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.

Association of Diet-dependent Systemic Acid Load, Renal Function, and Serum Albumin Concentration.

OBJECTIVE: Inflammation may be present with chronic kidney disease CKD and diet composition high in protein intake and fats may affect inflammation thereby impacting kidney health. We investigated whether acid load estimated from urine measures is associated with kidney function decline and whether the effect of acid load on an inflammatory marker, serum albumin, is a pathway to this association. METHODS: We studied 188 postmenopausal women in a randomized clinical trial of potassium bicarbonate treatment for up to 36 months. Twenty-four-hour urine and arterialized blood collections were done at baseline and at subsequent follow-up visits at 3 months interval. Acid load was estimated from potential renal acid load calculated using urinary measures of chloride, phosphate, sodium, potassium, calcium, and magnesium (UPRAL). Mixed effects model with random-intercept and slope was used to estimate subjects' annual decline rate in creatinine clearance (CrCl), and the association between (i) UPRAL and serum albumin and (ii) serum albumin and CrCl, adjusting for age, body mass index, systolic BP, and glucose. A Cox proportional regression model was used to study the relative hazard (RH) for rapid progression of kidney function decline (defined as loss of ≥5 mL/min CrCl/yr based on the last CrCl in the rolling window) with UPRAL, adjusting for the potential covariates and baseline CrCl. RESULTS: A 25 mEq/day increase in UPRAL was inversely associated with serum albumin (Adjusted ß[95% CI]: -0.02[-0.09;-0.001). During a mean follow-up of 28 months, 19 women (10%) had a rapid decline in kidney function. For each 25 mEq/day increase in UPRAL, the risk of a rapid decline in CrCl increased by 17% (95% CI: 1.06-1.28). On adjustment for potential confounders, the risk attenuated to 5% (1.02-1.14). Mediation analysis indicated that of the total effect of the association between UPRAL and CrCl, the proportion mediated by serum albumin increased to 0.346 (i.e. 34.6%). CONCLUSION: Higher UPRAL was associated with lower serum albumin as well as greater kidney function decline in postmenopausal women. Our findings suggest inflammatory response may exert a modulatory effect on the association of UPRAL and kidney function and might be a potential pathway explaining the effects of systemic acid load on progression of kidney failure.

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.

Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease.

Insulin resistance causes diminished glucose uptake in similar regions of the brain in Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2). Brain tissue studies suggested that insulin resistance is caused by low insulin receptor signaling attributable to its abnormal association with more phospho (P)-serine-type 1 insulin receptor substrate (IRS-1) and less P-tyrosine-IRS-1. Plasma exosomes enriched for neural sources by immunoabsorption were obtained once from 26 patients with AD, 20 patients with DM2, 16 patients with frontotemporal dementia (FTD), and matched case control subjects. At 2 time points, they were obtained from 22 others when cognitively normal and 1 to 10 yr later when diagnosed with AD. Mean exosomal levels of extracted P-serine 312-IRS-1 and P-pan-tyrosine-IRS-1 by ELISA and the ratio of P-serine 312-IRS-1 to P-pan-tyrosine-IRS-1 (insulin resistance factor, R) for AD and DM2 and P-serine 312-IRS-1 and R for FTD were significantly different from those for case control subjects. The levels of R for AD were significantly higher than those for DM2 or FTD. Stepwise discriminant modeling showed correct classification of 100% of patients with AD, 97.5% of patients with DM2, and 84% of patients with FTD. In longitudinal studies of 22 patients with AD, exosomal levels of P-serine 312-IRS-1, P-pan-tyrosine-IRS-1, and R were significantly different 1 to 10 yr before and at the time of diagnosis compared with control subjects. Insulin resistance reflected in R values from this blood test is higher for patients with AD, DM2, and FTD than case control subjects; higher for patients with AD than patients with DM2 or FTD; and accurately predicts development of AD up to 10 yr prior to clinical onset.

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.

Changes in clearance, volume and bioavailability of immunosuppressants when given with HAART in HIV-1 infected liver and kidney transplant recipients.

Solid organ transplantation in human immunodeficiency virus 1 (HIV)-infected individuals requiring the concomitant use of immunosuppressants (IS) [e.g. cyclosporine (CsA) or tacrolimus (TAC)] and antiretrovirals (ARVs) [e.g. protease inhibitors (PIs) and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs)] is complicated by significant drug interactions. This paper describes the pharmacokinetics of CsA and TAC in 52 patients on both IS and NNRTIs, PIs or combined NNRTIs + PIs, in studies conducted at 2 weeks, 3, 6, 12 and 24 months after transplantation. Cyclosporine and TAC blood concentrations were measured by LC/MS/MS. This multisubject, varied ARV-IS drug combination, longitudinal observational patient study provided a unique opportunity to examine the effect of different ARV drugs on IS pharmacokinetics (PK) by comparing the ratios of parameters over time and between PK parameters. Subjects taking concomitant PIs exhibited increases in CsA and TAC exposure (AUC/dose) due to the increased apparent oral bioavailability and decreased apparent oral clearance. Those subjects taking CsA and concomitant efavirenz (EFV) showed time dependent increases in exposure due to ~30% increases in the apparent oral bioavailability over time as well as a decreased apparent oral clearance, while subjects on TAC and EFV showed time-dependent changes in all PK parameters. The increased bioavailability was not observed in patients on CsA and nevirapine (NVP). These differences between IS drugs and the changes in PK parameters are not easily predicted, illustrating the importance of continued therapeutic drug monitoring in patients on these complex medication regimens. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

Patient Preference Trade-offs for Next-Generation Kidney Replacement Therapies.

BACKGROUND: Next-generation implantable and wearable KRTs may revolutionize the lives of patients undergoing dialysis by providing more frequent and/or prolonged therapy along with greater mobility compared with in-center hemodialysis. Medical device innovators would benefit from patient input to inform product design and development. Our objective was to determine key risk/benefit considerations for patients with kidney failure and test how these trade-offs could drive patient treatment choices. METHODS: We developed a choice-based conjoint discrete choice instrument and surveyed 498 patients with kidney failure. The choice-based conjoint instrument consisted of nine attributes of risk and benefit pertinent across KRT modalities. Attributes were derived from literature reviews, patient/clinician interviews, and pilot testing. The risk attributes were serious infection, death within 5 years, permanent device failure, surgical requirements, and follow-up requirements. The benefit attributes were fewer diet restrictions, improved mobility, pill burden, and fatigue. We created a random, full-profile, balanced overlap design with 14 choice pairs plus five fixed tasks to test validity. We used a mixed-effects regression model with attribute levels as independent predictor variables and choice decisions as dependent variables. RESULTS: All variables were significantly important to patient choice preferences, except follow-up requirements. For each 1% higher risk of death within 5 years, preference utility was lower by 2.22 ( ß =-2.22; 95% confidence interval [CI], -2.52 to -1.91), while for each 1% higher risk of serious infection, utility was lower by 1.38 ( ß =-1.46; 95% CI, -1.77 to -1.00) according to comparisons of the ß coefficients. Patients were willing to trade a 1% infection risk and 0.5% risk of death to gain complete mobility and freedom from in-center hemodialysis ( ß =1.46; 95% CI, 1.27 to 1.64). CONCLUSIONS: Despite an aversion to even a 1% higher risk of death within 5 years, serious infection, and permanent device rejection, patients with kidney failure suggested that they would trade these risks for the benefit of complete mobility.

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.

Dietary Contributions to Metabolic Acidosis.

Eating a net acid-producing diet can produce an "acid stress" of severity proportional to the diet net acid load, as indexed by the steady-state renal net acid excretion rate. Depending on how much acid or base is ingested or produced from endogenous metabolic processes and how well our homeostatic mechanisms can buffer or eliminate the additional acids or bases, we can alter our systemic acid-base balance. With increasing age, the kidney's ability to excrete daily net acid loads declines (a condition similar to that of mild CKD), invoking increased utilization of potential base stores (eg, bone, skeletal muscle) on a daily basis to mitigate the acid accumulation, thereby contributing to development of osteoporosis, loss of muscle mass, and age-related renal insufficiency. Patients suffering from more advanced CKD often present with more severe acid stress or metabolic acidosis, as the kidney can no longer excrete the entire acid load. Alkaline diets based on fruits and vegetables may have a positive effect on long-term preservation of renal function while maintaining nutritional status. This chapter discusses the biochemistry of dietary precursors that affect acid or base production.

Diet-dependent acid load is associated with mean arterial pressure in a cohort of non-obese, non-black, postmenopausal women.

Higher sodium (Na+) intake is associated with higher blood pressure (BP). Whether this relationship is stronger with diet-dependent acid load (DAL) and in patients diagnosed with hypertension or normal BP is not well determined. We studied 170 postmenopausal women randomized to receive potassium bicarbonate or placebo for 36 months, after which 24-hour urine and arterialized blood samples were collected. We investigated the association between DAL estimated as urinary potential renal acid load (UPRAL) and mean arterial pressure (MAP) using a mixed-effects model, adjusting for age, anthropometrics, creatinine clearance, and treatment. Adjusted regression estimates for changes in Na+ and UPRAL on MAP after 12 months of follow-up were calculated, and further adjustments were made for changes in potassium (K+) and body mass index (BMI). MAP was inversely associated with UPRAL (ß [95% confidence interval]: -0.11 [-0.25, -0.001]). There was an effect modification by hypertension (p-interaction = 0.04); MAP decreased significantly in normotensives, but the association was not significant in hypertensives. A decrease of 0.70 mm Hg in MAP [0.13, 1.69] per 50 mmol/24 hour reduction in Na+ was noted when the model was adjusted for change in K+. Our results with UPRAL exhibited a stronger dose-response for MAP, which remained significant after adjusting for BMI. UPRAL was independently associated with MAP even after adjusting for potential confounders, and the data showed that this association was more pronounced in normotensive patients. Novelty: First longitudinal study on the association of UPRAL and MAP. Association was a more robust relationship than that between U [Na+/K+] ratio and MAP. UPRAL may play a significant role in the pathogenesis of primary hypertension.

Diagnosis of acute intermittent porphyria in a renal transplant patient: A case report.

BACKGROUND: Acute intermittent porphyria (AIP) is an inherited disorder of porphyrin metabolism with a worldwide distribution and a prevalence ranging from 1 to 9 per million population. AIP is caused by an autosomal dominant-inherited mutation of low penetrance resulting in a deficiency of porphobilinogen deaminase (PBGD) activity. Acute attacks are provoked by stressors such as certain medications, alcohol, and infection. We herein present the first case report of AIP detected in a post-renal transplant patient. CASE SUMMARY: The patient was a 65-year-old man who underwent transplantation 2 years previously for suspected nephroangiosclerosis and chronic interstitial nephro-pathy. He subsequently developed diabetes mellitus which required insulin therapy. He had been treated in the recent past with local mesalamine for proctitis. He presented with classic but common symptoms of AIP including intense abdominal pain, hypertension, and anxiety. He had multiple visits to the emergency room over a 6-mo period for these same symptoms before the diagnosis of AIP was entertained. His urinary postprandial blood glucose level was 60 mg/24 h (normal, < 2 mg/24 h). He was placed on a high carbohydrate diet, and his symptoms slowly improved. CONCLUSION: This case report describes a common presentation of an uncommon disease, in which post-transplant complications and medications may have contributed to precipitating the previously undiagnosed AIP. We hypothesize that the low-carbohydrate diet and insulin with which our patient was treated may have led to the attacks of AIP. Alternatively, our patient's mesalamine treatment for proctitis may have led to an acute AIP crisis. A high index of suspicion is needed to consider the diagnosis of a heme synthesis disorder, which presents with the common symptoms of abdominal pain, high blood pressure, and anxiety.

Effects of modality change and transplant on peak oxygen uptake in patients with kidney failure.

BACKGROUND: Exercise capacity as measured by peak oxygen uptake (Vo2(peak)) is low in hemodialysis patients. The present study assesses determinants of VO2(peak) in patients with chronic kidney failure who either changed kidney replacement modality to frequent hemodialysis therapy or received a kidney transplant. STUDY DESIGN: Cohort study with assessment at baseline and 6 months after modality change. SETTING & PARTICIPANTS: Participants included nondiabetic individuals receiving conventional hemodialysis who: (1) remained on conventional hemodialysis therapy (n = 13), (2) changed to short daily hemodialysis therapy (n = 10), or (3) received a transplant (n = 5) and (4) individuals who underwent a pre-emptive transplant (n = 15). Additionally, 34 healthy controls were assessed at baseline only. PREDICTOR: Modality change. MEASUREMENT & OUTCOMES: Exercise capacity, assessed using the physiologic components of the Fick equation (Vo2 = cardiac output × a-vo2(dif), where a-vo2(dif) is arterial to venous oxygen difference) was determined using measurement of Vo2(peak) and cardiac output during symptom-limited exercise testing. Analysis of covariance was used to compare differences in changes in Vo2(peak), cardiac output, heart rate, stroke volume, and a-vo2(dif) at peak exercise between participants who remained on hemodialysis therapy and those who underwent transplant. RESULTS: Transplant was the only modality change associated with a significant change in Vo2(peak), occurring as a result of increased peak cardiac output and reflecting increased heart rate without a change in peak a-vo2(dif) despite increased hemoglobin levels. There were no differences in participants who changed to daily hemodialysis therapy compared with those who remained on conventional hemodialysis therapy. LIMITATIONS: Small nonrandomized study. CONCLUSIONS: Vo2(peak) increases significantly after kidney transplant, but not with daily hemodialysis; this improvement reflects increased peak cardiac output through increased peak heart rate. Despite statistical significance, the increase in Vo2(peak) was not clinically significant, suggesting the need for interventions such as exercise training to increase Vo2(peak) in all patients regardless of treatment modality.

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.

Treatment and prevention of kidney stones: an update.

The incidence of nephrolithiasis (kidney stones) is rising worldwide, especially in women and with increasing age. Kidney stones are associated with chronic kidney disease. Preventing recurrence is largely specific to the type of stone (e.g., calcium oxalate, calcium phosphate, cystine, struvite [magnesium ammonium phosphate]), and uric acid stones); however, even when the stone cannot be retrieved, urine pH and 24-hour urine assessment provide information about stone-forming factors that can guide prevention. Medications, such as protease inhibitors, antibiotics, and some diuretics, increase the risk of some types of kidney stones, and patients should be counseled about the risks of using these medications. Managing diet, medication use, and nutrient intake can help prevent the formation of kidney stones. Obesity increases the risk of kidney stones. However, weight loss could undermine prevention of kidney stones if associated with a high animal protein intake, laxative abuse, rapid loss of lean tissue, or poor hydration. For prevention of calcium oxalate, cystine, and uric acid stones, urine should be alkalinized by eating a diet high in fruits and vegetables, taking supplemental or prescription citrate, or drinking alkaline mineral waters. For prevention of calcium phosphate and struvite stones, urine should be acidified; cranberry juice or betaine can lower urine pH. Antispasmodic medications, ureteroscopy, and metabolic testing are increasingly being used to augment fluid and pain medications in the acute management of kidney stones.

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.

How metabolic acidosis and kidney disease may accelerate the aging process.

Consuming a lower acid (and particularly lower phosphate) diet and/or supplementing the diet with base precursors, such as bicarbonate, might have a number of mitigating effects on the aging process. These include: (1) slowing progression of fibrosis by reduction of high endogenous acid production to preserve net acid excretion and minimize the degree of systemic acidosis; (2) avoiding the downregulation of klotho, a membrane and soluble factor associated with aging. Klotho declines when constant high dietary phosphate intake leads to an increase in FGF23 production; and (3) increasing activity of the enzyme telomerase, an important factor in maintaining telomere length, another factor associated with longer lifespan. Current evidence is based on studies in invertebrate and small animal models. These results, and extrapolations of associated human studies, suggest that low acid-producing diets, or neutralization of the low grade metabolic acidosis seen in humans with age-related renal dysfunction could potentially lead to a longer, healthier lifespan.