Effects of Alterations in Acid-Base Effects on Insulin Signaling.

Insulin tightly regulates glucose levels within a narrow range through its action on muscle, adipose tissue and the liver. The activation of insulin receptors activates multiple intracellular pathways with different functions. Another tightly regulated complex system in the body is acid-base balance. Metabolic acidosis, defined as a blood pH < 7.35 and serum bicarbonate < 22 mmol/L, has clear pathophysiologic consequences including an effect on insulin action. With the ongoing intake of typical acid-producing Western diets and the age-related decline in renal function, there is an increase in acid levels within the range considered to be normal. This modest increase in acidosis is referred to as "acid stress" and it may have some pathophysiological consequences. In this article, we discuss the effects of acid stress on insulin actions in different tissues.

Higher Renal Net Acid Excretion, but Not Higher Phosphate Excretion, during Childhood and Adolescence Associates with the Circulating Renal Tubular Injury Marker Interleukin-18 in Adulthood.

High dietary phosphorus intake (P-In) and high acid loads may adversely affect kidney function. In animal models, excessive phosphorus intake causes renal injury, which, in humans, is also inducible by chronic metabolic acidosis. We thus examined whether habitually high P-In and endogenous acid production during childhood and adolescence may be early indicators of incipient renal inflammatory processes later in adulthood. P-In and acid-base status were longitudinally and exclusively determined by biomarker-based assessment in 277 healthy children, utilizing phosphate and net acid excretion (NAE) measurements in 24 h urine samples repeatedly collected between the ages of 3 and 17 years. Standard deviation scores (by sex and age) were calculated for anthropometric data and for the urinary biomarkers available within age range 3-17 years. Multivariable linear regression was used to analyze the relations of phosphate excretion and NAE with the adulthood outcome circulating interleukin-18 (IL-18), a marker of inflammation and kidney dysfunction. After adjusting for growth- and adulthood-related covariates and pro-inflammatory biomarkers to rule out confounding by non-renal inflammatory processes, regression models revealed a significant positive relationship of long-term NAE (p = 0.01), but not of long-term phosphate excretion with adult serum IL-18. Similar significant positive regression results were obtained after replacing NAE with 24 h urinary ammonium excretion as the exposition variable. Our results suggest that even moderate elevations in renal ammonia production, as caused by habitually higher acid loading during growth, may affect the intrarenal pro-inflammatory system in the long-term, known to be boosted by acidosis-induced raised ammoniagenesis.

Food, Acid Supplementation and Drug Absorption - a Complicated Gastric Mix: a Randomized Control Trial.

PURPOSE: The purpose of this study was to determine the impact of food on gastric pH and the ability of over the counter betaine hydrochloride (BHCl) acid to reacidify gastric pH after food-induced elevations in gastric pH. METHODS: This open-label cross over clinical study (NCT02758015) included 9 subjects who were randomly assigned to one of 16 possible, 4-period cross-over sequences to determine the impact and relationship of food and gastric pH with acid supplementation. Subjects were administered various doses (1500 mg, 3000 mg and 4500 mg) of betaine hydrochloride (BHCl) to determine the ability of acid supplementation to reacidify gastric pH after the elevation of gastric pH caused by the ingestion of food. RESULTS: Following the administration of food and the resulting elevation in gastric pH, time to return to baseline gastric pH levels without acid supplementation was 49.7 ± 14.0 min. Administering 4500 mg of BHCl acid in capsules was able to reacidify gastric pH levels back to baseline following the administration of food in approximately 17.3 ± 5.9 min. AUCpH of each treatment were similar and not statistically different. Mean max pH following the administration of food was 3.20 ± 0.55. CONCLUSION: The ability of food to elevate and maintain gastric pH levels in the presence of acid supplementation was made evident throughout the study. A 4500 mg dose of BHCl was required to reacidify gastric pH after the administration of food. This study details the difficulty faced by clinicians in dosing a poorly soluble, weakly basic drug to patients receiving acid reducing agents where administration with food is recommended to avoid gastric side effects. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02758015.

Meal Effects Confound Attempts to Counteract Rabeprazole-Induced Hypochlorhydria Decreases in Atazanavir Absorption.

PURPOSE: Clinically relevant pharmacokinetic interactions exist between gastric acid-reducing agents and certain weakly basic drugs that rely on acidic environments for optimal oral absorption. In this study, we examine whether the administration of betaine hydrochloride under fed conditions can enhance the absorption of atazanavir, an HIV-1 protease inhibitor, during pharmacologically-induced hypochlorhydria. METHODS: In this randomized, single-dose, 3 period, crossover study healthy volunteers received ritonavir-boosted atazanavir (atazanavir/ritonavir 300/100 mg) alone, following pretreatment with the proton pump inhibitor rabeprazole (20 mg twice daily), and with 1500 mg of betaine HCl after rabeprazole pretreatment. Atazanavir was administered with a light meal and gastric pH was monitored using the Heidelberg Capsule. RESULTS: Pretreatment with rabeprazole resulted in significant reductions in atazanavir Cmax (p < 0.01) and AUC0-last (p < 0.001) (71 and 70%, respectively), and modest decreases in ritonavir Cmax and AUClast (p < 0.01) (40% and 41%, respectively). The addition of betaine HCl restored 13% of ATV Cmax and 12% of AUClast lost due to rabeprazole. CONCLUSIONS: The co-administration of rabeprazole with atazanavir resulted in significant decreases in atazanavir exposure. The addition of betaine HCl did not sufficiently mitigate the loss of ATV exposure observed during RAB-induced hypochlorhydria. Meal effects lead to a marked difference in the outcome of betaine HCl on atazanavir exposure than we previously reported for dasatanib under fasting conditions.

Gastric reacidification with betaine HCl in healthy volunteers with rabeprazole-induced hypochlorhydria.

Previous studies have demonstrated that increased gastric pH from the use of acid-reducing agents, such as proton-pump inhibitors or H2-receptor antagonists, can significantly impact the absorption of weakly basic drugs that exhibit pH-dependent solubility. Clinically practical strategies to mitigate this interaction have not been developed. This pilot study evaluated the extent and time course of gastric reacidification after a solid oral dosage form of anhydrous betaine HCl in healthy volunteers with pharmacologically induced hypochlorhydria. Six healthy volunteers with baseline normochlorhydria (fasting gastric pH < 4) were enrolled in this single period study. Hypochlorhydria was induced via 20 mg oral rabeprazole twice daily for four days. On the fifth day, an additional 20 mg dose of oral rabeprazole was given and gastric pH was monitored continuously using the Heidelberg pH capsule. After gastric pH > 4 was confirmed for 15 min, 1500 mg of betaine HCl was given orally with 90 mL of water and gastric pH was continuously monitored for 2 h. Betaine HCl significantly lowered gastric pH by 4.5 (± 0.5) units from 5.2 (± 0.5) to 0.6 (± 0.2) (P < 0.001) during the 30 min interval after administration. The onset of effect of betaine HCl was rapid, with a mean time to pH < 3 of 6.3 (± 4.3) min. The reacidification period was temporary with a gastric pH < 3 and < 4 lasting 73 (± 33) and 77 (± 30) min, respectively. Betaine HCl was well tolerated by all subjects. In healthy volunteers with pharmacologically induced hypochlorhydria, betaine HCl was effective at temporarily lowering gastric pH. The rapid onset and relatively short duration of gastric pH reduction gives betaine HCl the potential to aid the absorption of orally administered weakly basic drugs that exhibit pH-dependent solubility when administered under hypochlorhydric conditions.

Renal Embolization-Induced Uremic Swine Model for Assessment of Next-Generation Implantable Hemodialyzers.

Reliable models of renal failure in large animals are critical to the successful translation of the next generation of renal replacement therapies (RRT) into humans. While models exist for the induction of renal failure, none are optimized for the implantation of devices to the retroperitoneal vasculature. We successfully piloted an embolization-to-implantation protocol enabling the first implant of a silicon nanopore membrane hemodialyzer (SNMHD) in a swine renal failure model. Renal arterial embolization is a non-invasive approach to near-total nephrectomy that preserves retroperitoneal anatomy for device implants. Silicon nanopore membranes (SNM) are efficient blood-compatible membranes that enable novel approaches to RRT. Yucatan minipigs underwent staged bilateral renal arterial embolization to induce renal failure, managed by intermittent hemodialysis. A small-scale arteriovenous SNMHD prototype was implanted into the retroperitoneum. Dialysate catheters were tunneled externally for connection to a dialysate recirculation pump. SNMHD clearance was determined by intermittent sampling of recirculating dialysate. Creatinine and urea clearance through the SNMHD were 76-105 mL/min/m2 and 140-165 mL/min/m2, respectively, without albumin leakage. Normalized creatinine and urea clearance measured in the SNMHD may translate to a fully implantable clinical-scale device. This pilot study establishes a path toward therapeutic testing of the clinical-scale SNMHD and other implantable RRT devices.

Pharmacokinetic differences corroborate observed low tacrolimus dosage in Native American renal transplant patients.

We have observed in clinical practice that Native Americans require lower dosages of tacrolimus to attain similar target blood trough levels compared to whites after renal transplant. Because there are no pharmacokinetic studies of tacrolimus in this ethnic group, we investigated whether this clinical observation could be corroborated by pharmacokinetic differences between Native Americans and other ethnic and racial groups. We recruited 24 adult Native American kidney transplant recipients on stable oral doses of tacrolimus for at least 1 month posttransplant. We conducted a 12-h steady-state pharmacokinetic profile for all of the patients and estimated pharmacokinetic parameters using NONMEM. The concentration-time data were fit to a linear two compartment model with first-order absorption and lag time using an empirical Bayesian approach. The mean estimate of oral clearance (CL/F) was 11.1 l/h. Compared with previously reported data in other ethnic and racial groups, the Native American cohort has approximately one third the clearance of other groups. Our pharmacokinetic study reveals the clinically observed low dose of tacrolimus in Native American renal transplant patients is associated with a decreased oral tacrolimus clearance. There is scant information available on the genetic or environmental characteristics unique to this ethnic group that affect pharmacokinetics compared to other, better-studied groups, and elucidation of these factors will provide information to further facilitate individualized drug treatment for tacrolimus and a wide range of other drugs with similar clearance processes.

Effects of Single Dose Rifampin on the Pharmacokinetics of Fluvastatin in Healthy Volunteers.

The objective of this study was to determine the effects of the OATP inhibitor rifampin on pharmacokinetic of Biopharmaceutics Drug Disposition Classification System Class 1 compound fluvastatin. A crossover study was carried out in 10 healthy subjects who were randomized to 2 phases to receive fluvastatin 20 mg orally alone and following a 30-minute 600 mg i.v. infusion of rifampin. The results demonstrated that i.v. rifampin increased the mean area under the plasma fluvastatin concentration-time curve (AUC0-∞ ) by 255%, mean peak plasma concentration (Cmax ) by 254%, decreased oral volume of distribution by 71%, whereas the mean elimination terminal half-life (T1/2 ), mean absorption time (MAT), and time to peak concentration (Tpeak ) of fluvastatin did not significantly change. The study demonstrated that rifampin exhibited a significant drug interaction with fluvastatin. The mechanism of the increased plasma concentrations is likely due to inhibition of OATP transporters in hepatocytes.

Management of osteoporosis in CKD Stages 3 to 5.

Osteoporosis and chronic kidney disease (CKD) are both common conditions of older adults and both may be associated with substantial morbidity. However, biochemical and histologic changes that occur with progressive kidney disease require specific interventions, some of which may be concordant with osteoporosis management in the general population, whereas others may be less relevant or perhaps even harmful. In this article, we review the diagnosis of and management strategies for osteoporosis in individuals with CKD, placing these into perspective with the recently published KDIGO (Kidney Disease: Improving Global Outcomes) guidelines for treatment of CKD-mineral and bone disorder (CKD-MBD). Specifically, we highlight osteoporosis treatment recommendations by CKD stage and discuss new avenues for osteoporosis treatment that may be useful in individuals with CKD.

Diet-induced acidosis: is it real and clinically relevant?

The concept of diet-induced 'acidosis' as a cause of disease has been a subject of interest for more than a century. The present article reviews the history of our evolving understanding of physiological pH, the physiological support for the concept of 'acidosis', the causes of acidosis, how it is recognised, its short-term effects as well as the long-term clinical relevance of preventative measures, and the research support for normalisation of pH. Further, we suggest differentiation of the terms 'acidosis' and 'acidaemia' as a way to resolve the conflation of these topics which has led to confusion and controversy. The available research makes a compelling case that diet-induced acidosis, not diet-induced acidaemia, is a real phenomenon, and has a significant, clinical, long-term pathophysiological effect that should be recognised and potentially counterbalanced by dietary means.

Performance of Predictive Equations and Biochemical Measures Quantifying Net Endogenous Acid Production and the Potential Renal Acid Load.

INTRODUCTION: A limited number of studies have assessed the accuracy and precision of methods for determining the net endogenous acid production (NEAP) and its components. We aimed to investigate the performance of methods quantifying the diet dependent acid-base load. METHODS: Data from metabolic balance studies enabled calculations of NEAP according to the biochemical measures (of net acid excretion [NAE], urinary net endogenous acid production [UNEAP], and urinary potential renal acid load [UPRAL]) as well as estimative diet equations (by Frassetto et al., Remer and Manz, Sebastian et al., and Lemann) that were compared among themselves in healthy participants fed both acid and base forming diets for 6 days each. RESULTS: Seventeen participants (mean ± SD age, 60 ± 8 years; body mass index, 23 ± 2 kg/m2) provided 102 twenty-four-hour urine samples for analysis (NAE, 39 ± 38 mEq/d [range, -9 to 95 mEq/d]). Bland-Altman analysis comparing UNEAP to NAE showed good accuracy (bias, -2 mEq/d [95% confidence interval {CI}, -8 to 3]) and modest precision (limits of agreement, -32 to 28 mEq/d). Accurate diet equations included potential renal acid load (PRAL) by Sebastian et al. (bias, -4 mEq/d [95% CI, -8 to 0]) as well as NEAP by Lemann et al. (bias, 4 mEq/d [95% CI, -1 to 9]) and Remer and Manz (bias, -1 mEq/d [95% CI, -6 to 3]). CONCLUSIONS: Researchers are encouraged to collect measures of UPRAL and UNEAP; however, investigators drawing conclusions between the diet-dependent acid-base load and human health should consider the limitations within all methods.

Evaluating Within-Subject Variability for Narrow Therapeutic Index Drugs.

The US Food and Drug Administration (FDA) reference-scaled average bioequivalence approach scales the bioequivalence (BE) limits of narrow therapeutic index drugs (NTIDs) to the intrasubject or within-subject variability (WSV) of the reference-listed drug. A clinical study was conducted to evaluate the WSV of warfarin (Coumadin), 10 mg, administered to 10 healthy volunteers exhibiting similar cytochrome P450 2C9 and vitamin K epoxide reductase alleles on 3 study days. Individual intrasubject coefficients of variation for maximum plasma concentration and area under the curve (0-72 hour) ranged from 3.7-15% and from 4.3-16.2%, respectively (R-warfarin) and from 5.4-19.1% and from 2.5-11.9%, respectively (S-warfarin). Two BE tests were performed on a WSV distribution obtained by bootstrapping 1,000 replicates of the clinical data, yielding passing rates of 95-97% for the mean comparison and 84-87% for the variability comparison. The variability comparison passing rate was lower than expected for an NTID product tested against itself, but it may provide further assurance of BE.

Adverse effects of sodium chloride on bone in the aging human population resulting from habitual consumption of typical American diets.

A typical American diet contains amounts of sodium chloride far above evolutionary norms and potassium far below those norms. It also contains larger amounts of foods that are metabolized to noncarbonic acids than to organic bases. At baseline, in a steady state, diets that contain substantial sodium chloride and diets that are net acid producing each independently induce and sustain increased acidity of body fluid. With increasing age, the kidney's ability to excrete daily net acid loads declines, invoking homeostatically increased utilization of base stores (bone, skeletal muscle) on a daily basis to mitigate the otherwise increasing baseline metabolic acidosis, which results in increased calciuria and net losses of body calcium. Those effects of net acid production and its attendant increased body fluid acidity may contribute to development of osteoporosis and renal stones, loss of muscle mass, and age-related renal insufficiency. The inverted ratio of potassium to sodium in the diet compared with preagricultural diets affects cardiovascular function adversely and contributes to hypertension and stroke. The diet can return to its evolutionary norms of net base production inducing low-grade metabolic alkalosis and a high potassium-to-sodium ratio by 1) greatly reducing content of energy-dense nutrient-poor foods and potassium-poor acid-producing cereal grains, which would entail increasing consumption of potassium-rich net base-producing fruits and vegetables for maintenance of energy balance, and 2) greatly reducing sodium chloride consumption. Increasingly, evidence supports the health benefits of reestablishing evolutionary norms of dietary net base loads and high potassium and low sodium chloride loads. We focus here on the American diet's potential effects on bone through its superphysiologic content of sodium chloride.

Estimates of daily net endogenous acid production in the elderly UK population: analysis of the National Diet and Nutrition Survey (NDNS) of British adults aged 65 years and over.

Dietary intake has been shown to influence acid-base balance in human subjects under tightly controlled conditions. However, the net effect of food groups on alkali/acid loading in population groups is unclear. The aims of the present study were to: (1) quantify estimates of daily net endogenous acid production (NEAP) (mEq/d) in a representative group of British elderly aged 65 years and older; (2) compare and characterise NEAP by specific nutrients and food groups likely to influence dietary acid loading; (3) determine whether geographical location influenced NEAP. The National Diet and Nutrition Survey dataset, consisting of a 4 d weighed record and anthropometric data, was used to estimate dietary acidity. Dietary under-reporters were excluded by analysing only subjects with energy intakes >/= 1.2 x BMR. NEAP was estimated as the dietary potential renal acid load+organic acid excretion, the latter as a multiple of estimated body surface area. NEAP was lower in women compared with men (P < 0.001), and lower than values reported in a Swedish elderly cohort. Lower dietary acidity was significantly associated with higher consumption of fruit and potatoes and lower consumption of meat, bread and eggs (P < 0.02 to P < 0.001). Lower intakes of fish and cheese were associated with lower NEAP in men only (P < 0.01 to P < 0.001). There were regional differences for NEAP, with higher intakes in Scotland/Northern regions compared with Central/South-Western and London/South-Eastern regions (P = 0.01). These data provide an insight into the acid-generating potential of the diet in the British elderly population, which may have important consequences in this vulnerable group.

Effects of 12-Week Low or Moderate Dietary Acid Intake on Acid-Base Status and Kidney Function at Rest and during Submaximal Cycling.

Prolonged effects of dietary acid intake on acid-base status and kidney function have not yet been studied in an intervention study in healthy subjects. Dietary acid load can be estimated by calculating the potential renal acid load (PRAL) of foods. Effects of low-PRAL and moderate-PRAL diets on acid-base status and kidney function were investigated during a 12-week exercise training period. Healthy, 20-50-year-old men (n = 21) and women (n = 25) participated in the study and were randomly divided into low-PRAL and moderate-PRAL groups. Before (PRE), mid-phase (MID) and after the intervention (POST), the subjects participated in measurement sessions, where a 12-h urine sample and fasting blood samples were collected, and a submaximal cycle ergometer test was performed. Net acid excretion was significantly lower after 12 weeks of the low-PRAL diet as compared to the moderate-PRAL diet, both in men and women. In low-PRAL females, capillary pH and bicarbonate were significantly higher at 75% of VO2max at POST as compared to PRE. Glomerular filtration rate decreased over the study period in moderate-PRAL men and women. The results of the present study suggest that an acidogenic diet and regularly training together may increase the acidic load of the body and start to impair the kidney function in recreationally active subjects.

Spot-testing urine pH, a novel dietary biomarker? A randomised cross-over trial.

AIM: Spot-tests of urine pH are claimed to be an accessible biomarker of net acid excretion (NAE), and as such, they may be able to determine changes in an individual's intake of acid- or base-forming foods. To test this hypothesis, we aimed to determine if spot-tests of urine pH could index NAE and relay the consumption of a fruit and vegetable (F&V) concentrate whilst determining this concentrate's capacity to modulate NAE. METHODS: In a double blind, placebo-controlled, cross-over trial, healthy adults (n = 13) were allocated by simple randomisation to receive a F&V concentrate or placebo for three days each, with diet standardised throughout. Measurements of 24-hour NAE, 24-hour urine pH and spot-tests of urine pH were taken throughout the study. RESULTS: The 24-hour urine pH predicted 24-hour NAE (P = <0.0001). However, spot-tested urine pH displayed prediction intervals too wide to infer 24-hour NAE and inconsistent ability to reflect concentrate ingestion, despite 24-hour NAE and 24-hour urine pH decreasing (-25.8 mEq, 95% CI -44.3 to -7.4, P = 0.01, d = 0.94) and increasing (+0.51, 95% CI 0.25-0.79, P = 0.002, d = 1.3), respectively, following supplementation. CONCLUSIONS: Spot-tests of urine pH are not a valid dietary biomarker of daily NAE and were unable to reliably track changes, despite a F&V concentrate clearly modulating the daily rate of NAE.

Accuracy and precision of estimation equations to predict net endogenous acid excretion using the Australian food database.

AIM: The gold standard of measurement for net endogenous acid production (NEAP) is net acid excretion (NAE), a test that is not readily available, and consequently, estimative equations by Remer and Manz and Frassetto et al. are often used. These equations rely on nutrient databases and it is recommended that their validity be assessed using a country's database before their application in research in that country. We sought to delineate the accuracy and precision of these estimation equations using the Australian food database. METHODS: In a double blind, randomised, cross-over fashion, healthy participants (n = 13) residing in regional Australia were exposed to varying net acid loads while they collected weighted food diaries and 24-hour urine samples for measurement of NAE. RESULTS: In comparison to the Frassetto et al. equations (equation one bias = -57.1 mEq/day, equation two bias = -32.8 mEq/day), only the Remer and Manz equation was accurate (bias = -5.4 mEq/day); however, all equations were imprecise. CONCLUSIONS: Using the Australian database, the performance of these equations to predict NEAP appears equal to other databases; however, caveats apply in their application. For future research, the equation by Remer and Manz is preferential for group estimates. None of the equations are recommended for individual estimates.

Dietary acid load and renal function have varying effects on blood acid-base status and exercise performance across age and sex.

Diet composition influences acid-base status of the body. This may become more relevant as renal functional capacity declines with aging. We examined the effects of low (LD) versus high dietary acid load (HD) on blood acid-base status and exercise performance. Participants included 22 adolescents, 33 young adults (YA), and 33 elderly (EL), who followed a 7-day LD and HD in a randomized order. At the end of both diet periods the subjects performed a cycle ergometer test (3 × 10 min at 35%, 55%, 75%, and (except EL) until exhaustion at 100% of maximal oxygen uptake). At the beginning of and after the diet periods, blood samples were collected at rest and after all workloads. Oxygen uptake, respiratory exchange ratio (RER), and heart rate (HR) were monitored during cycling. In YA and EL, bicarbonate (HCO3-) and base excess (BE) decreased over the HD period, and HCO3-, BE, and pH were lower at rest after HD compared with LD. In YA and EL women, HCO3- and BE were lower at submaximal workloads after HD compared with LD. In YA women, the maximal workload was 19% shorter and maximal oxygen uptake, RER, and HR were lower after HD compared with LD. Our data uniquely suggests that better renal function is associated with higher availability of bases, which may diminish exercise-induced acidosis and improve maximal aerobic performance. Differences in glomerular filtration rate between the subject groups likely explains the larger effects of dietary acid load in the elderly compared with younger subjects and in women compared with men.