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Net endogenous acid production is associated with a faster decline in GFR in African Americans

2012; Elsevier BV; Volume: 82; Issue: 1 Linguagem: Inglês

10.1038/ki.2012.82

ISSN

1523-1755

Autores

Julia J. Scialla, Lawrence J. Appel, Brad C. Astor, Edgar R. Miller, Srinivasan Beddhu, Mark Woodward, Rulan S. Parekh, Cheryl A.M. Anderson,

Tópico(s)

Sodium Intake and Health

Resumo

Increased acid excretion may promote renal injury. To evaluate this in African Americans with hypertensive nephrosclerosis, we studied the association between the net endogenous acid production and progression of kidney disease in 632 patients in the AASK trial. Protein and potassium intakes were estimated from 24h urea nitrogen and potassium excretion, and used to estimate net endogenous acid production, averaged over 2 years, approximating routine intake. The link between net endogenous acid production and the I125iothalamate glomerular filtration rate (iGFR) and time to end-stage renal disease or doubling of serum creatinine was analyzed using mixed models and Cox proportional hazards regressions. The trend in higher net endogenous acid production was significantly associated with a faster decline in iGFR over a median of 3.2 years. After adjustment for age, body mass index, baseline iGFR, urine protein-to-creatinine ratio, and randomized treatment group, the trend in higher net endogenous acid production remained significantly associated with a faster decline in iGFR at a rate of 1.01ml/min per 1.73m2 per year faster in the highest compared to the lowest quartile. However, in time-to-event analyses over a median of 7.7 years, the adjusted hazard ratio (1.10) for composite renal events per 25mEq/day higher net endogenous acid production was not significant. Hence, our findings implicate endogenous acid production as a potential modifiable risk factor for progressive kidney disease. Increased acid excretion may promote renal injury. To evaluate this in African Americans with hypertensive nephrosclerosis, we studied the association between the net endogenous acid production and progression of kidney disease in 632 patients in the AASK trial. Protein and potassium intakes were estimated from 24h urea nitrogen and potassium excretion, and used to estimate net endogenous acid production, averaged over 2 years, approximating routine intake. The link between net endogenous acid production and the I125iothalamate glomerular filtration rate (iGFR) and time to end-stage renal disease or doubling of serum creatinine was analyzed using mixed models and Cox proportional hazards regressions. The trend in higher net endogenous acid production was significantly associated with a faster decline in iGFR over a median of 3.2 years. After adjustment for age, body mass index, baseline iGFR, urine protein-to-creatinine ratio, and randomized treatment group, the trend in higher net endogenous acid production remained significantly associated with a faster decline in iGFR at a rate of 1.01ml/min per 1.73m2 per year faster in the highest compared to the lowest quartile. However, in time-to-event analyses over a median of 7.7 years, the adjusted hazard ratio (1.10) for composite renal events per 25mEq/day higher net endogenous acid production was not significant. Hence, our findings implicate endogenous acid production as a potential modifiable risk factor for progressive kidney disease. Chronic kidney disease (CKD) is a major public health problem affecting 13% of the US population.1.Coresh J. Selvin E. Stevens L.A. et al.Prevalence of chronic kidney disease in the United States.JAMA. 2007; 298: 2038-2047Crossref PubMed Scopus (3881) Google Scholar Increased risks of morbidity and mortality are evident even among those with only mild decreases in kidney function.2.van der Velde M. Matsushita K. Coresh J. et al.Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts.Kidney Int. 2011; 79: 1341-1352Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar Preventive strategies that are low cost, low risk, and scalable are needed to address the epidemic of kidney disease. Metabolic acidosis, a consequence of decreased renal acid excretion, is a modifiable risk factor for CKD progression.3.Raphael K.L. Wei G. Baird B.C. et al.Higher serum bicarbonate levels within the normal range are associated with better survival and renal outcomes in African Americans.Kidney Int. 2010; 79: 356-362Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 4.de Brito-Ashurst I. Varagunam M. Raftery M.J. et al.Bicarbonate supplementation slows progression of CKD and improves nutritional status.J Am Soc Nephrol. 2009; 20: 2075-2084Crossref PubMed Scopus (630) Google Scholar, 5.Shah S.N. Abramowitz M. Hostetter T.H. et al.Serum bicarbonate levels and the progression of kidney disease: a cohort study.Am J Kidney Dis. 2009; 54: 270-277Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar In CKD, overall acid excretion is impaired with increased per nephron acid excretion to compensate for nephron loss.6.Dorhout-Mees E.J. Machado M. Slatopolsky E. et al.The functional adaptation of the diseased kidney: III. Ammonium excretion.J Clin Invest. 1966; 45: 289-296Crossref PubMed Scopus (26) Google Scholar,7.Goodman A.D. Lemann Jr, J. Lennon E.J. et al.Production, excretion and net balance of fixed acid in patients with renal acidosis.J Clin Invest. 1965; 44: 495-506Crossref PubMed Scopus (137) Google Scholar In turn, increased acid excretion by the nephron may promote tubulointerstitial injury and contribute to disease progression.8.Nath K.A. Hostetter M.K. Hostetter T.H. Pathophysiology of chronic tubulo-interstitial disease in rats: interactions of dietary acid load, ammonia, and complement component-C3.J Clin Invest. 1985; 76: 667-675Crossref PubMed Scopus (415) Google Scholar,9.Phisitkul S. Hacker C. Simoni J. et al.Dietary protein causes a decline in the glomerular filtration rate of the remnant kidney mediated by metabolic acidosis and endothelin receptors.Kidney Int. 2008; 73: 192-199Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar Alkali supplements can lower acid excretion and slow disease progression.4.de Brito-Ashurst I. Varagunam M. Raftery M.J. et al.Bicarbonate supplementation slows progression of CKD and improves nutritional status.J Am Soc Nephrol. 2009; 20: 2075-2084Crossref PubMed Scopus (630) Google Scholar,10.Mahajan A. Simoni J. Sheather S.J. et al.Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy.Kidney Int. 2010; 78: 303-309Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar Manipulation of the net endogenous acid production through diet may be an additional strategy to decrease renal acid excretion that may be more amenable to wide implementation as a public health initiative. Net endogenous acid production is determined by the balance of fixed acid and alkali precursors in the diet. Fixed acid in the diet is derived largely from protein intake and alkali from organic anions such as citrate and acetate, which are naturally bound to cations, such as potassium.11.Frassetto L.A. Lanham-New S.A. Macdonald H.M. et al.Standardizing terminology for estimating the diet-dependent net acid load to the metabolic system.J Nutr. 2007; 137: 1491-1492PubMed Scopus (80) Google Scholar For this reason, net endogenous acid production can be estimated from the ratio of protein and potassium in the diet.12.Frassetto L.A. Todd K.M. Morris Jr, R.C. et al.Estimation of net endogenous noncarbonic acid production in humans from diet potassium and protein contents.Am J Clin Nutr. 1998; 68: 576-583PubMed Google Scholar, 13.Scialla J.J. Appel L.J. Astor B.C. et al.Estimated net endogenous acid production and serum bicarbonate in African Americans with chronic kidney disease.Clin J Am Soc Nephrol. 2011; 6: 1526-1532Crossref PubMed Scopus (58) Google Scholar, 14.Zhang L. Curhan G.C. Forman J.P. Diet-dependent net acid load and risk of incident hypertension in United States women.Hypertension. 2009; 54: 751-755Crossref PubMed Scopus (103) Google Scholar In this study, we estimate net endogenous acid production in this manner and evaluate its association with CKD progression in a cohort of African Americans with CKD. A total of 632 participants from the African American Study of Kidney Disease and Hypertension (AASK) trial and cohort study were included in this analysis. The reasons for exclusion are summarized in Figure 1. Median age was 55 years (range 22–70 years). Median I125iothalamate glomerular filtration rate (iGFR) was 48.6ml/min per 1.73m2 (interquartile range 36.6–58.5ml/min per 1.73m2). Median estimated net endogenous acid production was 72.8mEq/day (interquartile range 57.2–89.5mEq/day). Median estimated protein intake was 64.9g/day (interquartile range 53.1–76.3g/day) and median estimated potassium intake was 43.5mEq/day (interquartile range 33.8–55.9mEq/day). The baseline characteristics of the study population stratified by quartiles of net endogenous acid production are presented in Table 1. Higher net endogenous acid production was associated with current smoking, lower income, and lower serum bicarbonate. Differences in protein intake across categories of NEAP were smaller than differences in potassium intake.Table 1Baseline characteristics of the study population by quartiles of net endogenous acid production (NEAP)Characteristic: mean±s.d. or n (%)Quartiles of NEAP (mEq/day)P-valueaP-value is P-trend by univariate linear regression (continuous variables) or Pearson's χ2 (categorical variables).1 (18.2–57.1)2 (57.2–72.8)3 (72.9–89.5)4 (89.6–232.5)(n=158)(n=158)(n=158)(n=158)Age (years)55±1056±1054±1154±110.41Female sex (%)63 (39.9)56 (35.4)69 (43.7)51 (32.3)0.17History of heart disease (%)84 (53.2)75 (47.5)79 (50.0)87 (55.1)0.54Smoking (%)0.01 Never73 (46.2)63 (39.9)62 (39.2)66 (41.8) Former55 (34.8)55 (34.8)43 (27.2)35 (22.2) Current30 (19.0)40 (25.3)53 (33.5)57 (36.1)Total income (%)bColumn % do not total 100 because of missing data.0.01 <$15,00065 (41.1)66 (41.8)74 (46.8)84 (53.2) ≥$15,00068 (43.0)72 (45.6)50 (31.7)42 (26.6)Body mass index (kg/m2)30.3±6.430.3±6.229.3±5.529.5±6.40.10Body mass index (%)0.07 30kg/m266 (41.8)72 (45.6)61 (38.6)68 (43.0)Randomized to low BP goal (%)80 (50.6)86 (54.4)72 (45.6)69 (43.7)0.21Randomized drug (%)0.58 Ramipril57 (36.1)68 (43.0)64 (40.5)61 (38.6) Metoprolol65 (41.1)55 (34.8)68 (43.0)67 (42.4) Amlodipine36 (22.8)35 (22.2)26 (16.5)30 (19.0)Serum phosphorus (mg/dl)3.5±0.63.5±0.63.6±0.73.5±0.60.55Serum bicarbonate (mEq/l)25.7±2.925.7±2.825.0±2.924.6±3.3 5.0mEq/l7 (4.4)6 (3.8)9 (5.7)7 (4.4)0.88Urine protein/creatinine (%)bColumn % do not total 100 because of missing data.0.29 <0.22104 (65.8)118 (74.7)108 (68.4)116 (73.4) 0.22–0.9937 (23.4)27 (17.1)27 (17.1)29 (18.4) ≥1.0015 (9.4)13 (9.4)22 (13.9)12 (7.6)iGFR (ml/min per 1.73m2)46.5±13.448.1±13.746.4±13.948.1±13.10.52Estimated protein intake (g/day)cEstimated from 24h urine collections between 12 and 36 months after randomization in the African American Study of Kidney Disease and Hypertension (AASK) trial phase.64.6±19.164.6±16.466.3±16.668.4±20.40.04Estimated potassium intake (mEq/day)cEstimated from 24h urine collections between 12 and 36 months after randomization in the African American Study of Kidney Disease and Hypertension (AASK) trial phase.65.4±20.347.8±12.840.5±10.232.4±10.7 45ml/min per 1.73m2) versus more advanced CKD (iGFR ≤45ml/min per 1.73m2; P-interaction=0.69; Table 3). There was some evidence that the association between net endogenous acid production and iGFR slope may differ for those with proteinuria, defined as UPCR ≥0.22 versus not (UPCR <0.22). Among participants with UPCR <0.22, higher quartiles of net endogenous acid production were associated with a higher rate of decline in iGFR in a graded fashion (P-trend <0.01), but not among participants with UPCR ≥0.22 (P-trend=0.84). The interaction between quartiles of net endogenous acid production and UPCR was not statistically significant (P-interaction=0.19). Finally, the association between quartiles of net endogenous acid production and iGFR slope was present among a more restricted subgroup of participants with serum bicarbonate above current clinical practice targets (≥22mEq/l; n=564). In this subgroup, participants in the highest quartile of net endogenous acid production had an absolute difference in iGFR slope of -0.97ml/min per 1.73m2 per year (95% confidence interval -1.86 to -0.09; P=0.03) compared with the lowest quartile, with a trend across quartiles (P-trend=0.03).Table 3AdjustedaSlopes adjusted for randomized blood pressure and drug groups and categories of age and body mass index. Models stratified by baseline iGFR are also adjusted for categories of proteinuria and models stratified by UPCR are also adjusted for categories of baseline glomerular filtration rate. difference in I125iothalamate glomerular filtration rate (iGFR) slope (ml/min per 1.73m2 per year) compared with lowest quartile associated with quartiles of estimated net endogenous acid production (NEAP) stratified by urine protein-to-creatinine ratio (UPCR) and severity of kidney diseaseQuartilesDifference in iGFR slope (ml/min per 1.73m2 per year)UPCRBaseline iGFR 45ml/min per 1.73m2 (n=369)Difference from Q1 (95% CI)P-valueDifference from Q1 (95% CI)P-valueDifference from Q1 (95% CI)P-valueDifference from Q1 (95% CI)P-value1Ref—Ref—Ref—Ref—2−0.73 (−1.63, 0.18)0.120.09 (−1.46, 1.64)0.91−0.54 (−1.71, 0.63)0.36−0.67 (−1.69, 0.35)0.203−0.88 (−1.78, 0.03)0.06−0.30 (−1.78, 1.17)0.69−0.77 (−1.92, 0.39)0.19−0.83 (−1.86, 0.21)0.124−1.29 (−2.18, −0.40)<0.01−0.01 (−1.64, 1.62)0.99−1.68 (−2.89, −0.47)<0.01−0.69 (−1.70, 0.31)0.18P-trend<0.010.84 99%) because of missing covariate information in 6 participants.a Slopes adjusted for randomized blood pressure and drug groups and categories of age and body mass index. Models stratified by baseline iGFR are also adjusted for categories of proteinuria and models stratified by UPCR are also adjusted for categories of baseline glomerular filtration rate. Open table in a new tab Abbreviations: CI, confidence interval; Q1, quartile 1. Adjusted slope models include 626/632 participants (>99%) because of missing covariate information in 6 participants. There were 229 renal events (end-stage renal disease (ESRD) or doubling of serum creatinine from trial baseline) over long-term follow-up from 12 months after randomization through the trial and cohort phases. A total of 70 participants died before reaching the composite renal end point. Among those with UPCR <0.22, there were 101 renal events compared with 128 renal events among those with UPCR ≥0.22. The adjusted association between quartiles of net endogenous acid production and composite renal events is presented overall and stratified by categories of UPCR in Table 4. There was no statistically significant association between higher net endogenous acid production and composite renal events overall (P=0.17). Among those with UPCR <0.22, higher net endogenous acid production was associated with composite renal events (P=0.05), although the interaction was not statistically significant (P=0.32).Table 4AdjustedaAdjusted for age, sex, baseline glomerular filtration rate (GFR), proteinuria, body mass index, income, randomized blood pressure and drug assignment, and study phase. hazard ratios for composite end-stage renal disease (ESRD) or doubling of serum creatininebDeath is treated as a competing risk. associated with quartiles of net endogenous acid production (NEAP) and stratified by urine protein-to-creatinine ratio (UPCR)Quartiles of NEAPAdjusted HROverall (n=625)UPCR <0.22 (n=444)UPCR ≥0.22 (n=181)HR (95% CI)P-valueHR (95% CI)P-valueHR (95% CI)P-value11.0—1.0—1.0—20.95 (0.64, 1.41)0.811.02 (0.58, 1.79)0.950.77 (0.43, 1.37)0.3731.06 (0.73, 1.55)0.761.06 (0.61, 1.87)0.831.04 (0.62, 1.73)0.8941.22 (0.82, 1.83)0.331.38 (0.77, 2.48)0.281.26 (0.72, 2.18)0.42Continuous (per 25mEq/day)1.10 (0.96, 1.26)0.171.22 (1.00, 1.49)0.051.07 (0.90, 1.27)0.46Abbreviations: CI, confidence interval; HR, hazard ratio.Adjusted survival models include 625/632 participants (99%) because of missing covariate information in 7 participants.a Adjusted for age, sex, baseline glomerular filtration rate (GFR), proteinuria, body mass index, income, randomized blood pressure and drug assignment, and study phase.b Death is treated as a competing risk. Open table in a new tab Abbreviations: CI, confidence interval; HR, hazard ratio. Adjusted survival models include 625/632 participants (99%) because of missing covariate information in 7 participants. Analyses using estimates of net endogenous acid production obtained from all urine collections, without exclusion based on the total creatinine production, and using estimates obtained from urine collections averaged between trial baseline and 24 months after randomization, were unchanged from the primary analyses. Additionally, in time-to-event analyses, results were similar if death was included as a component of the composite end point in lieu of being treated as a competing risk. In this study of African Americans with hypertensive CKD, a dietary pattern resulting in higher net endogenous acid production was associated with a faster rate of CKD progression. To date, several observational and randomized studies have implicated low serum bicarbonate levels as a modifiable risk factor for CKD progression.3.Raphael K.L. Wei G. Baird B.C. et al.Higher serum bicarbonate levels within the normal range are associated with better survival and renal outcomes in African Americans.Kidney Int. 2010; 79: 356-362Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 4.de Brito-Ashurst I. Varagunam M. Raftery M.J. et al.Bicarbonate supplementation slows progression of CKD and improves nutritional status.J Am Soc Nephrol. 2009; 20: 2075-2084Crossref PubMed Scopus (630) Google Scholar, 5.Shah S.N. Abramowitz M. Hostetter T.H. et al.Serum bicarbonate levels and the progression of kidney disease: a cohort study.Am J Kidney Dis. 2009; 54: 270-277Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar Lowering net endogenous acid production of the diet may raise serum bicarbonate13.Scialla J.J. Appel L.J. Astor B.C. et al.Estimated net endogenous acid production and serum bicarbonate in African Americans with chronic kidney disease.Clin J Am Soc Nephrol. 2011; 6: 1526-1532Crossref PubMed Scopus (58) Google Scholar and may be an alternative strategy to target abnormal acid base homeostasis in CKD without large sodium loads. The association between net endogenous acid production and CKD progression was independent of serum bicarbonate and similar in a subset achieving target serum bicarbonate levels,15.Eknoyan G. Levin A. Levin N.W. Bone metabolism and disease in chronic kidney disease.Am J Kidney Dis. 2003; 42: 1-201Abstract Full Text Full Text PDF PubMed Google Scholar suggesting that the risk associated with net endogenous acid production may not be due to its effect on serum bicarbonate per se. We acknowledge that serum bicarbonate concentration can be prone to measurement error and it is possible that we were not able to fully account for the effect of serum bicarbonate in these models.3.Raphael K.L. Wei G. Baird B.C. et al.Higher serum bicarbonate levels within the normal range are associated with better survival and renal outcomes in African Americans.Kidney Int. 2010; 79: 356-362Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar However, several additional studies support mechanisms of renal injury due to acidic diets that are independent of serum bicarbonate concentration. Animal studies have shown that diets generating high net endogenous acid production may accelerate renal injury by increasing demand for renal ammonium excretion,8.Nath K.A. Hostetter M.K. Hostetter T.H. Pathophysiology of chronic tubulo-interstitial disease in rats: interactions of dietary acid load, ammonia, and complement component-C3.J Clin Invest. 1985; 76: 667-675Crossref PubMed Scopus (415) Google Scholar and by promoting intracellular acidosis, both of which develop before clinically overt metabolic acidosis.16.Wesson D.E. Simoni J. Increased tissue acid mediates a progressive decline in the glomerular filtration rate of animals with reduced nephron mass.Kidney Int. 2009; 75: 929-935Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar,17.Wesson D.E. Simoni J. Acid retention during kidney failure induces endothelin and aldosterone production which lead to progressive GFR decline, a situation ameliorated by alkali diet.Kidney Int. 2010; 78: 1128-1135Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar Other human studies have demonstrated that modulation of net endogenous acid production through administration of fixed acid or alkali alters the rate of GFR decline and profibrotic mediators in the urine such as endothelin and aldosterone without clinically relevant changes in serum bicarbonate.10.Mahajan A. Simoni J. Sheather S.J. et al.Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy.Kidney Int. 2010; 78: 303-309Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar,18.Wesson D.E. Simoni J. Broglio K. et al.Acid retention accompanies reduced GFR in humans and increases plasma levels of endothelin and aldosterone.Am J Physiol Renal Physiol. 2011; 300: F830-F837Crossref PubMed Scopus (164) Google Scholar In our analyses, we did not observe strong evidence that the association between net endogenous acid production and CKD progression varies by baseline CKD stage. In both the slope and time-to-event analyses, we did observe that the association between net endogenous acid production and CKD progression was stronger among those without proteinuria. We would interpret these findings cautiously given that the statistical test of interaction was not significant, and statistical significance within one subgroup could be related, in part, to a larger sample size. It is important to recognize, however, that these analyses were highly stratified and had limited power to test these interactions. Animal studies suggest that renal acid loading specifically promotes tubulointerstitial injury, a pattern characterized by less proteinuria.8.Nath K.A. Hostetter M.K. Hostetter T.H. Pathophysiology of chronic tubulo-interstitial disease in rats: interactions of dietary acid load, ammonia, and complement component-C3.J Clin Invest. 1985; 76: 667-675Crossref PubMed Scopus (415) Google Scholar,19.Phisitkul S. Khanna A. Simoni J. et al.Amelioration of metabolic acidosis in patients with low GFR reduced kidney endothelin production and kidney injury, and better preserved GFR.Kidney Int. 2010; 77: 617-623Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar Although the nonproteinuric group is at lower risk of ESRD, they remain at elevated risk for mortality associated in a graded fashion with decreased GFR.20.Astor B.C. Hallan S.I. Miller III, E.R. et al.Glomerular filtration rate, albuminuria, and risk of cardiovascular and all-cause mortality in the US population.Am J Epidemiol. 2008; 167: 1226-1234Crossref PubMed Scopus (272) Google Scholar Point estimates of the association between net endogenous acid production and time to ESRD or doubling of serum creatinine were consistent with the findings from slope analyses, but did not confirm these findings statistically. Our power in these models was limited and the confidence intervals did not exclude clinically important associations. Additionally, less than half of the events occurred in the large subpopulation of participants without proteinuria, the group in whom net endogenous acid production appeared to be a stronger risk factor in slope analyses. In this population, the net endogenous acid production was more strongly influenced by variability in potassium, rather than protein, intake. It is important to note that the net endogenous acid production considers the balance of protein and potassium intake in the diet and was more strongly associated with GFR decline than either protein or potassium intake alone. Current clinical guidelines recommend restricted protein intake in CKD.21.KDOQI KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease.Am J Kidney Dis. 2007; 49: S12-S154Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar Although our study does not refute these guidelines, it suggests that the balance of protein intake with natural sources of alkali, such as fruits and vegetables, may be more important. We were not able to definitively evaluate the safety of such diets in patients with CKD in this study, although the observed prevalence of hyperkalemia was low. This study has several limitations. The AASK study population was highly selected, including only African Americans with hypertensive kidney disease. For this reason, it is difficult to generalize these results to other racial groups with different dietary patterns or those with etiologies of kidney disease other than hypertension. We do not have direct measures of diet in this study. We are unable to account for dietary factors other than total protein and potassium intake that may affect endogenous acid production, including the differential impact of protein from plant versus animal sources and intake of additives in processed foods. This study also has several important strengths. We have multiple measures of the net endogenous acid production through frequent 24h urine collections, frequent measures of iGFR over long-term follow-up, and careful collection of patient characteristics, including detailed medication histories. Additionally, we also have event data over a long follow-up period across both the AASK trial and cohort phases, allowing consideration of both GFR slope and time-to-event analyses. In conclusion, we have observed that higher net endogenous acid production is associated with a faster rate of decline in GFR among African Americans with hypertensive kidney disease. This association may be stronger among patients without proteinuria. These results should be interpreted cautiously in light of results from time-to-event models that are consistent with, but do not confirm statistically, the findings seen in models of GFR slope. Our findings implicate net endogenous acid production as a potentially modifiable risk factor for progressive kidney disease worthy of further study. The AASK trial was a multicenter, 2 × 3 factorial, randomized, controlled trial of intensive vs. standard blood pressure control, using one of three primary antihypertensive agents (ramipril, metoprolol, or amlodipine), in self-identified African Americans with hypertensive nephrosclerosis.22.Agodoa L.Y. Appel L. Bakris G.L. et al.Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial.JAMA. 2001; 285: 2719-2728Crossref PubMed Scopus (858) Google Scholar Participants without ESRD at the end of the trial were offered enrollment in an observational cohort phase.23.Appel L.J. Middleton J. Miller III, E.R. et al.The rationale and design of the AASK cohort study.J Am Soc Nephrol. 2003; 14: S166-S172Crossref PubMed Google Scholar,24.Sika M. Lewis J. Douglas J. et al.Baseline characteristics of participants in the African American Study of Kidney Disease and Hypertension (AASK) Clinical Trial and Cohort Study.Am J Kidney Dis. 2007; 50 (.e71): 78-89Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar This analysis includes 632 participants from AASK with eligible urine collections between 12 and 36 months in the trial. Urine collections were eligible if the 24h total creatinine excretion was within 30% of the expected (22.1mg/kg in men and 17.2mg/kg in women), indicating a complete collection,25.Pak C.Y. Odvina C.V. Pearle M.S. et al.Effect of dietary modification on urinary stone risk factors.Kidney Int. 2005; 68: 2264-2273Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar and excluded if the participant was taking potassium or alkali supplements. The protocol and procedures were approved by the institutional review board of each center and all participants provided written informed consent. The 24h urine collections were performed every 6 months throughout the trial and annually in the cohort. Urine samples were analyzed at a central laboratory for urea nitrogen, potassium, sodium and creatinine. Ideal body weight (IBW) was calculated using previously published equations.26.Robinson J. Lupkiewicz S. Palenik L. et al.Determination of ideal body weight for drug dosage calculations.Am J Hosp Pharm. 1983; 40: 1016-1019PubMed Google Scholar Dietary protein intake was estimated from 24h urine urea nitrogen (UUN) excretion using the Maroni equation (protein intake=6.25 × (UUN+0.031 × IBW)–urinary protein (g/day) if daily urine protein excretion ≥5g).27.Maroni B.J. Steinman T.I. Mitch W.E. A method for estimating nitrogen intake of patients with chronic renal failure.Kidney Int. 1985; 27: 58-65Abstract Full Text PDF PubMed Scopus (656) Google Scholar Dietary potassium intake was estimated as the total 24h urine potassium excretion.28.Bingham S.A. Gill C. Welch A. et al.Validation of dietary assessment methods in the UK arm of EPIC using weighed records, and 24-h urinary nitrogen and potassium and serum vitamin C and carotenoids as biomarkers.Int J Epidemiol. 1997; 26: S137Crossref PubMed Google Scholar Net endogenous acid production was estimated from these intakes as previously described: net endogenous acid production (mEq/day)=-10.2+54.5 (protein intake (g/day) ÷ potassium intake (mEq/day)).12.Frassetto L.A. Todd K.M. Morris Jr, R.C. et al.Estimation of net endogenous noncarbonic acid production in humans from diet potassium and protein contents.Am J Clin Nutr. 1998; 68: 576-583PubMed Google Scholar Estimates derived from urine samples collected between 12 and 36 months after randomization were averaged to provide a measure of habitual dietary intake. Urine samples from the initial 12 months were not used because of frequent medication titrations during this time that may have altered steady-state potassium excretion. In all, 310 participants (49%) had 3 to 6 measurements available, 137 participants (22%) had 2 measurements, and 185 participants (29%) had 1 measurement. Intake was also estimated from eligible urine samples in the cohort phase and averaged over the first 24 months for use in time-dependent Cox models. I125iothalamate GFR was collected twice at baseline, and at 3, 6, and every 6 months thereafter during the AASK trial phase. Serum creatinine was used to estimate glomerular filtration rate using a study-specific equation in the cohort phase.23.Appel L.J. Middleton J. Miller III, E.R. et al.The rationale and design of the AASK cohort study.J Am Soc Nephrol. 2003; 14: S166-S172Crossref PubMed Google Scholar,29.Lewis J. Agodoa L. Cheek D. et al.Comparison of cross-sectional renal function measurements in African Americans with hypertensive nephrosclerosis and of primary formulas to estimate glomerular filtration rate.Am J Kidney Dis. 2001; 38: 744-753Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar UPCR was evaluated in spot urine samples at trial and cohort baseline. Renal events occurring over combined follow-up in the trial and cohort phases were defined as ESRD (initiation of dialysis or renal transplantation) or doubling of serum creatinine from trial baseline. Baseline characteristics of the study population were examined across quartiles of net endogenous acid production using linear regression (continuous variables) or Pearson's χ2 (categorical variables). Values from trial baseline were used for these analyses, except for serum phosphorus and bicarbonate, for which values from 12 months after randomization were used. UPCR and iGFR from trial baseline were selected given differential effects of the randomized drugs on proteinuria and acute effects on iGFR. The association between net endogenous acid production and the rate of change of iGFR from 12 months after randomization to the end of the trial was evaluated using linear mixed models with maximum likelihood estimation (median follow-up 3.2 years). Covariates hypothesized to contribute to CKD progression were included in adjusted models if they were associated with iGFR slope in univariate analyses (P<0.10) or significantly improved adjusted model fit. Models were adjusted for age (in quartiles), randomized group, body mass index (categorized as 30kg/m2), baseline iGFR (categorized as >60, 46–60, 31–45, and ≤30ml/min per 1.73m2) and proteinuria (categorized as baseline UPCR 45 vs. ≤45ml/min per 1.73m2), proteinuria (UPCR <0.22 vs. ≥0.22), and serum bicarbonate (<22 or ≥22mEq/l). The cut-point for proteinuria was prespecified and has been used as a standard threshold for all AASK analyses.31.Appel L.J. Wright J.T. Greene T. et al.Intensive blood-pressure control in hypertensive chronic kidney disease.N Engl J Med. 2010; 363: 918-929Crossref PubMed Scopus (437) Google Scholar,32.Appel L.J. Wright Jr, J.T. Greene T. et al.Long-term effects of renin-angiotensin system-blocking therapy and a low blood pressure goal on progression of hypertensive chronic kidney disease in African Americans.Arch Intern Med. 2008; 168: 832-839Crossref PubMed Scopus (137) Google Scholar Cut-points for GFR and serum bicarbonate are clinically relevant cut-points, consistent with prior literature and current practice guidelines.15.Eknoyan G. Levin A. Levin N.W. Bone metabolism and disease in chronic kidney disease.Am J Kidney Dis. 2003; 42: 1-201Abstract Full Text Full Text PDF PubMed Google Scholar Interactions were tested between net endogenous acid production and both baseline GFR and proteinuria using interaction terms in adjusted models. Sensitivity analyses were performed using estimates of net endogenous acid production obtained from all urine samples without exclusion based on the total creatinine, and using urine samples collections from trial baseline to 24 months after randomization instead of 12 to 36 months. All analyses were performed using STATA Special Edition 11.0 (College Station, TX, 2009). Hypotheses were tested using a two-sided type 1 error rate of 0.05. We acknowledge the time and commitment of the participants, investigators, and staff of the AASK study. AASK was supported by grants to each clinical center and the coordinating center from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). In addition, AASK was supported by the Office of Research in Minority Health (now the National Center on Minority Health and Health Disparities, NCMHD) 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, AstraZeneca Pharmaceuticals, Glaxo Smith Kline, Forest Laboratories, Pharmacia, and Upjohn donated antihypertensive medications. This work does not necessarily reflect the opinions of the AASK study or the NIDDK. JJS was supported by National Institute of Diabetes and Digestive and Kidney Diseases grant T32 DK 00732-14 and 5KL2RR025006 from the National Center for Research Resources, a component of the NIH and NIH Roadmap for Medical Research, as well as the National Kidney Foundation of Maryland. RSP is supported by grant 5R01DK072367-03 from the National Institute of Diabetes, Digestive and Kidney Diseases. BCA was supported in part by grant R21DK078218 from the National Institute of Diabetes and Digestive and Kidney Diseases. CAMA was supported by K01 HL092595-02 from the National Heart Lung and Blood Institute.

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