Urinary Net Acid Excretion Research Articles

Urinary acid-base excretion deciphers high acid load from colonic bicarbonate loss in intestinal failure patients with ileocolonic anastomosis – Guidance for composition of parenteral support

Background & AimsAcid-base disturbances are common in short bowel (SB) patients due to increased intestinal bicarbonate loss. However, the resulting systemic acid load has not been quantified. Base excess is used to monitor metabolic acid-base disturbances but inadequately reflects the acid load. Our aim was to investigate the systemic acid/base load in SB-patients to obtain quantitative estimates to guide the composition of parenteral support. MethodsWe calculated total acid load in SB patients by summing 24-hour urinary net acid excretion (NAE) and the provision of base equivalents in parenteral support. We then compared differences among anatomical SB-types: jejunostomy (SB-J), jejunocolostomy (SB-JC), and jejunoileostomy (SB-JIC). 47 urine samples from 34 SB patients were analyzed for bicarbonate (HCO3-), ammonium (NH4+), and titratable acidity (TA) concentrations. NAE was calculated as (TA + NH4+) - HCO3-. Mixed-effects repeated-measures models were used to statistically examine differences between SB-types and associations with parenteral nutrition and NAE. A healthy cohort served as control. ResultsIn comparison to SB-J, SB-JC patients had a 4.1 mmol/l lower base excess (95% CI: -6.3 to -1.8) and an 84.5 mmol/day higher total acid load (CI: 41.3 to 127.7). There were no significant differences between SB-JIC and SB-J regarding base excess, NAE, or total acid load. Higher amounts of infused acetate, sodium, and chloride, but not the acetate/chloride ratio, were associated with lower NAE and higher base excess. ConclusionsDue to increased colonic bicarbonate loss, patients with SB-JC have a ∼4.4-fold higher acid load than healthy controls. The ion transport mechanisms mediating this bicarbonate loss from the remaining colon need further experimental investigation. NAE could be a useful tool to adjust base infusion in SB.

The New Nordic Renal Diet Induces a Pronounced Reduction of Urine Acid Excretion and Uremic Toxins in Chronic Kidney Disease Patients (Stage 3 and 4)

Metabolic acidosis and the uremic toxins, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), are associated with increased risks of kidney disease progression, muscle catabolism, cardiovascular disease, and mortality in patients with chronic kidney disease (CKD). The New Nordic Renal Diet (NNRD) is a plant-focused meal pattern, with reduced phosphorus and protein content compared to an average Danish diet. Due to a higher amount of plant-based products, we hypothesized that NNRD would reduce renal excretion of acids and uremic toxins. Thus, we evaluated the effects of NNRD on metabolic acidosis and uremic toxins in patients with moderate CKD, stages 3-4. This post hoc analysis is based on a randomized controlled crossover trial comparing 1 week of the NNRD to a control 1-week period of an average Danish diet, in patients with CKD stages 3 and 4. Urine pH and urine excretion of bicarbonate, ammonium, titratable acids, IS, and PCS alongside plasma total CO2 (tCO2) were measured at days 1, 4, and 7 in 18 patients. After 7days on NNRD 24-hour urine net acid excretion was decreased by 80% (P<.001), 24-hour urine excretion of ammonium and bicarbonate decreased by 34% (P<.001), and increased by 678% (P<.001), respectively, compared with the control period. Plasma tCO2 was increased by 8% (P=.005). Moreover, 24-hour urine excretion of PCS and IS were reduced by 31% (P=.018) and 29% (P<.001), respectively. One week of NNRD in patients suffering from moderate CKD effectively improved metabolic acidosis with a marked reduction in urine net acid excretion that included a large increase in urine bicarbonate excretion. In addition, NNRD reduced urinary excretion of the uremic toxins PCS and IS. These results encourage further investigations of the long-term effects of NNRD on renal protection in patients with CKD.

A Randomized Study on the Effect of Dried Fruit on Acid-Base Balance, Diet Quality, and Markers of Musculoskeletal Health in Community Dwelling Adults

Objectives We tested whether 100 g/day of dried fruit (vs. no supplemental fruit control) for 6 months alters 24-hr urinary net acid excretion (NAE), bone resorption, weight, body composition, muscle performance, and diet quality. We explored consistency of self-selected dietary composition and potential renal acid load (PRAL). Methods This randomized, single-blind, 2-armed study included 83 normal- and over-weight men and postmenopausal women (age ≥50 years) on self-reported low fruit diets. Endpoints included group differences in NAE (primary), 24-hr urinary N-telopeptide (NTX), weight, body composition, muscle performance, and diet quality. Results At baseline, mean (±SD) age was 69 ± 8 years; 86% were Caucasian; body mass index was 24.5 ± 2.8 kg/m2; 46% female, and NAE was 32.4 ± 23.1 mmol with no significant baseline group differences. No significant group differences were noted in NAE (primary), NTX, weight, body composition, muscle performance or diet quality at 6 months. In the cohort as a whole, 6-month change in NAE was positively associated with change in NTX, but no significant associations were noted in other outcomes. PRAL on the day of the urine collection was positively associated with NAE. Comparison of two consecutive baseline 24-hr diet recalls revealed wide intra-individual variability in PRAL in self-selected diets in our participants. Conclusion In this field study of older adults consuming self-selected diets, making one change to the diet by adding 100 g/day of dried fruit (equivalent to 4 servings per day) had no significant impact on NAE when compared to a no supplemental fruit control. This null finding may be attributable to the high day-to-day variability in consumption of foods affecting NAE. Added fruit also had no significant effect on weight, fat, muscle, or bone outcomes over a 6-month period.

Drinking Natural Mineral Water Maintains Bone Health in Young Rats With Metabolic Acidosis

IntroductionMetabolic acidosis affects bone health. It remains unclear whether drinking natural mineral water is better for maintaining bone health in the youth with metabolic acidosis.Materials and MethodsSixty young female rats (3-weeks-old) were randomly divided into three groups and drank purified water (PW, as control), bicarbonate-rich natural mineral water (Bic-NMW), or sulfate-rich natural mineral water (Sul-NMW), which, respectively, contained calcium (0.17, 155, and 175 mg/L), bicarbonate (0.1360, and 139 mg/L) and sulfate (0, 35.6, and 532 mg/L), for 16 weeks. In the last 3 weeks, metabolic acidosis was induced in 10 rats per group by adding NH4Cl (0.28 mM) to drinking water. The rats' blood, urine, and femur were collected for assessing acid-base status, calcium metabolism, bone microstructure, and strength. The difference between the three groups was determined using one-way ANOVA followed by the Student–Newman–Keuls test or Dunnett's T3 test.ResultsCompared with the PW rats, the Bic-NMW rats and the Sul-NMW rats had less urine net acid excretion (−1.51, 0.20 vs. 10.77, EQ/L), higher bone mineral density (442.50, 407.49 vs. 373.28, mg/mm3), growth cartilage width (271.83, 283.83 vs. 233.27, μm) and cortical trabecular area (9.33, 9.55 vs. 5.05, mm2), and smaller cortical marrow cavity area (5.40, 5.49 vs. 7.27, mm2) in the femur (P < 0.05). Besides, the Bic-NMW rats had less serum calcium (2.53 vs. 2.68, mmol/L) and C-terminal cross-linked telopeptide of type-I collagen (1.35 vs. 1.93, ng/mL), and higher serum calcitonin (0.61 vs. 0.39, μg/L), femoral trabecular thickness (0.10 vs. 0.09, μm), bone volume/total volume (0.42 vs. 0.34, %), cortical bone area (15.91 vs. 12.80, mm2), and ultimate stress (35.12 vs. 29.32, MPa) (P < 0.05). The Sul-NMW rats had more osteoclasts (22.50 vs. 11.54, cells/field) (P < 0.05).ConclusionsDrinking natural mineral water, especially bicarbonate-rich natural mineral water, is effective in improving bone health in young rats with metabolic acidosis. These benefits include maintaining bone mineral density, and improving bone microstructure and biomechanical properties via moderating metabolic acidosis.

Effect of Bicarbonate on Net Acid Excretion, Blood Pressure, and Metabolism in Patients With and Without CKD: The Acid Base Compensation in CKD Study

Patients with CKD are at elevated risk of metabolic acidosis due to impaired net acid excretion (NAE). Identifying early markers of acidosis may guide prevention in chronic kidney disease (CKD). This study compared NAE in participants with and without CKD, as well as the NAE, blood pressure (BP), and metabolomic response to bicarbonate supplementation. Randomized order, cross-over study with controlled feeding. Participants consisted of 8 patients with CKD (estimated glomerular filtration rate 30-59mL/min/1.73m2 or 60-70mL/min/1.73m2 with albuminuria) and 6 patients without CKD. All participants had baseline serum bicarbonate concentrations between 20 and 28 mEq/L; they did not have diabetes mellitus and did not use alkali supplements at baseline. Participants were fed a fixed-acid-load diet with bicarbonate supplementation (7 days) and with sodium chloride control (7 days) in a randomized order, cross-over fashion. Urine NAE, 24-hour ambulatory BP, and 24-hour urine and plasma metabolomic profiles were measured after each period. During the control period, mean NAE was 28.3±10.2 mEq/d overall without differences across groups (P=0.5). Urine pH, ammonium, and citrate were significantly lower in CKD than in non-CKD (P<0.05 for each). Bicarbonate supplementation reduced NAE and urine ammonium in the CKD group, increased urine pH in both groups (but more in patients with CKD than in those without), and increased; urine citrate in the CKD group (P< 0.2 for interaction for each). Metabolomic analysis revealed several urine organic anions were increased with bicarbonate in CKD, including 3-indoleacetate, citrate/isocitrate, and glutarate. BP was not significantly changed. Small sample size and short feeding duration. Compared to patients without CKD, those with CKD had lower acid excretion in the form of ammonium but also lower base excretion such as citrate and other organic anions, a potential compensation to preserve acid-base homeostasis. In CKD, acid excretion decreased further, but base excretion (eg, citrate) increased in response to alkali. Urine citrate should be evaluated as an early and responsive marker of impaired acid-base homeostasis. National Institute of Diabetes and Digestive and Kidney Diseases and the Duke O'Brien Center for Kidney Research. Registered atClinicalTrials.gov with study number NCT02427594.

NBCn1 Increases NH4 + Reabsorption Across Thick Ascending Limbs, the Capacity for Urinary NH4 + Excretion, and Early Recovery from Metabolic Acidosis.

The electroneutral Na+/HCO3 - cotransporter NBCn1 (Slc4a7) is expressed in basolateral membranes of renal medullary thick ascending limbs (mTALs). However, direct evidence that NBCn1 contributes to acid-base handling in mTALs, urinary net acid excretion, and systemic acid-base homeostasis has been lacking. Metabolic acidosis was induced in wild-type and NBCn1 knockout mice. Fluorescence-based intracellular pH recordings were performed and NH4 + transport measured in isolated perfused mTALs. Quantitative RT-PCR and immunoblotting were used to evaluate NBCn1 expression. Tissue [NH4 +] was measured in renal biopsies, NH4 + excretion and titratable acid quantified in spot urine, and arterial blood gasses evaluated in normoventilated mice. Basolateral Na+/HCO3 - cotransport activity was similar in isolated perfused mTALs from wild-type and NBCn1 knockout mice under control conditions. During metabolic acidosis, basolateral Na+/HCO3 - cotransport activity increased four-fold in mTALs from wild-type mice, but remained unchanged in mTALs from NBCn1 knockout mice. Correspondingly, NBCn1 protein expression in wild-type mice increased ten-fold in the inner stripe of renal outer medulla during metabolic acidosis. During systemic acid loading, knockout of NBCn1 inhibited the net NH4 + reabsorption across mTALs by approximately 60%, abolished the renal corticomedullary NH4 + gradient, reduced the capacity for urinary NH4 + excretion by approximately 50%, and delayed recovery of arterial blood pH and standard [HCO3 -] from their initial decline. During metabolic acidosis, NBCn1 is required for the upregulated basolateral HCO3 - uptake and transepithelial NH4 + reabsorption in mTALs, renal medullary NH4 + accumulation, urinary NH4 + excretion, and early recovery of arterial blood pH and standard [HCO3 -]. These findings support that NBCn1 facilitates urinary net acid excretion by neutralizing intracellular H+ released during NH4 + reabsorption across mTALs.

Impaired renal HCO3- secretion in CFTR deficient mice causes metabolic alkalosis during chronic base-loading.

Cystic fibrosis patients have an increased risk of developing metabolic alkalosis presumably as a result of altered renal HCO3- handling. In this study, we directly assess the kidneys' ability to compensate for a chronic base-load in the absence of functional CFTR. Comprehensive urine and blood acid-base analyses were done in anaesthetized WT mice or mice lacking either CFTR or pendrin, with or without 7days of oral NaHCO3 loading. The in vivo experiments were complemented by a combination of immunoblotting and experiments with perfused isolated mouse cortical collecting ducts (CCD). Base-loaded WT mice maintained acid-base homeostasis by elevating urinary pH and HCO3- excretion and decreasing urinary net acid excretion. In contrast, pendrin KO mice and CFTR KO mice were unable to increase urinary pH and HCO3- excretion and unable to decrease urinary net acid excretion sufficiently and thus developed metabolic alkalosis in response to the same base-load. The expression of pendrin was increased in response to the base-load in WT mice with a paralleled increased pendrin function in the perfused CCD. In CFTR KO mice, 7days of base-loading did not upregulate pendrin expression and apical Cl- /HCO3- exchange function was strongly blunted in the CCD. CFTR KO mice develop metabolic alkalosis during a chronic base-load because they are unable to sufficiently elevate renal HCO3- excretion. This can be explained by markedly reduced pendrin function in the absence of CFTR.

Predictors of Net Acid Excretion in the Chronic Renal Insufficiency Cohort (CRIC) Study

Higher urine net acid excretion (NAE) is associated with slower chronic kidney disease progression, particularly in patients with diabetes mellitus. To better understand potential mechanisms and assess modifiable components, we explored independent predictors of NAE in the CRIC (Chronic Renal Insufficiency Cohort) Study. Cross-sectional. A randomly selected subcohort of adults with chronic kidney disease enrolled in the CRIC Study with NAE measurements. A comprehensive set of variables across prespecified domains including demographics, comorbid conditions, medications, laboratory values, diet, physical activity, and body composition. 24-hour urine NAE. NAE was defined as the sum of urine ammonium and calculated titratable acidity in a subset of CRIC participants. 22 individuals were excluded for urine pH< 4 (n= 1) or≥7.4 (n= 19) or extreme outliers of NAE values (n= 2). From an analytic sample of 978, we identified the association of individual variables with NAE in the selected domains using linear regression. We estimated the percent variance explained by each domain using the adjusted R2 from a domain-specific model. Mean NAE was 33.2 ± 17.4 (SD) mEq/d. Multiple variables were associated with NAE in models adjusted for age, sex, estimated glomerular filtration rate (eGFR), race/ethnicity, and body surface area, including insulin resistance, dietary potential renal acid load, and a variety of metabolically active medications (eg, metformin, allopurinol, and nonstatin lipid agents). Body size, as indicated by body surface area, body mass index, or fat-free mass; race/ethnicity; and eGFR also were independently associated with NAE. Bydomains, more variance was explained bydemographics, body composition, and laboratory values, which included eGFR and serum bicarbonate level. Cross-sectional; use of stored biological samples. NAE relates to several clinical domains including body composition, kidney function, and diet, but also to metabolic factors such as insulin resistance and the use of metabolically active medications.

Net Acid Excretion and Urinary Organic Anions in Idiopathic Uric Acid Nephrolithiasis.

Idiopathic uric acid nephrolithiasis, which is closely associated with obesity and the metabolic syndrome, is increasing in prevalence. Unduly acidic urine pH, the quintessential pathophysiologic feature of this disease, is in part explained by inadequate excretion of the principal urinary buffer ammonium. The role of net acid excretion in the pathogenesis of uric acid nephrolithiasis is incompletely understood. We compared acid-base parameters of patients with idiopathic uric acid nephrolithiasis with matched control subjects under controlled diets in an inpatient metabolic unit. Measurements included fasting blood and 24-hour urine chemistries and 24-hour urine metabolomic analysis. Comparisons between groups included analysis of covariance models controlling for urine pH or body mass index. Subjects with idiopathic uric acid nephrolithiasis had lower urine pH (5.5 versus 5.9; P<0.001) and higher net acid excretion (60 versus 43 mEq/24 h; P<0.001), with the excess H+ carried by nonammonium buffers. In all subjects, there was a positive relationship of net acid excretion with higher body mass index in spite of strictly controlled equivalent dietary acid intake. This relationship was most evident among control subjects (r=0.36; P=0.03). It was attenuated in patients with idiopathic uric acid nephrolithiasis whose net acid excretion remained fixedly high and ammonium excretion remained low relative to net acid excretion, resulting in low urine pH over a wide body mass index range. Urinary metabolomics was performed to attempt to identify excess organic acids presented to the kidney in idiopathic uric acid nephrolithiasis. Among the tricarboxylic acid cycle intermediates and amino acid and lipid metabolites analyzed, 26 organic anions with acid dissociation constants values in the range of urine pH showed greater protonation. However, protons carried by the identified organic acids did not entirely account for the higher titratable acidity seen in idiopathic uric acid nephrolithiasis. Higher acid load to the kidney, resulting in higher urinary net acid excretion, is an important factor in the pathogenesis of idiopathic uric acid nephrolithiasis.

Pilot Study Examining the Influence of Potassium Bicarbonate Supplementation on Nitrogen Balance and Whole-Body Ammonia and Urea Turnover Following Short-Term Energy Restriction in Older Men.

With aging there is a chronic low-grade metabolic-acidosis that may exacerbate negative protein balance during weight loss. The objective of this randomized pilot study was to assess the impact of 90 mmol∙day−1 potassium bicarbonate (KHCO3) versus a placebo (PLA) on 24-h urinary net acid excretion (NAE), nitrogen balance (NBAL), and whole-body ammonia and urea turnover following short-term diet-induced weight loss. Sixteen (KHCO3; n = 8, PLA; n = 8) older (64 ± 4 years) overweight (BMI: 28.5 ± 2.1 kg∙day−1) men completed a 35-day controlled feeding study, with a 7-day weight-maintenance phase followed by a 28-day 30% energy-restriction phase. KHCO3 or PLA supplementation began during energy restriction. NAE, NBAL, and whole-body ammonia and urea turnover (15N-glycine) were measured at the end of the weight-maintenance and energy-restriction phases. Following energy restriction, NAE was −9.8 ± 27.8 mmol∙day−1 in KHCO3 and 43.9 ± 27.8 mmol∙day−1 in PLA (p < 0.05). No significant group or time differences were observed in NBAL or ammonia and urea turnover. Ammonia synthesis and breakdown tended (p = 0.09) to be higher in KHCO3 vs. PLA following energy restriction, and NAE was inversely associated (r = −0.522; p < 0.05) with urea synthesis in all subjects. This pilot study suggests some benefit may exist with KHCO3 supplementation following energy restriction as lower NAE indicated higher urea synthesis.

Association of Urinary Citrate With Acid-Base Status, Bone Resorption, and Calcium Excretion in Older Men and Women

Elevated urine net acid excretion (NAE), indicative of subclinical metabolic acidosis, has been associated with higher bone turnover. Urine citrate, which is a common clinical measure, changes in response to acid-base status but its association with bone turnover is uncertain. We evaluated the association between change in urine citrate and change in bone turnover and calcium excretion. A total of 233 healthy men and women ≥60 years old were randomly assigned to 1.0 mmol/kg/d potassium bicarbonate (KHCO3), 1.5 mmol/kg/d KHCO3, or placebo for 84 days. Urine citrate, NAE, N-telopeptide of collagen type-I (NTX), calcium excretion, and serum amino-terminal propeptide of type 1 procollagen (P1NP) were measured before and after intervention. Urine citrate increased dose dependently after KHCO3 supplementation (P trend < 0.001). The urine citrate change was significantly inversely associated with P1NP change (P = 0.021) but not with change in NTX (P = 0.051) or calcium excretion (P = 0.652). The NAE change was positively associated with change in NTX and calcium excretion (P ≤ 0.003) but not with change in P1NP (P = 0.051). When the urine citrate change and NAE change were included in the same model, the urine citrate change was not associated with change in NTX, calcium excretion, or serum P1NP (P ≥ 0.086), whereas change in NAE remained associated with change in NTX and calcium excretion (P ≤ 0.003). Urine citrate may not be a suitable alternative to NAE when assessing acid-base status in relation to bone turnover in older adults.

Effects of Potassium Bicarbonate Supplements on Circulating microRNA Expression.

Several studies suggest that neutralizing acid load in the diet with alkali had favorable effects on intermediate markers of musculoskeletal health. We examined whether alkali supplementation with potassium bicarbonate [(KHCO3); 81 mmol/d; n = 12] vs placebo (n = 12) for 84 days altered serum microRNAs, potential biomarkers associated with innumerable biological processes including bone and muscle metabolism. Serum microRNAs, urinary net acid excretion (UNAE), urinary N-telopeptide (UNTX), urinary calcium (UCa), urinary nitrogen (UN), glomerular filtration rate, serum procollagen type 1 amino-terminal propeptide (P1NP), serum insulin-like growth factor-1 (IGF-1), and its serum binding protein IGFBP3 were measured at baseline and day 84. Baseline characteristics and measurements were similar in the two treatment groups. Eighty-four–day changes in UNAE differed by group (KHCO3, −47 ± 9 mmol; placebo, −5 ± 5 mmol; P < 0.01). KHCO3 significantly reduced UNTX, UCa, and serum P1NP but did not affect UN, serum IGF-1, or IGFBP3 levels compared with placebo over 84 days. Fold change in serum circulating microRNA (c-miR)-133b differed significantly by group (KHCO3, 2.26 ± 0.85; placebo, −1.23 ± 0.69; P < 0.01); there was a similar trend in c-miR-21-5p. Fold changes in c-miR-133b and c-miR-21-5p were inversely associated with changes in UNAE and UNTX; fold change in c-miR-21-5p was inversely associated with change in UCa, with a similar trend with c-miR-133b. In summary, reducing renal acid load with KHCO3 was associated with increased expressions of c-miR-133b and c-miR-21-5p. Furthermore, increases in c-miRNA-133b and c-miR-21-5p were inversely associated with bone resorption markers UNTX and UCa consistent with potential beneficial effects on bone in older adults. However, the broader significance of c-miRNAs as musculoskeletal biomarkers is still under investigation, and larger studies are needed to verify these preliminary results.

Acid retention with reduced glomerular filtration rate increases urine biomarkers of kidney and bone injury

Diets high in acid of developed societies that do not cause metabolic acidosis in patients with chronic kidney disease nevertheless appear to cause acid retention with associated morbidity, particularly in those with reduced glomerular filtration rate. Here we used a rat 2/3 nephrectomy model of chronic kidney disease to study induction and maintenance of acid retention and its consequences on indicators of kidney and bone injury. Dietary acid was increased in animals eating base-producing soy protein with acid-producing casein and in casein-eating animals with added ammonium chloride. Using microdialysis to measure the kidney cortical acid content, we found that nephrectomized animals had greater acid retention than sham-operated animals when both ate the soy diet. Each increment in dietary acid further increased acid retention more in nephrectomized than in sham rats. Nephrectomized and sham animals achieved similar steady-state daily urine net acid excretion in response to increments in dietary acid but nephrectomized animals took longer to do so, contributing to greater acid retention that was maintained until the increased dietary acid was stopped. Acid retention was associated with increased urine excretion of both N-acetyl-β-D-glucosaminidase and deoxypyridinoline, greater in nephrectomized than control rats, consistent with kidney tubulointerstitial and bone matrix injury, respectively. Greater acid retention in nephrectomized than control animals was induced by a slower increase in urinary net acid excretion rate in response to the increment in dietary acid and also maintained until the dietary acid increment was stopped. Thus, acid retention increased biomarkers of kidney and bone injury in the urine, supporting untoward consequences to these two tissues.

Food groups associated with measured net acid excretion in community-dwelling older adults.

BackgroundAcid-producing diets have been associated with adverse health conditions. Dietary acid load can be estimated from dietary intake data, but the available methods require a full dietary assessment. We sought to identify a simpler means to estimate 24-hour urinary net acid excretion (NAE), a robust measure of net endogenous acid production, using self-reported intakes of fruits, vegetables (acid-neutralizing foods), grain and/or protein (acid-producing foods)acquired by two different methods in community-dwelling older adults. Identifying food groups associated with NAE using a method not requiring a full diet assessment could have a broad clinical application.MethodsFruit, vegetable, protein, and grain servings/day were estimated with a widely-used food frequency questionnaire (study A, n=162, 63±8 years). Differences in their intakes across NAE categories (<5, ≥5to <15, ≥15to <50, ≥50 milliequivalents (mEq)/day) were analyzed using analysis of variance. The findings were verified in a second study which estimated dietary intakes using a more detailed record-assisted 24- hour recall (study B, n=232, 67±6 years).ResultsFruit intake was significantly associated with NAE in both studies. In study A, fruit intake was 9% lower with each categorical NAE increase (unstandardized beta=-0.21,p=0.01) and 7% lower with each categorical NAE increase in study B (unstandardized beta=-0.18;p=0.02). Grain intake was positively associated with NAE in study B only (unstandardized beta=+0.14;p=0.01). Vegetable and protein intake were not associated with NAE in either study.ConclusionThe inverse association between fruit intake and NAE suggests low self-reported fruit intake may be an indicator of acid-producing diets in older adults.

Dietary Acid Load is Associated With Serum Bicarbonate but not Insulin Sensitivity in Chronic Kidney Disease

In chronic kidney disease (CKD), dietary acid may promote metabolic acidosis and insulin resistance, which in turn may contribute to adverse clinical health outcomes. We examined associations between dietary acid load, serum bicarbonate, and insulin sensitivity in CKD. In a cross-sectional study, we collected 3-day prospective food diaries to quantify dietary acid load as net endogenous acid production (NEAP, the nonvolatile acid load produced by the diet's acid balance) and potential renal acid load (PRAL). We measured urine net acid excretion (NAE) in 24-hour urine samples. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp. Forty-two patients with CKD Stages 3 to 5 attending nephrology clinics in the Pacific Northwest and 21 control subjects (estimated glomerular filtration rate [eGFR] ≥ 60 mL/minute/1.73 m(2)). Serum bicarbonate and insulin sensitivity (SIclamp). Mean age was 60.8 ± 13.6 years, and 54% of participants were men. Mean eGFR and serum bicarbonate concentrations were 34.4 ± 13.1 mL/minute/1.73 m(2) and 24.1 ± 2.9 mEq/L for participants with CKD and 88.6 ± 14.5 mL/minute/1.73 m(2) and 26.3 ± 1.8 mEq/L for control subjects, respectively. Mean NEAP, PRAL, and NAE were 58.2 ± 24.3, 9.7 ± 18.4, and 32.1 ± 19.8 mEq/day, respectively. Considering all participants, dietary acid load was significantly, inversely associated with serum bicarbonate, adjusting for age, gender, race, eGFR, body mass index, and diuretic use: -1.2 mEq/L per standard deviation (SD) NEAP (95% confidence interval [CI] -1.8 to -0.6, P < .0001); -0.9 mEq/L bicarbonate per SD PRAL (95% CI -1.5 to -0.4, P = .0005); -0.7 mEq/L bicarbonate per SD NAE (95% CI -1.2 to -0.1, P = .01). These associations were similar in participants with and without CKD. However, neither NEAP and PRAL nor NAE was significantly associated with SIclamp. Serum bicarbonate was also not significantly associated with SIclamp. In CKD, dietary acid load is associated with serum bicarbonate, suggesting that acidosis may be improved by dietary changes, but not with insulin sensitivity.

Angiotensin II-mediated GFR decline in subtotal nephrectomy is due to acid retention associated with reduced GFR.

Angiotensin II (AII) mediates glomerular filtration rate (GFR) decline in animals with subtotal nephrectomy (Nx), but the mechanisms for increased AII activity are unknown. Because reduced GFR of Nx is associated with acid (H(+)) retention that increases kidney AII, AII-mediated GFR decline might be induced by H(+) retention. We measured GFR and kidney microdialyzate H(+) and AII content in Sham and 2/3 Nx rats in response to amelioration of H(+) retention with dietary NaHCO3, to AII receptor antagonism and to both. GFR was lower in Nx than that in Sham. Nx but not Sham GFR was lower at Week 24 than that at Week 1. Despite no differences in plasma acid-base parameters or urine net acid excretion, kidney H(+) content was higher in Nx than that in Sham, consistent with H(+) retention. Plasma and kidney microdialyzate AII were higher in Nx than that in Sham and dietary NaHCO3 reduced each in Nx but not in Sham. AII receptor antagonism was associated with higher Week 24 GFR in Nx with H(+) retention but not in Sham or in Nx in which H(+) retention had been corrected with dietary NaHCO3. Week 24 GFR after dietary NaHCO3 was higher than after AII receptor antagonism. Week 24 GFR was not different after adding AII receptor antagonism to dietary NaHCO3. AII-mediated GFR decline in 2/3 Nx was induced by H(+) retention and its amelioration with dietary HCO3 conserved GFR better than AII receptor antagonism in this CKD model. H(+) retention might induce AII-mediated GFR decline in patients with reduced GFR, even without metabolic acidosis.

Longitudinal relationships between diet-dependent renal acid load and blood pressure development in healthy children

Diets high in sulfur-rich protein and low in fruits and vegetables affect human acid-base balance adversely. Corresponding subclinical forms of metabolic acidosis have been linked to hypertension in adults. We longitudinally examined relations of dietary acid load with blood pressure in 257 healthy prepuberty children with 3 or more parallel 3-day weighed dietary records, 24-h urine, and blood pressure measurements. Urinary net acid excretion and the potential renal acid load (PRAL), determined as the difference of major urinary nonbicarbonate anions and mineral cations, were used to predict dietary acid load. PRAL was also calculated from dietary data. In repeated-measures regression analyses, adjusted for body size and dietary fiber, an intraindividual increase of 10 mEq above the 'usual' net acid excretion or urine PRAL were each significantly related to a 0.6-0.7 mm Hg increased systolic blood pressure. Differences in urine PRAL among the children also significantly predicted between-person differences in systolic blood pressure. A higher individual net acid excretion or urine PRAL and intraindividual increase in urine PRAL were significantly related to higher diastolic blood pressure. Blood pressure associations were nonsignificant for dietary PRAL and urinary sodium. Thus, in healthy children, renal biomarker analyses reveal an association of proton load with higher blood pressure. Especially for systolic blood pressure, a more alkalizing nutrition may be beneficial for blood pressure development within a given individual. Experimental confirmation of a causal acid load-blood pressure link is required.

Renal ammonium excretion after an acute acid load: blunted response in uric acid stone formers but not in patients with type 2 diabetes

Idiopathic uric acid nephrolithiasis is characterized by elevated urinary net acid excretion and insufficient buffering by ammonium, resulting in excessively acidic urine and titration of the relatively soluble urate anion to insoluble uric acid. Patients with type 2 diabetes have similar changes in urinary pH, net acid excretion, and ammonium in 24-h urine collections at baseline, even after controlling for dietary factors, and are at increased risk for uric acid nephrolithiasis. However, not all patients with type 2 diabetes develop kidney stones, suggesting that uric acid stone formers may have additional urinary defects, perhaps not apparent at baseline. We performed a metabolic study of 14 patients with idiopathic uric acid nephrolithiasis, 13 patients with type 2 diabetes, and 8 healthy control subjects of similar body mass index. After equilibration on a fixed diet for 5 days, subjects were given a single oral acid load (50 meq ammonium chloride), and urine was collected hourly for 4 h. Uric acid stone formers had a lower ammonium excretory response to acute acid loading compared with diabetic and nondiabetic nonstone formers, suggesting that an ammonium excretory defect unique to uric acid stone formers was unmasked by the acid challenge. The Zucker diabetic fatty rat also did not show impaired urinary ammonium excretion in response to acute acid challenge. A blunted renal ammonium excretory response to dietary acid loads may contribute to the pathogenesis of idiopathic uric acid nephrolithiasis.

Abstract P105: Dietary Acid Load of a Low Versus a High Protein Diet and Its Effect on Blood Pressure: A Fully Controlled Dietary Intervention Trial

Background: Mild metabolic acidosis may result in elevated blood pressure (BP). Several formulas to estimate dietary acid load have been developed. However, studies in which these formulas have been validated are limited. Objectives: To validate and/or improve existing formulas for dietary acid load and to examine the association between dietary protein, acid load and BP. Methods: We performed a randomized 14d crossover dietary intervention involving 37 healthy subjects (age: 21±2 y) who consumed individualized, isocaloric diets that were either low or high in protein (0.5 versus 2.0 g protein/kg BW/d). Duplicate portions of the provided diets were collected and analysed for energy and nutrients. We used two measures to characterize dietary acid load (i.e. PRAL and NEAP). Urinary Net Acid Excretion (NAE; i.e. titratable acid + ammonium - bicarbonate) was analysed. BP was measured according to standardized procedures. Results: Mean dietary intakes significantly differed between the low and high protein diet, resulting in significantly different acid load values (Table 1, all p&lt;0.001). The correlation between PRAL and NAE was 0.08 in the low protein diet and 0.62 in the high protein diet. For NEAP the correlations were 0.27 and 0.32. PRAL explained 69% of the variance of NAE, which could not be improved by adding other variables to the formula. Systolic BP was 108.4±7.5 and 109.5±8.0 mmHg on the low and high protein diet respectively (p=0.25). Conclusion: PRAL predicts NAE reasonably well in healthy adults for normal to high protein intake. PRAL can be influenced by diet, but this cannot be clearly attributed to protein intake alone. PRAL does not seem to influence short-term BP in healthy adults with normal BP.

11β-Hydroxysteroid-dehydrogenase type 2 and dietary acid load are independently associated with blood pressure in healthy children and adolescents

Background: The reduced activity of 11b hydroxysteroid dehydrogenase type 2 (11bHSD2) contributes to elevated blood pressure (BP) in clinical syndromes, but its effect on BP in the physiologic range is unclear. Objectives: We examined the association of 11bHSD2 activity with BP in healthy children independent of known BP-related dietary and other factors and determined whether the diet-dependent acid load may constitute a dietary factor related to BP. Design: We conducted a cross-sectional analysis in 267 healthy children (age range: 4–14 y) who provided a 24-h urine sample, a parallel 3-d weighed dietary record, and 1–3 BP measurements 6 1.5 y around the urine collection. The ratio of urinary free cortisone to cortisol measured by using a radioimmunoassay was used as an index for 11bHSD2. Urinary net acid excretion and the urinary and dietary potential renal acid load (PRAL) were used to predict the dietdependent acid load. The PRAL was calculated as the sum of major mineral nonbicarbonate anions minus the sum of mineral cations. Sex-, age- and height-independent SD scores (SDSs) of systolic and diastolic BP were used as outcomes in linear regression analyses. Results: 11bHSD2 was inversely associated with systolic BP SDSs in basic models and in analyses adjusted for body size, maternal BP, breastfeeding, and dietary intakes of total energy, salt, and fruit and vegetables (P = 0.03). In models that included indexes of dietary acid load instead of fruit and vegetables, all 3 acid-load biomarkers were significantly (P = 0.006–0.02) directly related to systolic BP. Conclusion: A lower 11bHSD2 activity and higher dietary acid load may independently contribute to higher systolic BP in healthy children. Am J Clin Nutr doi: 10.3945/ajcn.112.047829.