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There is no consensus on the physiologic decline in estimated glomerular filtration rate (GFR) due to geriatric conditions related with the aging or chronic kidney disease (CKD) itself. In this study, we aimed to compare the CKD progression and associated complications in a large sample of geriatric and non-geriatric patients. The data of in 506 patients at age between 30 to 90 years and diagnosed with CKD at stage 2 and above (15 mL/min/1.73 m2 ≤ eGFR < 90 mL/min/1.73 m2) were collected retrospectively and compared among geriatric (>65 years old) and non-geriatric individuals. The rate of hypertension was higher in geriatrics compared to non-geriatrics (96.6% vs 91.9%, P = .04). Among laboratory findings, only PTH level was significantly lower and HCO3 concentration was higher in geriatrics compared to non-geriatrics (P = .02, P < .001, respectively). There was no significant difference in last measured eGFR (P = .99) while that measured 4 years ago was lower in geriatrics compared to that of non-geriatrics (P < .001). eGFR change was smaller in geriatrics compared to non-geriatrics (P < .001), and rate of progressive renal disease among non-geriatric group (39%) was found to be significantly higher than in the geriatrics (17.2%) (P < .001). The prevalence of hyperkalemia was lower in geriatrics at stage 3a (P = .02); prevalence of hyperparathyroidism was lower in those at stage 3b (P = .02) and lastly the acidosis was observed significantly lower in geriatric patients at stage 3a, 3b, and 4 compared to the non-geriatrics at corresponding stages (P < .001, P = .03, and P = .04, respectively). The eGFR change was significantly smaller in geriatrics at stage 3b and 4 (P < .001 and P = .04, respectively) while the rate of progressed renal disease was lower in geriatrics at stage 3a and 3b (21.1% vs 9.9%, P = .03 and 41.2% vs 11.1%, P < .001, respectively). eGFR change in 4-year period and the rates of progressive renal disease are higher in the non-geriatrics and also the prevalence of secondary complications of CKD, such as hyperparathyroidism, acidosis, and hyperkalemia, are higher in non-geriatrics. This may reflect that decline of GFR in geriatric individuals is at least partially related to physiological aging rather than kidney disease. Therefore, devising age related CKD definitions might be appropriate., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Diabetic ketoacidosis (DKA) is a life-threatening complication of pediatric diabetes mellitus (DM). A bedside closed-loop artificial pancreas (AP) (STG-55; NIKKISO, Tokyo, Japan) maintains the blood glucose (BG) levels within the target range via automatic infusion of insulin and glucose. We report the application of the closed-loop AP to safely control the BG levels of a pediatric patient with DKA. A 12-year-old child with an unremarkable medical history presented with fever and restlessness. The patient was diagnosed with DKA secondary to fulminant type 1 DM and was treated with insulin infusion. He presented with Glasgow Coma Scale of E2V3M4. Arterial blood gas analysis revealed metabolic acidosis and BG levels of 489 mg/dL. His urine test was positive for ketones. Along with infusion therapy, automatic BG control using a closed-loop AP was initiated after ICU admission. This was adjusted to maintain BG levels within 100 mg/dL/6 h or less. After 24 h in the ICU, the patient regained consciousness and recovered from the metabolic acidosis. His general condition improved, and he was prescribed a diet treatment. The treatment was shifted to continuous insulin infusion, and he was transferred to the general ward, and was discharged on the 33rd day of hospitalization. The closed-loop AP prevented repetitive blood extractions, achieved prompt glycemic control, and prevented cerebral edema in a pediatric patient with DKA. This is the first report of successful treatment of DKA using a bedside closed-loop AP., (© 2022. The Japanese Society for Artificial Organs.)

Background: D-lactic acidosis (DLA) is a serious complication of short bowel syndrome (SBS) in children with intestinal failure (IF). Malabsorbed carbohydrates are metabolized by bacteria in the intestine to D-lactate which can lead to metabolic acidosis and neurologic symptoms., Methods: A retrospective chart review was performed in children ≤18 years old with SBS who had one of the following criteria: unexplained metabolic acidosis, neurologic signs or symptoms, history of antibiotic therapy for small bowel bacterial overgrowth, or high clinical suspicion of DLA. Cases had serum D-lactate concentration >0.25 mmol/L; controls with concentrations ≤0.25 mmol/L., Results: Of forty-six children, median age was 3.16 (interquartile range (IQR): 1.98, 5.82) years, and median residual bowel length was 40 (IQR: 25, 59) cm. There were 23 cases and 23 controls. Univariate analysis showed that cases had significantly lower median bicarbonate (19 vs. 24 mEq/L, p = 0.001), higher anion gap (17 vs. 14 mEq/L, p < 0.001) and were less likely to be receiving parenteral nutrition, compared with children without DLA. Multivariable analysis identified midgut volvulus, history of intestinal lengthening procedure, and anion gap as significant independent risk factors. Midgut volvulus was the strongest independent factor associated with DLA (adjusted odds ratio = 17.1, 95% CI: 2.21, 133, p = 0.007)., Conclusion: DLA is an important complication of pediatric IF due to SBS. Patients with IF, particularly those with history of midgut volvulus, having undergone intestinal lengthening, or with anion gap acidosis, should be closely monitored for DLA., (© 2023 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

A 58-year-old woman was admitted to our hospital. At 10 years old, she had undergone bilateral uretero-sigmoid anastomosis for congenital epispadias, and at 57 years old, she had received transverse colostomy. Biochemical tests showed marked metabolic acidosis. Computed tomography showed urine stagnation in the sigmoid colon, leading to a diagnosis of metabolic acidosis associated with transverse stoma after bilateral uretero-sigmoid anastomosis. Her bone mineral density was below normal, and the bone metabolic marker levels were high, indicating high-turnover osteoporosis. Both metabolic acidosis and bone metabolism were stabilized by treatment with a transanal urinary catheter, sodium bicarbonate, and vitamin D.

Chronic metabolic acidosis, arising as a complication of chronic kidney disease (CKD), not only reduces patients' quality of life but also aggravates renal impairment. The only available therapeutic modality, involving intravenous infusion of NaHCO 3 , engenders undesirable sodium retention, thereby increasing hemodynamic load and seriously exacerbating the primary disease. This deleterious cascade extends to the development of cardiovascular diseases. Herein, an orally administered, gut-restricted inorganic adsorbent that can effectively alleviate chronic metabolic acidosis without causing any electrolytic derangement or superfluous cardiovascular strain is developed. The genesis of ABC-350 entails the engineering of bismuth subcarbonate via annealing, thereby yielding a partially β-Bi 2 O 3 -doped (BiO) 2 CO 3 biphasic crystalline structure framework enriched with atomic vacancies. ABC-350 can selectively remove chloride ions and protons from the gastrointestinal tract, mimicking the physiological response to gastric acid removal and resulting in increased serum bicarbonate. Owing to its gut-restricted nature, ABC-350 exhibits commendable biosafety, averting undue systemic exposure. In two rat models of metabolic acidosis, ABC-350 emerges not only as a potent mitigator of acidosis but also effects discernible amelioration concerning proximal tubular morphology, interstitial fibrosis, and the incendiary cascades incited by metabolic acidosis. ABC-350, as the translationally relevant material, provides a promising strategy for the treatment of metabolic acidosis., (© 2023 Wiley-VCH GmbH.)

Although veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has been used to aid myocardial recovery in patients with postcardiotomy cardiogenic shock (PCCS), it has been associated with adverse effects. The combined use of VA-ECMO and Impella (ECPELLA) for PCCS, however, has been reported to be efficacious with few reports of thromboembolic events. We present a case of aortic thrombosis with visceral malperfusion during ECPELLA management for PCCS. We performed the Bentall procedure, mitral valve repair, tricuspid annuloplasty, and coronary artery bypass graft on a 73-year-old man admitted with congestive heart failure caused by annuloaortic ectasia, along with severe aortic and mitral regurgitation. VA-ECMO and Impella were required, since the cardiopulmonary bypass weaning was difficult. Impella was removed on postoperative day 4. On postoperative days 5 and 6, laboratory data showed worsening renal dysfunction, lactate levels, and acidosis. Contrast-enhanced computed tomography showed thrombosis in the celiac and superior mesenteric arteries. Aortic thrombectomy was performed. Hyperkalemia, caused by a reperfusion injury, resulted in ventricular fibrillation. Continuous hemodiafiltration improved the hyperkalemia. However, irreversible acidosis progressed, and the VA-ECMO flow rate could not be sustained. On postoperative day 7, the patient died. Perioperative use of Impella for PCCS may be effective in improving postoperative cardiac function. When sudden organ failure is observed after surgery, it is necessary to not only keep the exacerbation of cardiogenic shock in mind, but also the possibility of thrombosis., (© 2023. The Japanese Society for Artificial Organs.)

A 51-year-old male with a history of chronic alcoholism presented to the emergency department with an abrupt onset of complete bilateral blindness lasting for one hour. Funduscopic examination yielded unremarkable findings. Systemic evaluations revealed the presence of severe ketoacidosis. The patient spontaneously regained light perception after experiencing total blindness for 3 hours; however, he subsequently developed hypothermia and entered a state of shock. Following treatment with sodium bicarbonate and aggressive fluid resuscitation, his condition stabilized, and there was a rapid improvement in his visual acuity. The diagnosis of alcoholic ketoacidosis was established based on the patient's history of chronic alcohol abuse, physical examination findings, and blood analysis results.

We report an infant case of transient distal renal tubular acidosis and Fanconi syndrome caused by rotavirus gastroenteritis. A 10-month-old boy was admitted to the hospital because of frequent vomiting, lack of vitality, and dehydration. He was diagnosed with rotavirus gastroenteritis on account of his positive stool rotavirus antigen test. Although he presented with acidemia and severe mixed metabolic acidosis, he also had a urine pH of 6.0, indicating impaired urinary acidification. Therefore, he was diagnosed with distal renal tubular acidosis. On the third day of hospitalization, a relatively low %tubular reabsorption of phosphate level with hypophosphatemia, increased fractional excretion of uric acid with hypouricemia, and high urinary β2-microglobulin levels were observed. Moreover, he was diagnosed with Fanconi syndrome on account of multiple proximal tubular dysfunctions. After remission of rotavirus gastroenteritis, the signs of renal tubular dysfunction improved. This was a case of rotavirus gastroenteritis-caused transient distal renal tubular acidosis and Fanconi syndrome. Severe metabolic acidosis resulted from anion-gap metabolic acidosis due to acute kidney injury by rotavirus gastroenteritis and normal anion-gap acidosis due to renal tubular acidosis. When renal tubular acidosis is associated with a disease that causes anion-gap metabolic acidosis, mixed metabolic acidosis occurs and becomes exacerbated. Furthermore, it is important to consider the complications of renal tubular acidosis in the case of severe metabolic acidosis.

Objectives: Metabolic alkalosis, although uncommon in small animals, has been previously associated with gastrointestinal obstructions. Depending on the population and disease process evaluated, previous prevalence of metabolic alkalosis is reported as ranging from 2% to 45% in canine patients. The objective of this study was to determine the prevalence of metabolic alkalosis and other acid-base and electrolyte disorders in a cohort of dogs with a confirmed upper gastrointestinal obstruction., Materials and Methods: Electronic medical records were reviewed to identify dogs who presented for vomiting with evidence of an upper gastrointestinal obstruction from January 2015 to October 2021. Patients were enrolled only if a preoperative venous blood gas was obtained and analysed in house. Traditional acid-base analysis was utilised to determine an acid-base status before relieving the obstruction. When available, post-operative venous acid-base status was determined within 24 hours after surgery, and compared to preoperative results., Results: A total of 115 dogs were included in the study. Twenty-five out of 115 (22%) dogs displayed either a simple metabolic alkalosis or a mixed acid-base disturbance before surgery. Twenty-seven out of 115 dogs (37%) had a normal acid-base status at entry. Seventy-one dogs had pre- and post-operative venous blood gas results available. Metabolic alkalosis was resolved in nearly all patients post-operatively, with no patients displaying a simple metabolic alkalosis. A mixed metabolic acidosis and respiratory alkalosis was the most common condition post-operatively, found in 25 of 71 (35%) dogs. Severe derangements of electrolytes were infrequent preoperatively (3/115; 2.6%). A majority of patients in this study exhibited hypokalaemia (64.4%), hypochloraemia (72.8%) and hyponatraemia (77.4%) on preoperative venous blood gases. Venous pH, P v CO 2 , bicarbonate and base excess were significantly higher preoperatively when compared to the post-operative results., Clinical Significance: This study found the prevalence of pre-operative metabolic alkalosis in dogs with a documented upper gastrointestinal obstruction to be lower than previously reported. Surgical or endoscopic alleviation of the upper gastrointestinal obstruction resulted in resolution of metabolic alkalosis in nearly all patients., (© 2023 British Small Animal Veterinary Association.)

Purpose: To investigate the risks of metabolic acidosis and renal outcomes after topical carbonic anhydrase inhibitor (CAI) use in patients with both primary open-angle glaucoma (POAG) and advanced chronic kidney disease (CKD)., Design: Nationwide, population-based cohort study., Methods: This study was conducted with population data from Taiwan's National Health Insurance (NHI) Research Database between January 2000 and June 2009. Patients with advanced CKD who were diagnosed with glaucoma (International Classification of Diseases, Ninth Revision [ICD-9] code 365) and had been receiving eye drops for glaucoma (including carbonic anhydrase inhibitors selected by NHI drug code) were enrolled. Using Kaplan-Meier methods, we compared the cumulative incidence of mortality, long-term dialysis, and cumulative incidence of metabolic acidosis over time between CAI users and CAI non-users. Primary outcomes comprised mortality, renal outcome (progression to hemodialysis), and metabolic acidosis., Results: In this cohort, topical CAI users had a higher incidence of long-term dialysis than non-users (incidence = 1,216.85 vs 764.17 events per 100 patient-years; adjusted hazard ratio = 1.17, 95% CI = 1.01-1.37). Hospital admissions due to metabolic acidosis were higher in CAI users compared with non-users (incidence = 21.54 vs 11.87 events per 100 patient-years; adjusted hazard ratio = 1.89, 95% CI = 1.07-3.36)., Conclusions: Topical CAIs may be associated with higher risks of long-term dialysis and metabolic acidosis in patients with POAG and pre-dialysis advanced CKD. Therefore, topical CAIs should be used with caution in advanced CKD patients., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Endocrinological or metabolic disorders often affect a wide variety of functions of the organism. This can also include an impairment of respiratory function. Diabetic ketoacidosis as a result of insulin deficiency is a typical metabolic acidosis, which the body tries to compensate by an increased exhalation of carbon dioxide. This leads to the classic picture of "Kussmaul" breathing. Due to the increased use of SGLT2 inhibitors, which can reduce the otherwise typical hyperglycemia and thus complicate diagnosis, the occurrence of diabetic ketoacidosis has remained an important differential diagnosis in recent years. Pathologies of the thyroid gland can lead to dyspnea not only by morphological changes, for example in the case of goiter (compression). Functional disorders must also be considered here. Both hypo- and hyperthyroidism affect the cardiovascular system in different ways and may ultimately lead to the clinical picture of dyspnea. If the corresponding entities are thought of, the laboratory diagnosis of the aforementioned metabolic/endocrinological disorders is then basically straightforward. Accordingly, knowledge of these disorders as a differential diagnosis of tachy- and dyspnea is important., (© 2023 Aerzteverlag medinfo AG.)

Pseudohypoaldosteronism (PHA) type II (PHA2) is a genetic disorder that leads to volume overload and hyperkalemic metabolic acidosis. PHA2 and PHA type I (PHA1) have been considered to be genetic and pediatric counterparts to type IV renal tubular acidosis (RTA). Type IV RTA is frequently found in adults with chronic kidney disease and is characterized by hyperchloremic hyperkalemic acidosis with normal anion gap (AG). However, we recently observed that PHA1 was not always identical to type IV RTA. In this study, we focused on the acid-base balance in PHA2. Through a literature search published between 2008-2020, 46 molecularly diagnosed cases with PHA2 were identified (median age of 14 years). They comprised 11 sets of familial and 16 sporadic cases and the pathology was associated with mutations in WNK 4 (n = 1), KLHL3 (n = 17), and CUL3 (n = 9). The mean potassium (K + ) level was 6.2 ± 0.9 mEq/L (n = 46, range 4.0-8.6 mEq/L), whereas that of chloride (Cl - ) was 110 ± 3.5 mEq/L (n = 41, 100-119 mEq/L), with 28 of 41 cases identified as hyperchloremic. More than half of the cases (18/35) presented with metabolic acidosis. Although AG data was obtained only in 16 cases, all but one cases were within normal AG range. Both Cl - and HCO3 - levels showed significant correlations with K + levels, which suggested that the degree of hyperchloremia and acidosis reflect the clinical severity, and is closely related to the fundamental pathophysiology of PHA2. In conclusion, our study confirmed that PHA2 is compatible with type IV RTA based on laboratory findings.

Sensing acidosis is an important somatosensory function in responses to ischemia, inflammation, and metabolic alteration. Accumulating evidence has shown that acidosis is an effective factor for pain induction and that many intractable chronic pain diseases are associated with acidosis signaling. Various receptors have been known to detect extracellular acidosis and all express in the somatosensory neurons, such as acid sensing ion channels (ASIC), transient receptor potential (TRP) channels and proton-sensing G-protein coupled receptors. In addition to sense noxious acidic stimulation, these proton-sensing receptors also play a vital role in pain processing. For example, ASICs and TRPs are involved in not only nociceptive activation but also anti-nociceptive effects as well as some other non-nociceptive pathways. Herein, we review recent progress in probing the roles of proton-sensing receptors in preclinical pain research and their clinical relevance. We also propose a new concept of sngception to address the specific somatosensory function of acid sensation. This review aims to connect these acid-sensing receptors with basic pain research and clinical pain diseases, thus helping with better understanding the acid-related pain pathogenesis and their potential therapeutic roles via the mechanism of acid-mediated antinociception., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Infants with perinatal asphyxia are at risk for organ failure aside from the brain, regardless of the severity of the asphyxial insult. We aimed to evaluate the presence of organ dysfunction other than the brain in newborns with moderate to severe acidosis at birth, in the absence of moderate to severe hypoxic ischemic encephalopathy., Materials and Methods: Data of 2 years were retrospectively recorded. Late preterm and term infants admitted to the intensive care unit with ph < 7.10 and BE < -12 mmol/l in the first hour were included in the absence of moderate to severe hypoxic ischemic encephalopathy. Respiratory dysfunction, hepatic dysfunction, renal dysfunction, myocardial depression, gastrointestinal problems, hematologic system dysfunction, and circulatory failure were evaluated., Results: Sixty-five infants were included [39 (37-40) weeks, 3040 (2655-3380) grams]. Fifty-six (86 %) infants had one or more dysfunction in any system [respiratory: 76.9 %, hepatic: 20.0 %, coagulation: 18.5 %, renal: 9.2 %, hematologic: 7.7 %, gastrointestinal: 3.0 %, and cardiac: 3.0 %]. Twenty infants had at least two affected systems. The incidence of coagulation dysfunctions was higher in the infants with severe acidosis (n = 25, ph < 7.00) than the infants with moderate acidosis (n = 40: pH = 7.00-7.10); 32 % vs 10 %; p = 0.03., Conclusions: Moderate to severe fetal acidosis is associated with the development of extra-cranial organ dysfunctions in infants who do not require therapeutic hypothermia. A monitoring protocol is needed for infants with mild asphyxia in order to identify and manage potential complications. Coagulation system should be carefully evaluated., Competing Interests: Conflict of interest Authors declare no financial or non-financial conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: Studies have shown that low or high serum bicarbonate levels (reflecting metabolic acidosis or alkalosis) are associated with increased all-cause mortality rates in moderate and advanced chronic kidney disease (CKD) cases. Correction of presumed acidosis using sodium bicarbonate, targeting serum levels around 22 mmol/L, has proven to be beneficial in delaying the progression of the disease and provided mortality benefit. A similar prognostic association may exist between uncorrected metabolic acidosis in chronic liver disease. Correcting it with sodium-containing salts may require more interventions due to increased sodium/fluid load. In patients with liver failure, a naturally alkalotic state, where sodium load is a concern, the impact of this intervention is unclear., Design: This study aims to generate proof of concept through a retrospective chart review in individuals with CKD-related metabolic acidosis and liver cirrhosis., Result: Our analysis revealed a statistically significant association between the need for paracentesis and bicarbonate therapy. Our study has multiple drawbacks, including a retrospective chart review and limitation of data due to single-center patients., Conclusion: We extrapolate that lowering bicarbonate targets in other clinical scenarios like liver failure, pregnancy, and cardiac failure may be prudent and will lead to a lower sodium load., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Euglycemic diabetic ketoacidosis associated with SGLT2 inhibitors is a rare, relatively new and potentially fatal clinical entity, characterized by metabolic acidosis with normal or only moderately elevated glycemia. The mechanisms are not fully understood but involve increased ketogenesis and complex renal metabolic dysfunction, resulting in both ketoacidosis and hyperchloremic acidosis. We report a rare case of fatal empagliflozin-associated acidosis with profound hyperchloremia and review its pathogenesis., Case Presentation: A patient with type 2 diabetes mellitus treated with empagliflozin underwent an elective hip replacement surgery. Since day 4 after surgery, he felt generally unwell, leading to cardiac arrest on the day 5. Empagliflozin-associated euglycemic diabetic ketoacidosis with severe hyperchloremic acidosis was identified as the cause of the cardiac arrest., Conclusions: This unique case documents the possibility of severe SGLT2 inhibitor-associated mixed metabolic acidosis with a predominant hyperchloremic component. Awareness of this possibility and a high index of suspicion are crucial for correct and early diagnosis., (© 2023. The Author(s).)

Significance Statement: Renal osteodystrophy (ROD) contributes substantially to morbidity in CKD, including increased fracture risk. Metabolic acidosis (MA) contributes to the development of ROD, but an up-to-date skeletal phenotype in CKD-associated acidosis has not been described. We comprehensively studied associations between acidosis and bone in patients with CKD using advanced methods to image the skeleton and analyze bone-tissue, along with biochemical testing. Cross-sectionally, acidosis was associated with higher markers of bone remodeling and female-specific impairments in cortical and trabecular bone quality. Prospectively, acidosis was associated with cortical expansion and trabecular microarchitectural deterioration. At the bone-tissue level, acidosis was associated with deficits in bone mineral content. Future work investigating acidosis correction on bone quality is warranted., Background: Renal osteodystrophy is a state of impaired bone quality and strength. Metabolic acidosis (MA) is associated with alterations in bone quality including remodeling, microarchitecture, and mineralization. No studies in patients with CKD have provided a comprehensive multimodal skeletal phenotype of MA. We aim to describe the structure and makeup of bone in patients with MA in the setting of CKD using biochemistry, noninvasive imaging, and histomorphometry., Methods: The retrospective cross-sectional analyses included 180 patients with CKD. MA was defined as bicarbonate ≤22 mEq/L. We evaluated circulating bone turnover markers and skeletal imaging with dual energy x-ray absorptiometry and high-resolution peripheral computed tomography. A subset of 54 participants had follow-up. We assessed associations between baseline and change in bicarbonate with change in bone outcomes. Histomorphometry, microCT, and quantitative backscatter electron microscopy assessed bone biopsy outcomes in 22 participants., Results: The mean age was 68±10 years, 54% of participants were male, and 55% were White. At baseline, acidotic subjects had higher markers of bone turnover, lower areal bone mineral density at the radius by dual energy x-ray absorptiometry, and lower cortical and trabecular volumetric bone mineral density and impaired trabecular microarchitecture. Over time, acidosis was associated with opposing cortical and trabecular effects: cortical expansion but trabecular deterioration. Bone-tissue analyses showed reduced tissue mineral density with increased heterogeneity of calcium distribution in acidotic participants., Conclusions: MA is associated with multiple impairments in bone quality. Future work should examine whether correction of acidosis improves bone quality and strength in patients with CKD., (Copyright © 2023 by the American Society of Nephrology.)

Aim: The aim of this study was to investigate how individual markers for birth asphyxia, so-called A criteria, were associated with the probability of receiving therapeutic hypothermia., Methods: This population-based cohort study included 1336 live-born singleton term infants with any A criterion in the Stockholm-Gotland Region, Sweden during 2008 to 2014. The Swedish Neonatal Quality Register and National Patient Register were used for data collection. Results were presented as adjusted odds ratios (aORs) with 95% confidence intervals (CIs)., Results: There were 89 infants, 44 boys and 45 girls with mean gestational age 40.5 weeks, who received therapeutic hypothermia. Low Apgar score, aOR 12.44 (95% CI 5.99-25.86), and resuscitation, aOR 9.18 (95% CI 3.77-22.34), were strongly associated with therapeutic hypothermia. A pH <7.0 was less associated with the outcome, aOR 2.02 (95% CI 1.02-4.0). No infant who received therapeutic hypothermia fulfilled the criteria of base deficit ≥16 mmol/L only., Conclusion: A low Apgar score of and/or a need for resuscitation is more relevant for identifying infants eligible for therapeutic hypothermia, compared to other A criteria. This knowledge could be used clinically to identify cases for review and avoid unnecessary monitoring of infants., (© 2022 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Metabolic acidosis is a common complication in patients with chronic kidney disease that occurs when the daily nonvolatile acid load produced in metabolism cannot be excreted fully by the kidney. A reduction in urine net acid excretion coupled with a high nonvolatile acid load may play a role in its pathogenesis. Diet is important in generation of the nonvolatile acid load. Acids are produced from metabolism of dietary protein and from the endogenous production of organic anions from neutral precursors. Acids can be balanced by alkali precursors ingested in the diet in the form of combustible organic anions. These typically are reflected indirectly by the excess of mineral cations to mineral anions in a food or diet. These principles underscore widely used methods to estimate the nonvolatile acid load from dietary intake using formulas such as the net endogenous acid production equation and the potential renal acid load equation. Empiric data largely validate these paradigms with high net endogenous acid production and potential renal acid load contributed by foods such as protein, grains, and dairy, and low net endogenous acid production and potential renal acid load contributed by fruits and vegetables along with corresponding dietary patterns. Although further studies are needed to understand the health benefits of altering nonvolatile acid load via diet, this review provides a detailed assessment on our current understanding of the role of diet in chronic kidney disease-related acidosis, providing an updated resource for researchers and clinicians., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Acidosis is the most dangerous complication in subarachnoid hemorrhage (SAH). This study aimed to investigate the effect of acidic cerebrospinal fluid on central canal structures after SAH., Materials and Methods: Twenty-eight hybrid rabbits were studied. Blood and cerebrospinal fluid pH values were recorded before/during/after the experimental procedures. The structures related to the central canals at the level of C5 of the cervical spinal cord were then examined histopathologically. The relationship between pH values of ependymal cells and degenerated epithelial cell densities was statistically analyzed., Results: Mean blood pH values and degenerated ependymal cell density (n/mm 2 ) were as follows: 7.351 ± 0.033/23 ± 7 in control, 7.322 ± 0.059/78 ± 13 in SHAM, and 7.261 ± 0.048/254 ± 62 in study animals. Gross examinations revealed swelling, edema, pia-arachnoid adhesions, ventral canal dilatation, arachnoiditis, central canal hemorrhage, occlusions, and dilatation in the spinal cord., Conclusion: Cerebrospinal fluid acidosis-induced central channel pathologies should be considered an important complication of SAH following SAH., (Copyright: © 2023 Permanyer.)

Background: Serum creatinine and albuminuria are primary markers of glomerular function and injury, respectively. Tubular secretion, acid-base homeostasis, protein reabsorption, among other tubular functions, are largely ignored. This mini-review aimed to discuss how two tubular functions, secretion, and acid-base homeostasis are associated with major adverse kidney events (MAKEs)., Summary: Proximal tubular secretion is an essential function that allows the elimination of endogenous substances and drugs. Recently discovered endogenous markers in urine and plasma allow a noninvasive way of assessing tubular secretion markers. Several studies have found an association between these markers and a higher risk of chronic kidney disease (CKD) progression and mortality. In a study we recently performed among patients with CKD and at risk of cardiovascular events, lower tubular secretion was associated with an increased risk of acute kidney injury and metabolic acidosis, independent of baseline eGFR and albuminuria. The kidney tubules also play a crucial role in acid-base homeostasis. Although the standard clinical assessment of acidosis consists of measuring serum bicarbonate, urinary ammonium excretion decreases before over metabolic acidosis. Urinary ammonium excretion is associated with CKD progression, a higher risk of kidney failure, and an increased mortality risk, independent of baseline eGFR and albuminuria., Key Messages: Novel biomarkers of kidney tubular health consistently associate with MAKEs, above and beyond baseline eGFR, albuminuria, and other CKD risk factors. Tubular markers may provide new opportunities to improve kidney prognosis, drug dosing, and monitoring for adverse events., (© 2023 S. Karger AG, Basel.)

Background: Isotonic crystalloids are the preferred solution for the initial clinical management of patients with multiple trauma, among which lactated Ringer's solution and normal saline are the most widely used, but both have clinical limitations. Bicarbonated Ringer's solution (BRS), which provides physiological levels of bicarbonate ions and electrolyte ions, can be used to supplement missing extracellular fluid and correct metabolic acidosis., Methods: A prospective, randomized controlled study enrolled 63 patients with traumatic hepatic rupture and hemorrhagic shock. They were randomly assigned to the Bicarbonated group (n = 33) or the Control group (n = 30), which received restrictive fluid resuscitation with sodium bicarbonate Ringer's solution or sodium lactate Ringer's solution, respectively. The levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, arterial blood lactic acid and potential of hydrogen (pH) were measured prior to, 1, 3, 24, and 72 hours following resuscitation. The primary outcomes were patient survival, shock-related complications, and comparison of the inflammatory factors., Results: The incidence of complications in the Bicarbonated group was significantly lower than in the Control group (15.15% vs 40.0%; P < .05). The intensive care unit length of stay and mechanical ventilation time in the Bicarbonated group were significantly shorter than in the Control group (all P < .01). The levels of IL-6 and TNF-α in the Bicarbonated group were significantly lower 1 hour following resuscitation than prior to resuscitation (P < .01), whereas these levels in the Control group were increased following 1h of resuscitation as compared with before resuscitation (P < .01). Following resuscitation, the levels of IL-6, TNF-α and lactate in the Bicarbonated group were significantly lower than in the Control group (P < .01). Moreover, in the Bicarbonated group, the lactic acid level decreased and the pH value increased significantly following resuscitation, whereas there was no difference in lactic acid levels and pH value between pre- and 1 hour post-resuscitation in the Control group (P > .05)., Conclusion: The shock-related complications were dramatically reduced from using BRS in these patients. Additionally, the BRS was found to better inhibit the expression of inflammatory factors in their peripheral blood and could correct acidosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

During the progression of diabetic kidney disease (DKD), renal lactate metabolism is rewired. The relationship between alterations in renal lactate metabolism and renal fibrosis in patients with diabetes has only been partially established due to a lack of biopsy tissues from patients with DKD and the intricate mechanism of lactate homeostasis. The role of lactate dehydrogenase A (LDHA)-mediated lactate generation in renal fibrosis and dysfunction in human and animal models of DKD was explored in this study. Measures of lactate metabolism (urinary lactate levels and LDHA expression) and measures of DKD progression (estimated glomerular filtration rate and Wilms' tumor-1 expression) were strongly negatively correlated in patients with DKD. Experiments with streptozotocin-induced DKD rat models and the rat renal mesangial cell model confirmed our findings. We found that the pathogenesis of DKD is linked to hypoxia-mediated lactic acidosis, which leads to fibrosis and mitochondrial abnormalities. The pathogenic characteristics of DKD were significantly reduced when aerobic glycolysis or LDHA expression was inhibited. Further studies will aim to investigate whether local acidosis caused by renal LDHA might be exploited as a therapeutic target in patients with DKD., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Mortality in severe malaria remains high in children treated with intravenous artesunate. Acute kidney injury (AKI) is a common complication of severe malaria, but the interactions between AKI and other complications on the risk of mortality in severe malaria are not well characterized., Methods: Between 2014 and 2017, 600 children aged 6-48 months to 4 years hospitalized with severe malaria were enrolled in a prospective clinical cohort study evaluating clinical predictors of mortality in children with severe malaria., Results: The mean age of children in this cohort was 2.1 years (standard deviation, 0.9 years) and 338 children (56.3%) were male. Mortality was 7.3%, and 52.3% of deaths occurred within 12 hours of admission. Coma, acidosis, impaired perfusion, AKI, elevated blood urea nitrogen (BUN), and hyperkalemia were associated with increased mortality (all P < .001). AKI interacted with each risk factor to increase mortality (P < .001 for interaction). Children with clinical indications for dialysis (14.4% of all children) had an increased risk of death compared with those with no indications for dialysis (odds ratio, 6.56; 95% confidence interval, 3.41-12.59)., Conclusions: AKI interacts with coma, acidosis, or impaired perfusion to significantly increase the risk of death in severe malaria. Among children with AKI, those who have hyperkalemia or elevated BUN have a higher risk of death. A better understanding of the causes of these complications of severe malaria, and development and implementation of measures to prevent and treat them, such as dialysis, are needed to reduce mortality in severe malaria., Competing Interests: Potential conflicts of interest. A. L. C. reports being a member of the XXV pediatric Acute Dialysis Quality Initiative on Setting the Landscape and Designing the Future of Pediatric Critical Care Nephrology. C. C. J. reports participation on FEVER DSMB (Birbeck, principal investigator) and Treating Brain Welling in Cerebral Malaria (Taylor, principal investigator). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Introduction: Hypoaldosteronism can be congenital or acquired, isolated or part of primary adrenal insufficiency, and caused by an aldosterone deficit, resistance, or a combination of both. Reduced mineralocorticoid action can induce a decrease in urine K+ and H+ excretion and an increase in urine Na+ excretion, leading to hyperkalemia, and/or hyponatremia, often combined with metabolic acidosis. We aimed to characterize the clinical manifestations of hypoaldosteronism, and their associated factors., Methods: Retrospective analysis of 112 episodes of hypoaldosteronism diagnosed in 86 adult patients from 2012-2019 by the Endocrinology and Nutrition Department of a tertiary hospital. The frequency of hyperkalemia, hypovolemic hyponatremia (HH) and metabolic acidosis (MA), and their associated factors were evaluated., Results: Patients had a median age of 77 [65 - 84], 55.4% were male. 94.6% cases showed hyperkalemia, 54.5% HH, and 60.3% MA. The mean serum K+ of all cases was 5.4 ± 0.5 mmol/L, Na+: 132.1 ± 6.3 mmol/L, HCO3: 22.6 ± 3.3 mmol/L. Hypoaldosteronism was isolated in the majority of cases: only 6/112 (5%) had primary adrenal insufficiency. Hypovolemia was associated with hyponatremia and a more florid clinical presentation. HH was associated with a combined presence of aldosterone-lowering and mineralocorticoid resistance factors. MA was associated with the presence of mineralocorticoid resistance factors., Conclusions: Hypoaldosteronism in adult endocrinological clinical practice is primarily isolated, and acquired. It predisposes not only to the development of hyperkalemia and MA, but also to that of HH. Hypoaldosteronism must be considered in the differential diagnosis of HH with urinary sodium wasting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ruiz-Sánchez, Calle-Pascual, Rubio-Herrera, De Miguel Novoa, Gómez-Hoyos and Runkle.)

Objectives: Neonatal-onset organic acidemias (OAs) account for 80% of neonatal intensive care unit (NICU) admissions due to inborn errors of metabolism. The aim of this study is to analyze clinical features and follow-up of neonates diagnosed with OAs in a metabolic referral center, focusing on perinatal characteristics and the impact of first the metabolic crisis on long-term outcome., Methods: Perinatal features, clinical and laboratory characteristics on admission and follow-up of 108 neonates diagnosed with OAs were retrospectively analyzed. Global developmental delay, abnormal electroencephalogram (EEG) or brain magnetic resonance imaging (MRI), chronic complications, and overall mortality. Associations between clinical findings on admission and outcome measures were evaluated., Results: Most prevalent OA was maple syrup urine disease (MSUD) (34.3%). Neonates with methylmalonic acidemia (MMA) had significantly lower birth weight (p<0.001). Metabolic acidosis with increased anion gap was more frequent in MMA and propionic acidemia (PA) (p=0.003). 89.1% of OAs were admitted for recurrent metabolic crisis. 46% had chronic non-neurologic complications; 19.3% of MMA had chronic kidney disease. Abnormal findings were present in 26/34 of EEG, 19/29 of MRI studies, and 32/33 of developmental screening tests. Metabolic acidosis on admission was associated with increased incidence of abnormal EEG (p=0.005) and overall mortality (p<0.001). Severe hyperammonemia in MMA was associated with overall mortality (33.3%) (p=0.047). Patients diagnosed between 2007-2017 had lower overall mortality compared to earlier years (p<0.001)., Conclusions: Metabolic acidosis and hyperammonemia are emerging predictors of poor outcome and mortality. Based on a large number of infants from a single center, survival in neonatal-onset OA has increased over the course of 30 years, but long-term complications and neurodevelopmental results remain similar. While prompt onset of more effective treatment may improve survival, newer treatment modalities are urgently needed for prevention and treatment of chronic complications., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Functional gastrointestinal disorders (FGIDs) are common in early childhood. It has been demonstrated that neonatal acidemia at delivery can lead to significant neonatal morbidity. The primary aim of this study was to evaluate the relationship between acidemia at birth and the development of FGIDs, as regurgitation, colic, and constipation, in term infants. Term newborns born at the Foggia University Hospital, Italy during the year 2020 were included in the study. As per routine clinical practice, a cord blood gas analysis on a blood sample drawn from the umbilical artery (UA) of each infant immediately after birth was performed, and Apgar score was recorded. One year after birth, each infant's parents were interviewed through a phone call to investigate development of FGIDs, feeding practices, and morbidities. During the study period, 1574 term newborns met the inclusion criteria. The prevalence of infantile colic, regurgitation, and constipation was higher in infants with low UA pH (colic 51.5% vs. 25.4%, p < 0.001; regurgitation 30.6% vs. 15.2%, p < 0.001; constipation 24.6% vs. 16.0%, p = 0.015), with infants having moderate-severe acidemia facing the highest risk for all the examined FGIDs. In binary logistic regression analyses, UA pH and perinatal antibiotic exposure proved to be independently associated with the later diagnosis of each FGID., Conclusion: Newborns with acidemia at birth appear to face a higher risk of FGIDs in infancy. Avoiding low cord blood pH should continue to be the goal for obstetricians, while enhanced long-term surveillance for infants who experienced birth acidemia should be required., What Is Known: • Cord blood gas analysis is recommended in all high-risk deliveries, and in some centers, it is performed after all deliveries. • Neonatal acidemia at birth has been linked to adverse outcomes, mainly neurological. Recently, perinatal asphyxia has been reported to increase the risk of developing necrotizing enterocolitis in term infants., What Is New: • An association between acidemia at birth and risk of developing FGIDs such as regurgitation and colic during the first year of life had never been described so far. • An increased surveillance of infants with low UA pH at birth may be beneficial and could allow for early detection of any of the reported FGIDs., (© 2022. The Author(s).)

Background: The prevalence of chronic kidney disease (CKD) is increasing worldwide; black patients have an increased risk of developing CKD and end stage kidney disease (ESKD) at significantly higher rates than other races., Methods: A cross sectional study was carried out on black patients with CKD attending the kidney outpatient clinic at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) in South Africa, between September 2019 to March 2020. Demographic and clinical data were extracted from the ongoing kidney outpatient clinic records and interviews, and were filled in a questionnaire. Patients provided blood and urine for laboratory investigations as standard of care, and data were descriptively and inferentially entered into REDcap and analysed using STATA version 17. Multivariable logistic regression analysis was used to identify demographic and clinical variables associated with advanced CKD., Results: A total of 312 black patients with CKD were enrolled in the study with a median age of 58 (IQR 46-67) years; 58% patients had advanced CKD, 31.5% of whom had grossly increased proteinuria, 96.7% had hypertension, 38.7% had diabetes mellitus and 38.1% had both hypertension and diabetes mellitus. In patients with advanced CKD, the median age was 61 (IQR 51-69) years, eGFR 33 (30-39) mL/min/1.73 m2, serum bicarbonate 22 (IQR 20-24), haemoglobin 12.9 (IQR 11.5-14.0) g/dl and serum uric acid 0.43 (IQR 0.37-0.53). The prevalence of metabolic acidosis was 62.4%, anemia 46.4% and gout 30.9% among those with advanced CKD, while the prevalence of metabolic acidosis and anaemia was 46.6% and 25.9% respectively in those with early CKD. Variables with higher odds for advanced CKD after multivariable logistic regression analysis were hypertension (OR 3.3, 95% CI 1.2-9.2, P = 0.020), diabetes mellitus (OR 1.8, 95% CI 1.1-3.3, P = 0.024), severe proteinuria (OR 3.5, 95% CI 1.9-6.5, P = 0.001), angina (OR 2.5, 95% CI 1.2-5.1, P = 0.008), anaemia (OR 2.9, 95% CI 1.7-4.9, P = 0.001), hyperuricemia (OR 2.4, 95% CI 1.4-4.1, P = 0.001), and metabolic acidosis (OR 2.0, 95% CI 1.2-3.1, P = 0.005). Other associations with advanced CKD were loss of spouse (widow/widower) (OR 3.2, 95% CI 1.4-7.4, P = 0.006), low transferrin (OR 2.4, 95% CI 1.1-5.1, P = 0.028), hyperkalemia (OR 5.4, 95% CI 1.2-24.1, P = 0.029), use of allopurinol (OR 2.4, 95% CI 1.4-4.3, P = 0.005) and doxazosin (OR 1.9, 95% CI 1.2-3.1, P = 0.006)., Conclusion: Hypertension and diabetes mellitus were strongly associated with advanced CKD, suggesting a need for primary and secondary population-based prevention measures. Metabolic acidosis, anemia with low transferrin levels, hyperuricemia and hyperkalemia were highly prevalent in our patients, including those with early CKD, and they were strongly associated with advanced CKD, requiring clinicians and dietitians to be proactive in supporting the needs of CKD patients in meeting their daily dietary requirements towards preventing and slowing the progression of CKD., Competing Interests: The authors have declared that no competing interests exist.

Chronic kidney disease (CKD) in children has a significant impact on morbidity, mortality, and quality of life. The degree of renal dysfunction should be calculated using pediatric-specific formulas and the degree of CKD staged; this allows for appropriate dosing of medications based on renal function and monitoring for progression and comorbid conditions including metabolic acidosis, bone disease, anemia, cardiovascular complications, malnutrition and electrolyte abnormalities, growth failure, and psychosocial issues. Treatment strategies include treating the underlying disease and using general renal protective measures. Effective management of these complex issues requires a specialized multidisciplinary team approach., Competing Interests: Disclosure V. Panzarino, J. Lesser, and F.A. Cassini do not have any commercial or financial conflicts of interest or related funding sources relevant to the authorship of this article., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: There are variable complications of hyperthyroidism, including atrial fibrillation, heart failure, osteoporosis, and thyroid storm. One infrequent complication of hyperthyroidism is non-diabetic ketoacidosis (NDKA). To the best of our knowledge, our case is the third report of NDKA related to thyrotoxicosis., Patient Concern: We describe a case of a 41-year-old African lady with no past medical history presented to our hospital with severe abdominal pain and vomiting for three weeks. This was associated with decreased appetite and weight loss., Diagnosis: Laboratory findings were significant for high anion gap metabolic acidosis, positive ketones in the urine, and high serum B-hydroxybutyrate. The blood glucose readings and HbA1c were within normal limits. Also, serum lactic acid and salicylate levels were within the normal range. The diagnosis of NDKA was made. Later, the thyroid functions test (TFT) confirmed the diagnosis of primary hyperthyroidism., Intervention and Outcomes: The patient was managed initially with intravenous fluid and antiemetics. Then, she was started on propranolol and carbimazole. After which, her symptoms improved dramatically, and the metabolic acidosis (with serum ketones) were corrected within a few days of starting anti-thyroid medications., Conclusion: Despite its rarity, NDKA can be associated with severe thyrotoxicosis. Vigorous intravenous hydration and anti-thyroid medication are the mainstay treatment. TFT should be requested in a patient with unexplained NDKA., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Diabetic ketoacidosis (DKA) is a complication of diabetes presenting with high anion gap metabolic acidosis. Methanol poisoning, on the other hand, is a toxicology emergency which presents with the same feature. We present a case of methanol poisoning who presented with DKA., Case Presentation: A 28-year-old male was referred to us with blurred vision and loss of consciousness three days after ingestion of 1.5 L of an unknown mixture of bootleg alcoholic beverage. He had history of insulin-dependent diabetes and had neglected his insulin shots on the day prior to hospital admission due to progressive loss of consciousness. Vital signs were normal and venous blood gas analysis showed severe metabolic acidosis and a methanol level of 10.2 mg/dL. After eight hours of hemodialysis, he remained unresponsive. Diabetic ketoacidosis was suspected due to positive urine ketone and blood sugar of 411 mg/dL. Insulin infusion was initiated which was followed by full awakening and extubation. He was discharged completely symptom-free after 4 weeks., Conclusions: Diabetic ketoacidosis and methanol poisoning can happen simultaneously in a diabetic patient. Given the analogous high anion gap metabolic acidosis, physicians should pay particular attention to examination of the diabetic patients. Meticulous evaluation for both conditions is highly recommended., (© 2022. The Author(s).)

Type 3 renal tubular acidosis is a pathological condition characterized by the simultaneous occurrence of distal renal tubular acidosis, which causes urinary acidification disorders, and proximal renal tubular acidosis, which causes impaired reabsorption of bicarbonate ions. Type 3 renal tubular acidosis is considered rare. A 5-year-old boy was admitted to our hospital because of frequent vomiting, poor vitality, and fever. He was diagnosed with cyclic vomiting syndrome. Type 3 renal tubular acidosis was also diagnosed because of severe mixed metabolic acidosis with impaired urinary acidification, a low tubular phosphorus reabsorption rate with hypophosphatemia, low-molecular-weight proteinuria, pan-aminoaciduria, and glucosuria. Fluid infusion was performed. On the second day of hospitalization, the vomiting disappeared and the patient was able to eat and drink. He was discharged on the eighth day of hospitalization. The laboratory test abnormalities associated with the renal tubular acidosis gradually improved, and testing at discharge on the eighth day of admission showed no metabolic acidosis, hypophosphatemia, low-molecular-weight proteinuria, or glucosuria. These findings suggested that the type 3 renal tubular acidosis was transient. Severe metabolic acidosis was observed in this patient because of both normal anion gap metabolic acidosis due to type 3 renal tubular acidosis and anion gap metabolic acidosis due to cyclic vomiting syndrome. Although type 3 tubular acidosis is rare, the resultant metabolic acidosis worsens when combined with a disease that causes metabolic acidosis. Type 3 tubular acidosis should be ruled out when severe metabolic acidosis is present.

We report the case of a 36-year-old woman who developed non-diabetic ketoacidosis following a low carbohydrate diet in order to lose weight while actively breast feeding her newborn. She was admitted in intensive care unit because of severe metabolic acidosis. She rapidly recovered after refeeding process. Lactation ketoacidosis, a special condition that occurs in non-diabetic breastfeeding women, is rare and life-threatening. This report highlights the importance of nutritional education of lactating women in the post-partum period., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The relationship between acidosis and coagulopathy has long been described in vitro and in trauma patients, but not yet in orthotopic liver transplantation (OLT). The association of metabolic acidosis with coagulopathy and with transfusion requirements was evaluated in patients submitted to OLT. Changes in acid-base and coagulation parameters were analyzed by repeated measures. Regression analyses [adjusted for sex, age, model for end stage liver disease (MELD) score, and baseline values of hemoglobin, fibrinogen, international normalized ratio, platelets] determined the association of acid-base parameters with coagulation markers and transfusion requirement. We included 95 patients, 66% were male, 49.5% of the patients had hepatocellular carcinoma and the mean MELD score was 20.4 (SD 8.9). The values of all the coagulation and acid-base parameters significantly changed during OLT, particularly in the reperfusion phase. After adjustments for baseline parameters, the decrease in pH and base excess (BE) values were associated with a decrease in fibrinogen levels (mean decrease of fibrinogen level = 14.88 mg/dL per 0.1 unit reduction of pH values and 3.6 mg/dL per 1 mmol/L reduction of BE levels) and an increase in red blood cells transfusion (2.16 units of RBC per 0.1 unit reduction of pH and 0.38 units of RBC per 1 mmol/L reduction of BE levels). Among multiple factors potentially associated with adverse outcomes, decreasing pH levels were independently associated with the length of hospitalization but not with in-hospital mortality. Metabolic acidosis is independently associated with decreased fibrinogen levels and increased intraoperative transfusion requirement during OLT. Awareness of that association may improve treatment strategies to reduce intraoperative bleeding risk in OLT., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chronic kidney disease (CKD) affects approximately 10-13% of the population worldwide and halting its progression is a major clinical challenge. Metabolic acidosis is both a consequence and a possible driver of CKD progression. Alkali therapy counteracts these effects in CKD patients, but underlying mechanisms remain incompletely understood. Here we show that bicarbonate supplementation protected renal function in a murine CKD model induced by an oxalate-rich diet. Alkali therapy had no effect on the aldosterone-endothelin axis but promoted levels of the anti-aging protein klotho; moreover, it suppressed adhesion molecules required for immune cell invasion along with reducing T-helper cell and inflammatory monocyte invasion. Comparing transcriptomes from the murine crystallopathy model and from human biopsies of kidney transplant recipients (KTRs) suffering from acidosis with or without alkali therapy unveils parallel transcriptome responses mainly associated with lipid metabolism and oxidoreductase activity. Our data reveal novel pathways associated with acidosis in kidney disease and sensitive to alkali therapy and identifies potential targets through which alkali therapy may act on CKD and that may be amenable for more targeted therapies., (© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Background: Globally, the prevalence of chronic kidney disease (CKD) is higher in women than in men; however, women have been historically under-represented in nephrology clinical trials. Metabolic acidosis increases risk of progressive loss of kidney function, causes bone demineralization and muscle protein catabolism, and may be more consequential in women given their lower bone and muscle mass. Veverimer, an investigational, non-absorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as treatment for metabolic acidosis., Methods: This was a Phase 3, multicenter, randomised, blinded, placebo-controlled trial in 196 patients with CKD (eGFR: 20-40 mL/min/1.73 m 2 ) and metabolic acidosis who were treated for up to 1 year with veverimer or placebo. We present the findings from a pre-specified subgroup analysis evaluating the effects of veverimer on metabolic acidosis and physical function among women (N = 77) enrolled in this trial., Results: At week 52, women treated with veverimer had a greater increase in mean (± standard error) serum bicarbonate than the placebo group (5.4 [0.5] vs. 2.2 [0.6] mmol/L; P < 0.0001). Physical Function reported by patients on the Kidney Disease and Quality of Life - Physical Function Domain, a measure that includes items related to walking, stair climbing, carrying groceries and other activities improved significantly in women randomized to veverimer vs placebo (+ 13.2 vs. -5.2, respectively, P < 0.0031). Objectively measured performance time on the repeated chair stand test also improved significantly in the veverimer group vs. placebo (P = 0.0002)., Conclusions: Veverimer was effective in treating metabolic acidosis in women with CKD, and significantly improved how they felt and functioned., Trial Registration: ClinicalTrials.gov Identifier: NCT03390842 . Registered on January 4, 2018., (© 2022. The Author(s).)

Background: Poor linear growth is a consequence of chronic kidney disease (CKD) that has been linked to adverse outcomes. Metabolic acidosis (MA) has been identified as a risk factor for growth failure. We investigated the longitudinal relationship between MA and linear growth in children with CKD and examined whether treatment of MA modified linear growth., Methods: To describe longitudinal associations between MA and linear growth, we used serum bicarbonate levels, height measurements, and standard deviation (z scores) of children enrolled in the prospective cohort study Chronic Kidney Disease in Children. Analyses were adjusted for covariates recognized as correlating with poor growth, including demographic characteristics, glomerular filtration rate (GFR), proteinuria, calcium, phosphate, parathyroid hormone, and CKD duration. CKD diagnoses were analyzed by disease categories, nonglomerular or glomerular., Results: The study population included 1082 children with CKD: 808 with nonglomerular etiologies and 274 with glomerular etiologies. Baseline serum bicarbonate levels ≤22 mEq/L were associated with worse height z scores in all children. Longitudinally, serum bicarbonate levels ≤18 and 19-22 mEq/L were associated with worse height z scores in children with nonglomerular CKD causes, with adjusted mean values of -0.39 (95% CI, -0.58 to -0.2) and -0.17 (95% CI, -0.28 to -0.05), respectively. Children with nonglomerular disease and more severe GFR impairment had a higher risk for worse height z score. A significant association was not found in children with glomerular diseases. We also investigated the potential effect of treatment of MA on height in children with a history of alkali therapy use, finding that only persistent users had a significant positive association between their height z score and higher serum bicarbonate levels., Conclusions: We observed a longitudinal association between MA and lower height z score. Additionally, persistent alkali therapy use was associated with better height z scores. Future clinical trials of alkali therapy need to evaluate this relationship prospectively., Competing Interests: M. Carroll reports ownership interest in Verily Life Sciences and research funding from Verily Life Sciences. A. Dauber reports ownership interest in Ascendis, Biomarin, and Novo Nordisk and research funding from Biomarin. L.A. Greenbaum reports consultancy for Abbvie, Advicenne, Alexion, Arrowhead Pharmaceuticals, Aurinia, CorMedix, NephroDI Therapeutics, Natera, Novartis, Roche, and Otsuka; research funding from Abbvie, Advicenne, Alexion, Apellis, Aurinia, Horizon Pharmaceuticals, Reata Pharmaceuticals, and Vertex; honoraria from Alexion; an advisory or leadership role with Alexion; and other interests or relationships (DSMB payments) with Akebia, Alnylam, Relypsa, Travere, and UCSD. F.J. Kaskel reports research funding from NIDDK and an advisory or leadership role for Frost Valley YMCA and Nephcure, Inc. M.L. Melamed reports an advisory or leadership role for the American Board of Internal Medicine Nephrology Exam Committee and has other interests in or relationships with the American Society of Nephrology and the New York Society of Nephrology. D.K. Ng reports consultancy for Ashvattha Therapeutics. B.A. Warady reports consultancy for Amgen, Bayer, Lightline Medical, Reata, Relypsa, and UpToDate; research funding from Baxter Healthcare; honoraria from Amgen, Bayer, Reata, Relypsa, and UpToDate; and an advisory or leadership role with the Midwest Transplant Network Governing Board, the National Kidney Foundation, North American Pediatric Renal Trials and Collaborative Studies, and the NTDS Board of Directors. All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Introduction: Sodium zirconium cyclosilicate (SZC) is a selective potassium (K+) binder for hyperkalemia management that provides rapid and sustained correction of hyperkalemia. The NEUTRALIZE study is investigating whether SZC, in addition to correcting hyperkalemia and maintaining normal serum K+, can provide sustained increases in serum bicarbonate (HCO3-) in patients with hyperkalemia and metabolic acidosis associated with chronic kidney disease (CKD)., Methods: This is a prospective, randomized, double-blind, placebo-controlled phase 3b study of US adults with stage 3-5 CKD not on dialysis with hyperkalemia (K+ >5.0-≤5.9 mmol/L) and low-serum HCO3- (16-20 mmol/L). In the open-label correction phase, all eligible patients receive SZC 10 g three times daily for up to 48 h. Patients who achieve normokalemia (K+ ≥3.5-≤5.0 mmol/L) are then randomized 1:1 to once-daily SZC 10 g or placebo for a 4-week, double-blind, placebo-controlled maintenance phase. The primary endpoint is the proportion of patients with normokalemia at the end of treatment (EOT) without rescue therapy for hyperkalemia. Key secondary endpoints include mean change in serum HCO3-, the proportion of patients with an increase in serum HCO3- of ≥2 or ≥3 mmol/L without rescue therapy for metabolic acidosis, and the proportion of patients with serum HCO3- ≥22 mmol/L at EOT., Conclusions: NEUTRALIZE will establish whether SZC can provide sustained increases in serum HCO3- while lowering serum K+ in patients with hyperkalemia and CKD-associated metabolic acidosis and may provide insights on the mechanism(s) underlying the increased serum HCO3- with SZC treatment., (The Author(s). Published by S. Karger AG, Basel.)

Therapeutic outcomes in oncology may be aided by precision diagnostics that offer early detection, localization and the opportunity to monitor response to therapy. Here, we report a multimodal nanosensor engineered to target tumours through acidosis, respond to proteases in the microenvironment to release urinary reporters and (optionally) carry positron emission tomography probes to enable localization of primary and metastatic cancers in mouse models of colorectal cancer. We present a paradigm wherein this multimodal sensor can be employed longitudinally to assess burden of disease non-invasively, including tumour progression and response to chemotherapy. Specifically, we showed that acidosis-mediated tumour insertion enhanced on-target release of matrix metalloproteinase-responsive reporters in urine. Subsequent on-demand loading of the radiotracer 64 Cu allowed pH-dependent tumour visualization, enabling enriched microenvironmental characterization when compared with the conventional metabolic tracer 18 F-fluorodeoxyglucose. Through tailored target specificities, this modular platform has the capacity to be engineered as a pan-cancer test that may guide treatment decisions for numerous tumour types., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Acyl CoA Dehydrogenase 9 (ACAD9) is a member of the family of flavoenzymes that catalyze the dehydrogenation of acyl-CoAs to 2,3 enoyl-CoAs in mitochondrial fatty acid oxidation (FAO). Inborn errors of metabolism of all family members, including ACAD9, have been described in humans, and represent significant causes of morbidity and mortality particularly in children. ACAD9 deficiency leads to a combined defect in fatty acid oxidation and oxidative phosphorylation (OXPHOS) due to a dual role in the pathways. In addition to its function in mitochondrial FAO, ACAD9 has a second function as one of 14 factors responsible for assembly of complex I of the electron transport chain (ETC). Considerable controversy remains over the relative role of these two functions in normal physiology and the disparate clinical findings described in patients with ACAD9 deficiency. To better understand the normal function of ACAD9 and the pathophysiology of its deficiency, several knock out mouse models were developed. Homozygous total body knock out appeared to be lethal as no ACAD9 animals were obtained. Cre-lox technology was then used to generate tissue-specific deletion of the gene. Cardiac-specific ACAD9 deficient animals had severe neonatal cardiomyopathy and died by 17 days of age. They had severe mitochondrial dysfunction in vitro. Muscle-specific mutants were viable but exhibited muscle weakness. Additional studies of heart muscle from the cardiac specific deficient animals were used to examine the evolutionarily conserved signaling Intermediate in toll pathway (ECSIT) protein, a known binding partner of ACAD9 in the electron chain complex I assembly pathway. As expected, ECSIT levels were significantly reduced in the absence of ACAD9 protein, consistent with the demonstrated impairment of the complex I assembly. The various ACAD9 deficient animals should serve as useful models for development of novel therapeutics for this disorder., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: None declared.

Acid-related injury from chronic metabolic acidosis is recognized through growing evidence of its deleterious effects, including kidney and other organ injury. Progressive acid accumulation precedes the signature manifestation of chronic metabolic acidosis, decreased plasma bicarbonate concentration. Acid accumulation that is not enough to manifest as metabolic acidosis, known as eubicarbonatemic acidosis, also appears to cause kidney injury, with exacerbated progression of CKD. Chronic engagement of mechanisms to mitigate the acid challenge from Western-type diets also appears to cause kidney injury. Rather than considering chronic metabolic acidosis as the only acid-related condition requiring intervention to reduce kidney injury, this review supports consideration of acid-related injury as a continuum. This "acid stress" continuum has chronic metabolic acidosis at its most extreme end, and high-acid-producing diets at its less extreme, yet detrimental, end., (Copyright © 2021 by the American Society of Nephrology.)

Objectives: This study examined predictive factors, in addition to Category II Fetal Herat Rate (FHR) monitoring that might imply fetal acidosis and risk of asphyxia., Methods: This retrospective cohort study compared three groups of patients with Category II FHR monitoring indicating need for imminent delivery. Groups were divided based on fetal cord blood pH: pH≤7.0, 7.0