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This phase 3, randomized trial in China compared the efficacy and safety of roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, with placebo for anemia in patients with CKD who were not undergoing dialysis. Roxadustat was superior to placebo in increasing and maintaining hemoglobin levels.

Saline (0.9% sodium chloride), the fluid most commonly used to treat diabetic ketoacidosis (DKA), can cause hyperchloremic metabolic acidosis. Balanced crystalloids, an alternative class of fluids for volume expansion, do not cause acidosis and, therefore, may lead to faster resolution of DKA than saline. To compare the clinical effects of balanced crystalloids with the clinical effects of saline for the acute treatment of adults with DKA. This study was a subgroup analysis of adults with DKA in 2 previously reported companion trials-Saline Against Lactated Ringer's or Plasma-Lyte in the Emergency Department (SALT-ED) and the Isotonic Solutions and Major Adverse Renal Events Trial (SMART). These trials, conducted between January 2016 and March 2017 in an academic medical center in the US, were pragmatic, multiple-crossover, cluster, randomized clinical trials comparing balanced crystalloids vs saline in emergency department (ED) and intensive care unit (ICU) patients. This study included adults who presented to the ED with DKA, defined as a clinical diagnosis of DKA, plasma glucose greater than 250 mg/dL, plasma bicarbonate less than or equal to 18 mmol/L, and anion gap greater than 10 mmol/L. Data analysis was performed from January to April 2020. Balanced crystalloids (clinician's choice of Ringer lactate solution or Plasma-Lyte A solution) vs saline for fluid administration in the ED and ICU according to the same cluster-randomized multiple-crossover schedule. The primary outcome was time between ED presentation and DKA resolution, as defined by American Diabetes Association criteria. The secondary outcome was time between initiation and discontinuation of continuous insulin infusion. Among 172 adults included in this secondary analysis of cluster trials, 94 were assigned to balanced crystalloids and 78 to saline. The median (interquartile range [IQR]) age was 29 (24-45) years, and 90 (52.3%) were women. The median (IQR) volume of isotonic fluid administered in the ED and ICU was 4478 (3000-6372) mL. Cumulative incidence analysis revealed shorter time to DKA resolution in the balanced crystalloids group (median time to resolution: 13.0 hours; IQR: 9.5-18.8 hours) than the saline group (median: 16.9 hours; IQR: 11.9-34.5 hours) (adjusted hazard ratio [aHR] = 1.68; 95% CI, 1.18-2.38; P = .004). Cumulative incidence analysis also revealed shorter time to insulin infusion discontinuation in the balanced crystalloids group (median: 9.8 hours; IQR: 5.1-17.0 hours) than the saline group (median: 13.4 hours; IQR: 11.0-17.9 hours) (aHR = 1.45; 95% CI, 1.03-2.03; P = .03). In this secondary analysis of 2 cluster randomized clinical trials, compared with saline, treatment with balanced crystalloids resulted in more rapid resolution of DKA, suggesting that balanced crystalloids may be preferred over saline for acute management of adults with DKA. ClinicalTrials.gov Identifiers: NCT02614040; NCT02444988.

Metabolic acidosis may occasionally develop in the course of treatment with drugs used in everyday clinical practice, as well as with the exposure to certain chemicals. Drug-induced metabolic acidosis, although usually mild, may well be life-threatening, as in cases of lactic acidosis complicating antiretroviral therapy or treatment with biguanides. Therefore, a detailed medical history, with special attention to the recent use of culprit medications, is essential in patients with acid-base derangements. Effective clinical management can be handled through awareness of the adverse effect of certain pharmaceutical compounds on the acid-base status. In this review, we evaluate relevant literature with regard to metabolic acidosis associated with specific drug treatment, and discuss the clinical setting and underlying pathophysiological mechanisms. These mechanisms involve renal inability to excrete the dietaryH + load (including types I and IV renal tubular acidoses), metabolic acidosis owing to increased H + load (including lactic acidosis, ketoacidosis, ingestion of various substances, administration of hyperalimentation solutions and massive rhabdomyolysis) and metabolic acidosis due to HCO 3 − loss (including gastrointestinal loss and type II renal tubular acidosis). Determinations of arterial blood gases, the serum anion gap and, in some circumstances, the serum osmolar gap are helpful in delineating the pathogenesis of the acid-base disorder. In all cases of drug-related metabolic acidosis, discontinuation of the culprit medications and avoidance of readministration is advised.

Low-grade metabolic acidosis (LGMA), as induced by high dietary acid load or sodium chloride (NaCl) intake, has been shown to increase bone and protein catabolism. Underlying mechanisms are not fully understood, but from clinical metabolic acidosis interactions of acid–base balance with glucocorticoid (GC) metabolism are known. We aimed to investigate GC activity/metabolism under alkaline supplementation and NaCl-induced LGMA. Eight young, healthy, normal-weight men participated in two crossover designed interventional studies. In Study A, two 10-day high NaCl diet (32 g/d) periods were conducted, one supplemented with 90 mmol KHCO3/day. In Study B, participants received a high and a low NaCl diet (31 vs. 3 g/day), each for 14 days. During low NaCl, the diet was moderately acidified by replacement of a bicarbonate-rich mineral water (consumed during high NaCl) with a non-alkalizing drinking water. In repeatedly collected 24-h urine samples, potentially bioactive-free GCs (urinary-free cortisol + free cortisone) were analyzed, as well as tetrahydrocortisol (THF), 5α-THF, and tetrahydrocortisone (THE). With supplementation of 90 mmol KHCO3, the marker of total adrenal GC secretion (THF + 5α-THF + THE) dropped (p = 0.047) and potentially bioactive-free GCs were reduced (p = 0.003). In Study B, however, GC secretion and potentially bioactive-free GCs did not exhibit the expected fall with NaCl-reduction as net acid excretion was raised by 30 mEq/d. Diet-induced acidification/alkalization affects GC activity and metabolism, which in case of long-term ingestion of habitually acidifying western diets may constitute an independent risk factor for bone degradation and cardiometabolic diseases.

Background The majority of bicarbonate based dialysis fluids are acidified with acetate. Citrate, a well known anticoagulant and antioxidant, has been suggested as a biocompatible alternative. The objective of this study was to evaluate short term safety and biocompatibility of a citrate containing acetate-free dialysis fluid. Methods Twenty four (24) patients on maintenance dialysis three times per week, 13 on on-line hemodiafiltration (HDF) and 11 on hemodialysis (HD), were randomly assigned to start with either citrate dialysis fluid (1 mM citrate, 1.5 mM calcium) or control fluid (3 mM acetate, 1.5 mM calcium) in an open-labeled cross-over trial (6 + 6 weeks with 8 treatments wash-out in between). Twenty (20) patients, 11 on HDF and 9 on HD were included in the analyses. Main objective was short term safety assessed by acid–base status, plasma ionized calcium and parathyroid hormone (PTH). In addition, biocompatibility was assessed by markers of inflammation (pentraxin 3 (PTX-3), CRP, IL-6, TNF-α and IL-1β) and thrombogenicity (activated partial thromboplastin time (APTT) and visual clotting scores). Results No differences dependent on randomization order or treatment mode (HD vs. HDF) were detected. Citrate in the dialysis fluid reduced the intra-dialytic shift in pH (+0.04 week 6 vs. +0.06 week 0, p = 0.046) and base excess (+3.9 mM week 6 vs. +5.6 mM week 0, p = 0.006) over the study period. Using the same calcium concentration (1.5 mM), citrate dialysis fluid resulted in lower post-dialysis plasma ionized calcium level (1.10 mM vs. 1.27 mM for control, p < 0.0001) and higher post-dialysis PTH level (28.8 pM vs. 14.7 pM for control, p < 0.0001) while pre-dialysis levels were unaffected. Citrate reduced intra-dialytic induction of PTX-3 (+1.1 ng/ml vs. +1.4 ng/ml for control, p = 0.04) but had no effect on other markers of inflammation or oxidative stress. Citrate reduced visual clotting in the arterial air chamber during HDF (1.0 vs. 1.8 for control, p = 0.03) and caused an intra-dialytic increase in APTT (+6.8 s, p = 0.003) without affecting post-dialysis values compared to control. Conclusions During this small short term study citrate dialysis fluid was apparently safe to use in HD and on-line HDF treatments. Indications of reduced treatment-induced inflammation and thrombogenicity suggest citrate as a biocompatible alternative to acetate in dialysis fluid. However, the results need to be confirmed in long term studies. Trial registration ISRCTN: ISRCTN28536511

IntroductionSevere metabolic acidosis with elevated anion and osmol gap is suggestive of toxic alcohol ingestion. The absence of detectable methanol or ethylene glycol in the serum could mean that metabolism is complete or that other hypotheses have to be considered. Ingestion of less common alcohol or alcoholic ketoacidosis should be investigated as illustrated by the present observation.Case ReportA 46-year-old woman was admitted with altered consciousness in the Emergency Department. In the presence of a high anion gap (peak value 39 mEq/L) metabolic acidosis with mildly increased osmol gap (peak value 19 mOsm/kg), there was a high suspicion of toxic alcohol ingestion in an individual with alcohol use disorder (AUD). Serum arterial lactate concentration was particularly high at 27 mmol/L. Urinalysis failed to reveal the presence of ketone bodies or oxalate crystals. The results of the serum determination of ethanol, methanol, ethylene glycol, and isopropanol were obtained within 2 h and were negative. Due to the severity of lactic metabolic acidosis and the persisting suspicion of intoxication by a less common toxic alcohol, antidotal therapy with ethanol was initiated together with hemodialysis. Correction of lactic metabolic acidosis was obtained. Results of urinalysis obtained later revealed the presence not only of propylene glycol and D-lactate but also of significant concentrations of ß-hydroxybutyrate as a marker of alcoholic ketoacidosis.DiscussionThe combination of propylene glycol ingestion and alcoholic ketoacidosis may have contributed to the severity of lactic acidosis.

The aim of this study was to assess the effect of feeding high protein human milk fortifier (HMF) on growth in preterm infants. In this single-centre randomised trial, 60 infants born 28–32 weeks’ gestation were randomised to receive a higher protein HMF providing 1.8 g protein (n = 31) or standard HMF providing 1 g protein per 100 mL expressed breast milk (EBM) (n = 29). The primary outcome was rate of weight gain. Baseline characteristics were similar between groups. There was no difference between high and standard HMF groups for weight gain (mean difference (MD) −14 g/week; 95% CI −32, 4; p = 0.12), length gain (MD −0.01 cm/week; 95% CI −0.06, 0.03; p = 0.45) or head circumference gain (MD 0.007 cm/week; 95% CI −0.05, 0.06; p = 0.79), despite achieving a 0.7 g/kg/day increase in protein intake in the high protein group. Infants in the high protein group had a higher proportion of lean body mass at trial entry; however, there was no group by time effect on lean mass gains over the study. Increasing HMF protein content to 1.8 g per 100 mL EBM does not improve growth in preterm infants born 28–32 weeks’ gestation.

Metformin constitutes first-line treatment of type 2 diabetes mellitus. It is presumed to have lactic acidosis as a dangerous, but rare, side effect. To estimate the incidence rate of lactic acidosis in patients with type 2 diabetes mellitus as well as to estimate the relative risk of lactic acidosis associated with metformin treatment. This is a population-based combined cohort and case-control study among patients with type 2 diabetes mellitus who were acutely admitted with lactic acidosis at Odense University Hospital, Denmark; in the period from 1st June 2009 to 1st October 2013. The patients included as cases were all acutely hospitalized with lactic acidosis (pH <7.35 and lactate ≥2.0 mmol/l). For each case, we identified 24 age- and sex-matched controls sampled from the same cohort with type 2 diabetes mellitus. The use of metformin identified by using a prescription database. Analyses included multivariable logistic regression and adjusting for predefined confounding: renal function, HbA1c, comorbidity and diabetes duration. Our cohort included 10,652 patients with type 2 diabetes mellitus with a median age of 74 years, and 51.5% were male. During follow-up, 163 individuals were hospitalized with lactic acidosis, corresponding to an incidence rate of 391/100,000 person years. Use of metformin was not associated with lactic acidosis: adjusted odds ratio was 0.79 (95%CI 0.54-1.17). Among patients with type 2 diabetes mellitus, the incidence rate of acute hospitalization with lactic acidosis was 391/100,000 person years. Use of metformin did not increase the risk of lactic acidosis. However, comorbidity seems to be an important risk factor.

Previous evidence showed that use of phenylephrine was associated with higher umbilical artery pH (UA pH) than ephedrine after elective cesarean delivery (CD). However, the best choice of vasopressor and its effect on funic gases in cases of acute fetal compromise require additional studies. Ninety parturients showing acute fetal compromise during intrapartum period and taken up for CD (category II) under spinal anesthesia were randomized to receive prophylactic infusion of ephedrine 2.5mg/min or phenylephrine 30μg/min. Systolic blood pressure was targeted between 90% and 110% of baseline. Incidence of fetal acidosis (UA pH <7.2 and/or base deficit >12mmol/L) was recorded. Other parameters of cord gases, Apgar score, need for immediate resuscitation, maternal hemodynamics, and adverse events were also compared. Number of neonates showing acidosis with ephedrine or phenylephrine was comparable (P=.22). Of these, newborns with base deficit >12mmol had low 1-minute Apgar scores (n=15/23). The ephedrine group had higher oxygen content in UA (P=.03). There was no adverse neonatal outcome during the period of observation. Incidence of maternal nausea and vomiting was higher with ephedrine than with phenylephrine (22.2% vs 4.4%; P=.02). Maternal bradycardia was observed with phenylephrine (P=.02). Our data report similar fetal acidosis with either phenylephrine or ephedrine administered during spinal anesthesia for treating maternal hypotension in cases of emergency CD. •Fetal acidosis has been reported after spinal anesthesia.•Maintaining baseline blood pressure results in best neonatal outcome in elective CD.•Only retrospective data are available for CD indicated for acute fetal compromise.•We report fetal acidosis using vasopressor during CD for acute fetal compromise.

Background Bixalomer (BXL) was developed to improve gastrointestinal symptoms and reduce constipation, relative to sevelamer hydrochloride, in hemodialysis patients. We prospectively evaluated the safety and effectiveness of switching maintenance dialysis patients from sevelamer hydrochloride to BXL. Methods Twenty-eight patients were switched from sevelamer hydrochloride to BXL (1:1 dose) from July to October 2012, whereas 84 randomly selected patients not treated with sevelamer hydrochloride were enrolled as a control group. The primary endpoint was improvement of gastrointestinal symptoms; secondary endpoints included improvement in metabolic acidosis, changes in blood biochemistry, and safety 12 weeks after the switch. We also surveyed patient satisfaction with switching to BXL 12 weeks after the switch. Results Before switching, symptoms of epigastric fullness were significantly worse in the switch than in the control group. Twelve weeks after the switch, reflux, epigastric fullness, and constipation had improved significantly in the switch group. Other factors, including stomach ache, diarrhea, and form of stool, did not change significantly. Blood gas analysis showed that metabolic acidosis was significantly improved by switching. Four patients (14%) experienced grade 1 adverse events, all of which improved immediately after stopping BXL. Major adverse events were diarrhea and abdominal discomfort. Mean satisfaction score was 3.1 ± 0.7, with 64% of patients reporting they were “neither satisfied nor dissatisfied” after switching. Conclusions A switch from sevelamer hydrochloride to BXL improved symptoms of reflux, epigastric fullness, constipation, and metabolic acidosis in hemodialysis patients. Trial registration The study was registered as Clinical trial: ( UMIN000011150 ).