eGFR decline. These
These studies support that lower eGFR is associated with
data support that, like animal models of CKD (36, 37, 40, 41),
greater H⫹ retention and suggest the need for more aggressive
reduced eGFR in patients is associated with greater H⫹ reten-
dietary H⫹ reduction for optimal kidney protection. Future
tion and with faster eGFR decline. In addition, greater H⫹
studies remain to be done to determine if such therapy, which
retention with lower eGFR suggests that those with lower
might include base-producing food components shown to im-
eGFR require more aggressive dietary H⫹ reduction to correct
prove metabolic acidosis (12, 13) in concert with standard
H⫹ retention and thereby presumably prevent or ameliorate the
alkali therapy using Na⫹-based alkali, is a more effective
untoward kidney and possibly other effects of H⫹ retention.
kidney-protective intervention.
Earlier balance studies support that some CKD patients
eating dietary H⫹ have H⫹ retention (10) so the present and
200

CKD 1 CKD2 CKD3

recent studies (30, 38, 39) are not entirely new findings but
Systolic Blood Pressure (mmHg)
180

30

CKD 1 CKD2 CKD3

Plasma Total CO2 (mM)
160

δ
δ
25

δ δ
δ
* * *δ
140

20
120

*
δ
Baseline Year 5 Year 10
*
Fig. 2. Boxplots showing systolic blood pressure in mmHg for CKD 1, CKD
2, and CKD 3 individuals at baseline (year 0), year 5, and year 10 of
15

follow-up. The dark line through each box indicates the median value. The box
Baseline Year 5 Year 10
represents the inner quartile range of the differences in systolic blood pressure,
or the 25% and 75% percentile of the systolic blood pressure differences. The Fig. 3. Boxplots showing plasma total CO2 in mM for CKD 1, CKD 2, and
lines extending from the box indicate the range, or minimum and maximum, of CKD 3 individuals at baseline (year 0), year 5, and year 10 of follow- up.
the differences. Dots above or below the boxplots indicate values that are *P ⬍ 0.05 vs. respective CKD 1; ⫹P ⬍ 0.05 vs. respective CKD 2; ␦P ⬍ 0.05
considered outliers. ␦P ⬍ 0.05 vs. respective baseline value. vs. respective baseline value.

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 ACID RETENTION AND GFR REDUCTION
120 CKD 1 CKD2 CKD3
100
GFR (ml/min/1.73 m2)
80
δ
δ range for clinical laboratories. These studies are consistent
60
* with a scenario in which during the course of chronic GFR
*δ
40
* surpasses body capacity to buffer this “fixed” (as opposed to
20
* [H⫹] and/or decreases in plasma [HCO3]. Indeed, large in-
0
δ
Baseline Year 5
Fig. 4. Boxplots showing cystatin C-calculated estimated glomerular filtration
rate (eGFR) for the CKD 1, CKD 2, and CKD 3 individuals at baseline (year
0), year 5, and year 10 of follow-up. *P ⬍ 0.05 vs. respective CKD 1; ⫹P ⬍
0.05 vs. respective CKD 2; ␦P ⬍ 0.05 vs. respective baseline value.
more specifically identify the phenomenon of H⫹ retention
using the experimental strategy described. Like these earlier
studies (10) and more recent ones (30, 38, 39), H⫹ retention
was associated with minimal changes in PTCO2. These patient
studies are consistent with animal models of CKD with re-
duced GFR without metabolic acidosis by plasma acid-base
parameters that nevertheless have H⫹ retention by microdialy-
sis (36, 37, 40, 41). These animal CKD models show that the
same dietary H⫹ load induces greater H⫹ retention in animals
with reduced GFR compared with intact nephron mass and that
greater dietary H⫹ in animals with reduced eGFR induces even
higher H⫹ retention and higher urine indexes of kidney injury
(41). Together, these data support that individuals with reduced
eGFR ingesting the high-H⫹ diets of developed societies have
levels of H⫹ retention that are inversely associated with the
level of their remaining eGFR and so might require more
aggressive dietary H⫹ reduction to ameliorate its untoward
effects.
Dietary H⫹ reduction might be accomplished by adding
Na⫹-based alkali to an H⫹-producing diet or, alternatively, by
ingesting a base-producing diet. Each strategy reduced H⫹
retention and slowed GFR decline in animal CKD models (36,
37, 40). Epidemiologic studies support that a Mediterranean
diet, one with comparatively low dietary H⫹ compared with
diets typical of most developed societies, reduces CKD risk
(15, 17). The comparative kidney-protective effect of these
lower H⫹- producing diets suggested by these epidemiologic
studies might be due to less or no H⫹ retention induced by
these diets. In support of this hypothesis, base-producing diets
reduced H⫹ retention (33) and kidney injury (35) in animals
with intact nephron mass. Such diets also slowed eGFR decline
in animal CKD models (36), reduced kidney injury in individ-
uals with reduced eGFR and no metabolic acidosis (11), and
slowed eGFR decline in individuals with reduced eGFR and
metabolic acidosis (13). Whether base-producing diets reduce
H⫹ retention in individuals with reduced eGFR, as has been
shown for Na⫹-based alkali (38), awaits further study. In
addition, future studies remain to be done to determine if the
kidney-protective benefit of base-producing diets is mediated
by reduced H⫹ retention, and if so, if these diets are additive to
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F989
Na⫹-based alkali in reducing H⫹ and/or providing kidney
protection.
The present studies in concert with previous studies from
this and other laboratories (30) support a spectrum of H⫹ stress
in CKD, the milder degree of which might not be evident by
changes in plasma acid-base parameters outside of the normal
decline, subjects ingesting an H⫹-producing diet develop H⫹
*δ retention before the accumulated H⫹ increases to a level that
volatile or CO2-derived) H⫹ without an increase in plasma
creases in dietary H⫹ yield relatively minor increases in
Year 10 plasma [H⫹], and relatively minor decreases in plasma
[HCO3], and the change in each parameter typically occurs
within their normal ranges for clinical laboratories (18). On the
other hand, CKD patients with reduced GFR show greater
increases in [H⫹] and greater decreases in [HCO3] in response
to the same dietary H⫹ load, even developing metabolic
acidosis, at levels of dietary H⫹ that do not cause metabolic
acidosis in individuals with higher GFR (1). These data along
with the present studies support greater susceptibility of CKD
patients with reduced GFR to dietary H⫹ and support that
dietary H⫹ induces greater degrees of H⫹ stress, beginning
with H⫹ retention, in patients with lower GFR.
The concept of a spectrum of H⫹ stress that includes H⫹
retention without metabolic acidosis raises the question as to
where accumulated H⫹ resides before it increases to a level
that is reflected by the described changes in plasma acid-base
parameters. Classic studies support that bone buffers H⫹ in
patients with uremic metabolic acidosis (21) and more recent
studies support that H⫹-producing diets can increase bone
resorption in the absence of plasma acid-base parameters
reflective of metabolic acidosis (9), a scenario consistent with
H⫹ retention with H⫹ buffering by bone. Animal studies
showed that a dietary H⫹ increment sufficient to increase urine
H⫹ excretion but not to decrease PTCO2 in animals with intact
nephron mass increased H⫹ addition to microdialysate per-
fused against kidney cortical interstitium (33), consistent with
increased interstitial fluid H⫹ content. The H⫹ entering micro-
CKD 1 CKD2 CKD3
80
60
Acid Retention (mmol)
40
20
*δ * *δ
0
* * δ
-20
-40
Baseline Year 5 Year 10
Fig. 5. Boxplots showing acid (H⫹) retention for the CKD 1, CKD 2, and CKD
3 individuals at baseline (year 0), year 5, and year 10 of follow-up. *P ⬍ 0.05
vs. respective CKD 1; ⫹P ⬍ 0.05 vs. respective CKD 2; ␦P ⬍ 0.05 vs.
respective baseline value.
F990 ACID RETENTION AND GFR REDUCTION
dialysate might also have derived from plasma buffers and/or
intracellular stores. Other studies showing that this dietary
protocol increased H⫹ content in skeletal muscle support that
H⫹ retention is a systemic phenomenon (36). These data
support the interstitial fluid compartment as at least one locus
of retained H⫹ in these settings. Other investigators reported a
direct relationship between extracellular fluid volume and in-
terstitial fluid volume and pressure and that each of the latter
were higher in patients with reduced GFR (8), supporting that
the interstitial fluid compartment reflects systemic status of
other kidney-regulated phenomenon. Together, these data sup-
port that interstitial fluid can reflect systemic Na⫹ and H⫹
status before their respective manifestation in plasma, includ-
ing pathological excess of each observed with decreased GFR.
Although the present studies did not explore mechanisms by
which H⫹ retention in patients is inversely associated with the
level of remaining eGFR, animal studies provide some in-
sights. Animals with reduced compared with normal GFR can
achieve comparable steady-state levels of increased urine H⫹
excretion in response to the same increment in dietary H⫹ but
require a longer time to do so (41). In the meantime, continued
ingestion of the increment in dietary H⫹ during the delay
before urine H⫹ excretion increased to the new and higher
steady state led to higher H⫹ accumulation in animals with
reduced compared with normal GFR and to greater H⫹ reten-
tion (41). Animals with reduced GFR maintained their greater
H⫹ retention until the increment in dietary H⫹ stopped. These
animal studies support that continued dietary H⫹ ingestion by
individuals with declining GFR increases H⫹ retention in the
interval during which kidneys complete adjustments that in-
crease per nephron acidification (34) in an effort to maintain
acid-base balance in the setting of reduced GFR (10). The data
support that kidney adjustments increase overall kidney H⫹
excretion sufficient to maintain steady-state plasma acid-base
parameters (42) but not to completely correct the increment in
H⫹ retention.
Study limitations include our indirect method of assessing
H⫹ retention that has not been validated by others. In addition,
we studied only subjects with reduced GFR due to nondiabetic
CKD and so it is not known if these findings apply to those
with reduced GFR from other etiologies. Future studies must
examine these issues in patients with CKD due to other
etiologies.
In summary, these studies show that H⫹ retention in CKD
patients is inversely associated with eGFR in cross-sectional
and longitudinal analyses and that the higher H⫹ retention was
associated with faster eGFR decline rate. These data support
that greater H⫹ retention in CKD patients with reduced eGFR
mediates decline. Future studies remain to be done to deter-
mine if more aggressive dietary H⫹ reduction to correct H⫹
retention in CKD patients with reduced eGFR prevents or
ameliorates the untoward kidney and possibly other untoward
effects of H⫹ retention.
ACKNOWLEDGMENTS
We thank the nursing and clerical staff of the Internal Medicine Clinic of
the Department of Internal Medicine at Texas Tech University Health Sciences
Center for assistance and the Inside Out Community Outreach Program of
Lubbock, TX, for making these studies possible.
AJP-Renal Physiol • doi:10.1152/ajprenal.00463.2017 • www.ajprenal.org
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GRANTS
This work was supported by funds from the Larry and Jane Woirhaye
Memorial Endowment in Renal Research at the Texas Tech University Health
Sciences Center, by the Statistics Department of Texas A&M University, and
by the Academic Operations Division of Baylor Scott & White Health.
DISCLOSURES
D. E. Wesson receives consulting fees from Tricida, Inc., paid to Baylor
Scott & White Health, to support his salary. None of the other authors have
conflicts to disclose relevant to these studies.
AUTHOR CONTRIBUTIONS
N.G. and D.E.W. conceived and designed research; N.G. and J.S. per-
formed experiments; N.G. and D.E.W. interpreted results of experiments;
N.G., J.S., L.N.S., J.P., and D.E.W. approved final version of manuscript;
L.N.S. and J.P. analyzed data; L.N.S. prepared figures; D.E.W. drafted man-
uscript; D.E.W. edited and revised manuscript.
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