Estimated Net Endogenous Acid Production and Serum Bicarbonate in African Americans with Chronic Kidney Disease : Clinical Journal of the American Society of Nephrology

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Original Articles: Original Articles

Estimated Net Endogenous Acid Production and Serum Bicarbonate in African Americans with Chronic Kidney Disease

Scialla, Julia J.*; Appel, Lawrence J.*,†,‡; Astor, Brad C.*,†,‡; Miller, Edgar R. III*,†,‡; Beddhu, Srinivasan§; Woodward, Mark‡,‖; Parekh, Rulan S.*,†,¶; Anderson, Cheryl A.M.*,†,‡

Author Information

Departments of *Medicine and

†Epidemiology, Johns Hopkins University, Baltimore, Maryland;

‡Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland;

§Department of Medicine, University of Utah, Salt Lake City, Utah;

‖The George Institute for Global Health, Camperdown, Australia; and

Departments of Pediatrics and Medicine, University of Toronto, Toronto, Ontario, Canada

Correspondence: Dr. Julia J. Scialla, Division of Nephrology, Johns Hopkins University School of Medicine, 301 Mason F. Lord Drive, Suite 2500, Baltimore, MD 21224. Phone: 410-550-2820; Fax: 410-550-7950; E-mail: [email protected]

Received January 6, 2011

Accepted March 23, 2011

Clinical Journal of the American Society of Nephrology 6(7):p 1526-1532, July 2011. | DOI: 10.2215/CJN.00150111
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Abstract

Introduction

As chronic kidney disease (CKD) progresses, renal excretion of nonvolatile acid produced by metabolism of the diet is impaired, resulting in low-grade metabolic acidosis (1). Metabolic acidosis, in turn, may result in bone loss (2–4) and muscle wasting (5,6), prompting recommendations to maintain serum bicarbonate levels at 22 mEq/L or higher (7). Recently, lower serum bicarbonate has been shown to be a risk factor for CKD progression (8,9). Importantly, in randomized trials, the use of exogenous alkali supplements to achieve serum bicarbonate in the normal range delayed the need for dialysis among patients with advanced CKD (10).

Metabolic acidosis may be exacerbated by a contemporary Western diet, which delivers a high nonvolatile acid load, compared with the diet of our preagricultural ancestors (11–13). The nonvolatile acid load, also known as the net endogenous acid production (NEAP), is determined by the balance of acid and alkali precursors in the diet (14). Proteins are the major source of nonvolatile acid through metabolism to sulfates and other organic acids, whereas alkali is derived from potassium salts that naturally occur in fruits and vegetables (e.g. potassium citrate) (15). Previous studies have shown that the ratio of protein to potassium in the diet is linearly related to gold standard measurements of (NEAP) (i.e. renal net acid excretion) in healthy humans and is appropriate for use in epidemiologic studies (16,17). In this study, we estimate endogenous-acid production NEAP and evaluate its association with serum bicarbonate among African Americans with hypertensive kidney disease consuming their usual diets.

Materials and Methods

Study Population

The African American Study of Kidney Disease and Hypertension (AASK) was a multicenter, randomized trial of antihypertensive management in African American patients with presumed hypertensive nephrosclerosis. Included patients had diastolic BP >95 mmHg, and 125I-iothalamate GFR between 20 and 65 ml/min per 1.73 m2. Exclusion criteria included diabetes, accelerated or secondary hypertension, urine protein/creatinine ratio of >2.5, or congestive heart failure. Between 1995 and 1998, participants were randomized in a 2 × 3 factorial design to intensive versus standard BP control (mean arterial pressure <92 versus 102 to 107 mmHg) and either ramipril, metoprolol, or amlodipine as the primary BP agent. Participants (n = 691; 87% of those eligible) who were alive and had not reached stage renal disease ESRD by the end of the trial (April 2001) were enrolled in an observational cohort phase and were followed through 2007. The protocol and procedures were approved by the institutional review board of each participating center, and all of the participants provided written informed consent.

Four hundred sixty-three of 691 (67%) participants from the cohort phase were included in these analyses. Participants were excluded if no eligible urine collections were available (119 participants had no complete urine collections available; 96 participants were using potassium supplements at the time of urine collection; and two participants were using sodium polystyrene at the time urine collection) or were missing eligible serum bicarbonate measurements (five participants were missing serum bicarbonate and six participants were using bicarbonate supplements at the time of serum bicarbonate measurement).

Data Collection

Twenty-four-hour urine collections were analyzed at the central laboratory (Cleveland Clinic) for urea nitrogen, potassium, sodium, and creatinine and were used to estimate endogenous-acid production NEAP. Urines were included if the 24-hour total creatinine excretion was within 30% of the expected creatinine generation by sex (22.1 mg/kg in men and 17.2 mg/kg in women) to indicate a complete collection, as used in previous studies (18). Urines were excluded if the participant was using a potassium supplement or sodium polystyrene at the time of urine collection. Ideal body weight (IBW) was calculated using previously published equations (19). Daily dietary protein intake was estimated from 24-hour urine urea nitrogen (UUN) excretion using the Maroni equation (protein intake = 6.25 *[UUN + 0.031*IBW] − urinary protein (g/d) if daily urine protein excretion ≥5 g) (20). Daily dietary potassium intake was estimated using the total 24-hour urine potassium excretion (21). NEAP was estimated from these intakes using a previously validated equation: NEAP (mEq/d) = −10.2 + 54.5 (protein intake [g/d] ÷ potassium intake [mEq/d]) (17).

Serum bicarbonate and serum creatinine were measured annually using standard assays performed at a central laboratory. Estimated GFR (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) study equation (22). Demographic and medical history information was collected by interview at baseline. Updated medication histories were performed at each study visit.

Statistical Analyses

The distributions of estimated dietary intakes and serum bicarbonate were examined. One extreme outlier of potassium intake was excluded. The distribution of serum bicarbonate was truncated at 35 mEq/L (approximately 2 SD above mean) to approximate a normal distribution (22/3052 observations removed). Estimated dietary protein intake, dietary potassium intake, and NEAP were analyzed in two ways. First, each eligible annual measurement was calculated and considered continuously as well as categorized in quartiles. Second, eligible annual estimates of dietary protein intake, dietary potassium intake, and NEAP over the first 2 years of the study were averaged and then considered continuously as well as categorized in quartiles. One hundred four (30.3%) participants had three urines available for averaging, 127 (37.0%) participants had two urines available, and 112 (32.7%) participants had only one urine available. Characteristics of the study population at the 2-year study visit were compared across quartiles of the average estimated NEAP over the first 2 years of the study using linear regression (continuous variables) or Pearson's X2 (categorical variables).

The association between estimated NEAP and serum bicarbonate was evaluated in participants using all eligible annual measurements as distinct observations. Generalized linear-regression models were performed with clustering by subject, to account for correlated observations within individuals over time, and using a robust sandwich estimator of variance. These models were performed unadjusted and adjusted for age (continuous variable), gender, diabetes, eGFR (continuous variable), urine albumin/creatinine ratio (log transformed continuous variable), body mass index (BMI) (log transformed continuous variable), 24-hour urinary sodium (continuous variable), smoking (never/former/current), randomized treatment group in the trial phase, and current use of angiotensin-converting enzyme inhibitor/angiotensin receptor blockers and diuretics. Models stratified by early/moderate (stage 2/3) CKD versus advanced (stage 4/5) CKD were fit, and interactions were tested in fully adjusted models.

A sensitivity analysis was performed restricted to individuals least likely to violate the assumption of steady-state protein and potassium balance. The average rate of weight change per individual over follow-up was estimated using linear mixed models. Individuals who had a mass index BMI < 18 kg/m2 or who lost more than 5% body weight/year, on average, were excluded, as were individuals who had any measures of serum potassium less than 3.5 mEq/L or greater than 5.5 mEq/L. Two additional sensitivity analyses were performed: (1) in a larger study population, not excluding urines on the basis of the level of 24 hours creatinine excretion, and (2) including adjustment for continuous serum potassium.

We used two approaches to address day to day variation in our estimates of NEAP. First, we fit models using the average estimates of NEAP over the first 2 years in the study as described above. Average estimated NEAP was then tested for association with the serum bicarbonate value obtained at the 2-year (±6 months) study visit using linear regression. Given the possibility of measurement error because of day to day variability in diet, for which we could not account with averaging, we performed an additional sensitivity analysis in this population using errors in variables regression (23). These analyses simulate the measures of association that would be obtained if habitual NEAP could be precisely measured. Because data are limited on the reliability of our method of estimating dietary intake parameters, we performed these regressions across a range of theoretical reliabilities from 0.60 to 0.90.

All of the analyses were performed using STATA Special Edition 10.0 (College Station, TX). Hypotheses were tested using a two-sided type 1 error rate of 0.05. Linear-model assumptions were assessed using residual plots.

Results

Table 1 presents characteristics of the study population at the 2-year study visit (n = 343) stratified by quartiles of NEAP. Overall median age was 61 years (range, 27 to 76 years). Median eGFR was 41.3 ml/min per 1.73 m2 (interquartile range [IQR], 29.9 to 51.4 ml/min per 1.73 m2), and 5.3% of the population was diabetic. Median estimated NEAP in the study population was 71 mEq/d (IQR, 57 to 89 mEq/d). Median estimated protein intake was 65 g/d (IQR, 53 to 77 g/d), and median estimated potassium intake was 43 mEq/d (IQR, 35 to 58 mEq/d). Scaled to ideal body-weight median estimated protein intake was 1.02 g/kg per d (IQR, 0.86 to 1.19 g/kg per d), with 82.5% of the study population consuming more protein than recommended by current practice guidelines (i.e. > 0.8 g/kg per d) (24), and median estimated NEAP was 1.14 mEq/kg per d (IQR, 0.86 to 1.41 mEq/kg per d).

T1-5
Table 1:
Characteristics of the study population stratified by quartiles of net endogenous acid production (mEq/d)

In the full study population with measurements of serum bicarbonate and NEAP available at any time point (n = 462), the difference in serum bicarbonate by quartiles of NEAP compared with the lowest quartile was highly significant in unadjusted and adjusted models (Table 2). After adjustment for age, gender, diabetes, 24-hour urinary sodium, eGFR, albuminuria, mass index BMI, smoking, randomized group in trial phase, and current use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and diuretics, serum bicarbonate was 0.16 mEq/L lower for each 10 mEq/d higher NEAP (95% confidence interval [CI] −0.23 to −0.08; P < 0.001). By quartiles, the serum bicarbonate was 1.27 mEq/L lower (95% CI −1.79 to −0.74; P < 0.001) in the group with the highest quartile of NEAP compared with the lowest. The results were similar using the secondary modeling strategy, comparing average estimated NEAP over 2 years to the serum bicarbonate at the 2-year study visit (Table 2). The results were unchanged in a sensitivity analysis after adjustment for continuous serum potassium levels. In this analysis, serum bicarbonate was 0.16 mEq/L lower for each 10 mEq/d higher NEAP (95% CI −0.23 to −0.09; P < 0.001) and was 1.27 mEq/L lower (95% CI −1.79 to −0.75; P < 0.001) in the group with the highest quartile of NEAP compared with the lowest. In an additional analysis that did not exclude urine collections on the basis of the total 24-hour creatinine content, serum bicarbonate was 0.14 mEq/L lower for each 10 mEq/d higher NEAP (95% CI −0.20 to −0.09; P < 0.001) and was 1.29 mEq/L lower (95% CI −1.74 to −0.84; P < 0.001) among those in the highest quartile of NEAP compared with the lowest.

T2-5
Table 2:
Difference in serum bicarbonate (HCO3) in mEq/L by quartiles of estimated net endogenous acid production compared to the lowest quartile in unadjusted and adjusted models

Stratified by stage of CKD, higher quartiles of NEAP were associated with a larger difference in serum bicarbonate in participants with advanced CKD compared with those with early to moderate CKD (Figure 1; P-interaction = 0.02). The difference in serum bicarbonate between the highest and lowest quartiles of NEAP among patients with stage 4/5 CKD was −2.43 mEq/L (95% CI −3.32 to −1.54; P < 0.001) and among those with stage 2/3 disease was −0.77 mEq/L (95% CI −1.37 to −0.16; P = 0.01).

F1-5
Figure 1:
Adjusted difference in serum bicarbonate (mEq/L) by quartiles of estimated net endogenous acid production compared with the lowest quartile. The results are presented stratified by stage of chronic kidney disease. The models are adjusted for age, gender, diabetes, 24-hour urinary sodium, estimated GFR, albuminuria, body mass index, smoking, randomized treatment group in trial phase, and current use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and diuretics.

Supplemental Tables 1 and 2 present associations of estimated protein intake and estimated potassium intake with serum bicarbonate. There was no consistent association between quartiles of estimated protein intake and serum bicarbonate. Higher quartiles of estimated potassium intake were associated with higher serum-bicarbonate levels (P trend = 0.02).

In the sensitivity analysis among participants (n = 294) with stable weight and normal serum potassium values over follow-up, the results were qualitatively similar to those in the full study population (Figure 2). Of note, there was a marginal trend toward lower serum bicarbonate values among those in higher quartiles of estimated protein intake (P trend = 0.10), but this did not reach statistical significance. Higher quartiles of estimated potassium intake were associated with higher serum-bicarbonate levels, as expected (P trend = 0.01). Of these dietary estimates, higher quartiles of estimated NEAP were associated most strongly with serum-bicarbonate levels (P trend < 0.001).

F2-5
Figure 2:
Adjusted difference in serum bicarbonate (mEq/L) by quartiles of estimated net endogenous acid production (NEAP), estimated protein intake, and estimated potassium intake among those with stable weight and stable serum potassium (n = 294). Stable weight is defined as body mass index ≥18 kg/m2 and < 5% loss of body weight on average over follow-up. Stable potassium is defined as no values of serum potassium <3.5 or >5.5 over follow-up. The models are adjusted for age, gender, diabetes, 24-hour urinary sodium, estimated GFR, albuminuria, body mass index, smoking, randomized group in trial phase, and current use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and diuretics.

Because the 24-hour urinary biomarkers used to estimate NEAP represent short-term dietary intake, this measurement may be subject to day to day variability. To account for possible misclassification because of day to day variability in diet, we used errors in variable regression (23) to simulate the measures of association between estimated NEAP and serum bicarbonate that would be seen if habitual NEAP could be measured more precisely (Table 3). Estimated NEAP remained strongly associated with serum bicarbonate across a wide range of assumed reliabilities. In this simulation, we demonstrate a progressively larger difference in serum bicarbonate per 10 mEq/d higher NEAP with the assumption of less reliable estimation. Under the assumption of 60% reliability in the estimation of habitual NEAP, there is a near doubling of the magnitude of the association between higher NEAP and lower serum bicarbonate.

T3-5
Table 3:
Simulated difference in serum bicarbonate (HCO3) in mEq/L per 10 mEq/d higher net endogenous acid production (NEAP) using errors in variable regression across a range of reliabilities in net endogenous acid production estimation (n = 343)

Discussion

In this study we observed that NEAP, as estimated from urinary nitrogen and potassium excretion, is associated with serum bicarbonate among patients with CKD consuming their usual diets. Previous studies have demonstrated associations between the NEAP and serum bicarbonate among normal subjects consuming controlled diets (25–27). To our knowledge, this is the first study to address this association among participants consuming their usual diets. Our results suggest that dietary modifications that are achievable in clinical practice settings may mitigate metabolic acidosis in CKD. Additionally, we have built on previous work by extending these findings to patients with CKD and have found that the magnitude of the association between NEAP and serum bicarbonate is greater among participants with more advanced renal disease.

A post hoc analysis of the Modification of Diet in Renal Disease study has previously shown that lower dietary protein intake was associated with higher serum bicarbonate, presumably through reduction in the endogenous acid production (28). Our results are consistent with these findings, but additionally we found that the net endogenous acid production NEAP, which considers the balance of protein intake and alkali intake, was more strongly associated with serum bicarbonate than was protein intake alone. Current clinical recommendations in CKD focus heavily on protein restriction (24). Although our results do not contradict this recommendation, they suggest the need to more carefully consider the balance of protein and alkali when making dietary recommendations to patients with CKD.

We used validated recovery biomarkers in the urine to estimate the NEAP from the major dietary factors that contribute to the daily load of nonvolatile acid and to alkali buffers (21,29,30). Not surprisingly, the estimated intake of protein exceeded current clinical-practice recommendations for patients with CKD in a large fraction of participants (24). Additionally, potassium intake was low compared with intakes that are recommended to the general population on the basis of the DASH dietary pattern (about 100 to 120 mEq/d) (31). This resulted in a diet that was highly acidic with a median of approximately 71 mEq/d of nonvolatile acid. The ideal intake of potassium in patients with CKD has been poorly studied, and current clinical-practice recommendations are largely theoretical (24). Although our study does not evaluate the safety of increased potassium intake in CKD, it does provide a rationale to investigate whether increased intake of fruits and vegetables, which are rich in potassium, may improve acid base status in patients with CKD. It is important to note that this study was performed in participants with hypertensive kidney disease in whom the incidence of hyperkalemia has previously been shown to be low (32). Distal tubular function and potassium excretion may be more impaired among those with diabetic kidney disease, a subgroup that we cannot evaluate in this study.

The magnitude of the association between NEAP and serum bicarbonate in this study was relatively small. It is likely that the magnitude of the association is underestimated, because of a phenomenon termed “regression dilution bias” (33). It is also important to note from our results that the difference in serum bicarbonate between the lowest and highest quartile of NEAP was greater in patients with more severe kidney disease (i.e. CKD stages 4 and 5) compared with patients with less severe disease (i.e. CKD stage 2 and 3). This likely represents a decreased ability to compensate for acid load as renal function declines.

Even with the above caveats, the observed magnitude of the association in this study may have substantial implications for patients with CKD. A recent observational analysis using the AASK study population demonstrated a 7% decrease in risk of ESRD, halving of GFR, or absolute reduction of GFR of ≥25 ml/min per 1.73 m2 for each 1 mEq/L higher serum bicarbonate (9). Additionally, a randomized trial in patients with early stage kidney disease and relatively preserved serum bicarbonate demonstrated that sodium bicarbonate administration slowed the rate of kidney disease progression over 3 years without inducing any change in serum bicarbonate (34). The former suggests that it may not be the achieved serum bicarbonate, but the ability of the exogenous alkali supplement to lower the NEAP that slows progression of CKD.

This study also highlights opportunities to optimize diets on a population level. A number of recent studies have examined differences in the NEAP of a contemporary Western diet compared with diets of our preagricultural ancestors (13,35). These studies demonstrate that contemporary acid-inducing diets are a dramatic change from net alkali-inducing diets consumed during most of our evolutionary history. It is likely that renal physiology is poorly adapted to these dietary patterns contributing to chronic low-grade metabolic acidosis and potentially to high modern rates of osteoporosis and renal disease (11). The observed high-protein intake and low-potassium intake in our study population reveals an opportunity to intervene on a population level.

Our study has several strengths, including a well characterized study population and robust findings across several modeling strategies. This study also has limitations. We did not have direct measures of dietary intake available, and therefore we could not compare results using our urinary biomarkers with results obtained from dietary interviews. Previous validation studies have found that urinary nitrogen and urinary potassium correlate highly with gold-standard methods of dietary assessment, such as weighed dietary records, and correlate to a lower extent with measurements such as food frequency questionnaires and 24-h recalls, which are subject to reporting biases (29). However, without direct dietary measures, we could not distinguish plant-protein sources from animal-protein sources. Plant-protein sources may contribute less to the NEAP because of a lower sulfur content compared with animal sources (36). Previous data from the Third National Health and Nutrition Examination Survey demonstrates that African Americans eat a high proportion of protein from animal sources (37); therefore, we would not expect this to dramatically influence our results. Finally, this study is a cross-sectional, observational analysis, and we cannot exclude residual confounding because of unmeasured or poorly measured confounders or reverse causality.

Chronic metabolic acidosis in patients with CKD has many adverse effects, including bone loss (38), muscle wasting (39), and progressive kidney disease (10). We propose that manipulation of the NEAP, through protein restriction and increased intake of fruits and vegetables, may raise serum bicarbonate. In this way, dietary interventions that target the NEAP may mitigate morbidity in patients with CKD.

Disclosures

None.

Acknowledgments

We would like to acknowledge the time and commitment of the participants, investigators and staff of the AASK study, which was supported by grants to each clinical center and the coordinating center from the National Institute of Diabetes and Digestive and Kidney Diseases. In addition, AASK was supported by the Office of Research in Minority Health (now the National Center on Minority Health and Health Disparities) and the following institutional grants from the National Institutes of Health: M01 RR-00080, M01 RR-00071, M0100032, P20-RR11145, M01 RR00827, M01 RR00052, 2P20 RR11104, RR029887, and DK 2818-02. King Pharmaceuticals Pfizer Inc., AstraZeneca Pharmaceuticals, Glaxo SmithKline, Forest Laboratories, Pharmacia, and Upjohn donated antihypertensive medications. This work does not necessarily reflect the opinions of the AASK study or the National Institute of Diabetes and Digestive and Kidney Diseases. J.J.S. was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant T32 DK 00732-14 and Grant 5KL2RR025006 from the National Center for Research Resources, a component of the National Institutes of Health and NIH Roadmap for Medical Research, as well as the National Kidney Foundation of Maryland. R.S.P. is supported by Grant 5R01DK072367-03 from the National Institute of Diabetes, Digestive and Kidney Diseases. B.C.A. was supported in part by Grant R21DK078218 from the National Institute of Diabetes and Digestive and Kidney Diseases. C.A.M.A. was supported by Grant K01 HL092595-02 from the National Heart Lung and Blood Institute. This work was presented, in part, as a poster presentation at the American Society of Nephrology Renal Week in November 2010.

Published online ahead of print. Publication date available at www.cjasn.org.

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