Alkalosis-induced hypoventilation in cystic fibrosis: The importance of efficient renal adaptation.

The lungs and kidneys are pivotal organs in the regulation of body acid-base homeostasis. In cystic fibrosis (CF), the impaired renal ability to excrete an excess amount of HCO3- into the urine leads to metabolic alkalosis [P. Berg et al., J. Am. Soc. Nephrol. 31, 1711-1727 (2020); F. Al-Ghimlas, M. E. Faughnan, E. Tullis, Open Respir. Med. J. 6, 59-62 (2012)]. This is caused by defective HCO3- secretion in the ß-intercalated cells of the collecting duct that requires both the cystic fibrosis transmembrane conductance regulator (CFTR) and pendrin for normal function [P. Berg et al., J. Am. Soc. Nephrol. 31, 1711-1727 (2020)]. We studied the ventilatory consequences of acute oral base loading in normal, pendrin knockout (KO), and CFTR KO mice. In wild-type mice, oral base loading induced a dose-dependent metabolic alkalosis, fast urinary removal of base, and a moderate base load did not perturb ventilation. In contrast, CFTR and pendrin KO mice, which are unable to rapidly excrete excess base into the urine, developed a marked and transient depression of ventilation when subjected to the same base load. Therefore, swift renal base elimination in response to an acute oral base load is a necessary physiological function to avoid ventilatory depression. The transient urinary alkalization in the postprandial state is suggested to have evolved for proactive avoidance of hypoventilation. In CF, metabolic alkalosis may contribute to the commonly reduced lung function via a suppression of ventilatory drive.

The B1 H + -ATPase ( Atp6v1b1 ) Subunit in Non-Type A Intercalated Cells is Required for Driving Pendrin Activity and the Renal Defense Against Alkalosis.

SIGNIFICANCE STATEMENT: In the kidney, the B1 H + -ATPase subunit is mostly expressed in intercalated cells (IC). Its importance in acid-secreting type A ICs is evident in patients with inborn distal renal tubular acidosis and ATP6V1B1 mutations. However, the protein is also highly expressed in alkali-secreting non-type A ICs where its function is incompletely understood. We demonstrate in Atp6v1b1 knock out mice that the B1 subunit is critical for the renal response to defend against alkalosis during an alkali load or chronic furosemide treatment. These findings highlight the importance of non-type A ICs in maintaining acid-base balance in response to metabolic challenges or commonly used diuretics. BACKGROUND: Non-type A ICs in the collecting duct system express the luminal Cl - /HCO 3- exchanger pendrin and apical and/or basolateral H + -ATPases containing the B1 subunit isoform. Non-type A ICs excrete bicarbonate during metabolic alkalosis. Mutations in the B1 subunit (ATP6V1B1) cause distal renal tubular acidosis due to its role in acid secretory type A ICs. The function of B1 in non-type A ICs has remained elusive. METHODS: We examined the responses of Atp6v1b1-/- and Atp6v1b1+/+ mice to an alkali load and to chronic treatment with furosemide. RESULTS: An alkali load or 1 week of furosemide resulted in a more pronounced hypokalemic alkalosis in male ATP6v1b1-/- versus Atp6v1b1+/+ mice that could not be compensated by respiration. Total pendrin expression and activity in non-type A ICs of ex vivo microperfused cortical collecting ducts were reduced, and ß2 -adrenergic stimulation of pendrin activity was blunted in ATP6v1b1-/- mice. Basolateral H + -ATPase activity was strongly reduced, although the basolateral expression of the B2 isoform was increased. Ligation assays for H + -ATPase subunits indicated impaired assembly of V 0 and V 1 H + -ATPase domains. During chronic furosemide treatment, ATP6v1b1-/- mice also showed polyuria and hyperchloremia versus Atp6v1b1+/+ . The expression of pendrin, the water channel AQP2, and subunits of the epithelial sodium channel ENaC were reduced. CONCLUSIONS: Our data demonstrate a critical role of H + -ATPases in non-type A ICs function protecting against alkalosis and reveal a hitherto unrecognized need of basolateral B1 isoform for a proper H + -ATPase complexes assembly and ability to be stimulated.

Let's stop talking about 'citrate toxicity'.

PURPOSE OF REVIEW: Continuous renal replacement therapy (CRRT) is a vital medical intervention used in critically ill patients with acute kidney injury (AKI). One of the key components of adequate clearance with CRRT is the use of anticoagulants to prevent clotting of the extracorporeal circuit. Regional citrate anticoagulation is the most often recommended modality. The term 'citrate toxicity' is used to describe potential adverse effects of accumulation of citrate and subsequent hypocalcemia. However, citrate is itself not inherently toxic. The term and diagnosis of citrate toxicity are questioned in this review. RECENT FINDINGS: Citrate is being increasingly used for regional anticoagulation of the CRRT circuit. Citrate accumulation is infrequent and can cause hypocalcemia and metabolic alkalosis, which are potential adverse effects. Citrate itself, however, is not a toxic molecule. The term 'citrate toxicity' has been used to denote hypocalcemia and metabolic acidosis. However, citrate administration is well known to cause systemic and urinary alkalinization and under certain circumstances, metabolic alkalosis, but is not associated itself with any 'toxic' effects.We review the existing literature and debunk the perceived toxicity of citrate. We delve into the metabolism and clearance of citrate and question current data suggesting metabolic acidosis occurs as the result of citrate accumulation. SUMMARY: In conclusion, this article calls into question prevailing concerns about 'citrate toxicity'. We emphasize the need for a more nuanced understanding of its safety profile. We recommend discarding the term 'citrate toxicity' in favor of another frequently used, but more meaningful term: 'citrate accumulation'.

Severe Alkalemia and hypokalemia after chronic exposure to alkaline water.

Consumption of alkaline electrolyzed water (AEW) has become increasingly popular for consumer use. Although these alkaline water products are now commonly used, they are of questionable health benefit. Some individuals believe that it may help their dyspepsia. Furthermore, there is a paucity of evidence on its toxicologic profile and adverse effects. This is a single case report of a 42-year-old female with a past medical history of gestational diabetes, necrotizing pancreatitis, presented to the Emergency Department for 3 weeks of lethargy, weakness, difficulty walking, and vomiting. She endorsed consuming 5  liters (L) of alkaline water daily for the past month. Initial labs showed pH 7.69, potassium 1.6meQ/L, sodium 133 meQ/L, chloride 65 mmol/L, magnesium 0.9 meQ/L, and bicarbonate 46 mmol/L, and lactate of 13.2 mmol/L. EKG showed sinus tachycardia with QTc of 630 milliseconds. Patient was treated supportively with intravenous fluids and electrolyte replacement. The potassium rose to 6.6 meQ/L, which then the patient was treated for hyperkalemia. After four days of intravenous fluid and electrolyte replacement, the patient's electrolytes and acid-base status normalized, and she was transferred to the medical floors for further management. This case report illustrates severe metabolic alkalosis and hypokalemia in the setting of chronic alkaline water exposure. It also is an example of alkalemia with hyperlactatemia, or "lactic alkalosis". To our knowledge, there is no previous literature reporting serious adverse effects of alkaline bottled water products.

A safe and effective protocol for postdilution hemofiltration with regional citrate anticoagulation.

BACKGROUND: Regional citrate anticoagulation (RCA) is recommended during continuous renal replacement therapy. Compared to systemic anticoagulation, RCA provides a longer filter lifespan with the risk of metabolic alkalosis and impaired calcium homeostasis. Surprisingly, most RCA protocols are designed for continuous veno-venous hemodialysis or hemodiafiltration. Effective protocols for continuous veno-venous hemofiltration (CVVH) are rare, although CVVH is a standard treatment for high-molecular-weight clearance. Therefore, we evaluated a new RCA protocol for postdilution CVVH. METHODS: This is a monocentric prospective interventional study to evaluate a new RCA protocol for postdilution CVVH. We recruited surgical patients with stage III acute kidney injury who needed renal replacement therapy. We recorded dialysis and RCA data and hemodynamic and laboratory parameters during treatment sessions of 72 h. The primary endpoint was filter patency at 72 h. The major safety parameters were metabolic alkalosis and severe hypocalcemia at any time. RESULTS: We included 38 patients who underwent 66 treatment sessions. The mean filter lifespan was 66 ± 12 h, and 44 of 66 (66%) filters were patent at 72 h. After censoring for non-CVVH-related cessation of treatment, 83% of all filters were patent at 72 h. The delivered dialysis dose was 28 ± 5 ml/kgBW/h. The serum levels of creatinine, urea and beta2-microglobulin decreased significantly from day 0 to day 3. Metabolic alkalosis occurred in one patient. An iCa++ below 1.0 mmol/L occurred in four patients. Citrate accumulation did not occur. CONCLUSIONS: We describe a safe, effective, and easy-to-use RCA protocol for postdilution CVVH. This protocol provides a long and sustained filter lifespan without serious adverse effects. The risk of metabolic alkalosis and hypocalcemia is low. Using this protocol, a recommended dialysis dose can be safely administered with effective clearance of low- and middle-molecular-weight molecules. TRIAL REGISTRATION: The study was approved by the medical ethics committee of Heinrich-Heine University Duesseldorf (No. 2018-82KFogU). The trial was registered in the local study register of the university (No: 2018044660) on 07/04/2018 and was retrospectively registered at ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT03969966) on 31/05/2019.

Clinical Research on Rett Syndrome: Central Hypoxemia and Hypokalemic Metabolic Alkalosis.

Background: Rett syndrome (RTT) is now widely recognized as a profound neurological disorder that predominantly affects females and is closely associated with mutations in the methylated CpG binding protein 2 (MECP2) gene located on the X chromosome. The Characteristic symptoms of RTT include the loss of acquired language and motor skills, repetitive hand movements, irregular breathing, and seizures. Additionally, RTT patients may experience sporadic episodes of gastrointestinal problems, hypoplasia, early-onset osteoporosis, bruxism, and screaming episodes. It is worth noting that males exhibit a unique and variable phenotype, though rare in RTT cases, often accompanied by severe manifestations. Case Presentation: In this report, we present the case of a young male child with a de novo c.806delG hemizygous mutation, leading to an atypical presentation of RTT that remarkably mirrors the clinical features of Bartter syndrome, a genetic metabolic disorder. The clinical manifestations in this case included the loss of previously acquired language and motor skills, repetitive hand movements, breathing irregularities, seizures, sporadic episodes of gastrointestinal distress, hypoplasia, early-onset osteoporosis, bruxism, and episodes of screaming. This distinctive presentation underscores the complex diagnostic landscape of RTT, particularly in males, and highlights the need for vigilant clinical evaluation. Conclusions: This case report sheds light on an unusual and atypical presentation of RTT in a young male child with a de novo c.806delG hemizygous mutation. The resemblance of clinical features to Bartter syndrome underscores the diagnostic challenges posed by RTT and highlights the importance of comprehensive clinical assessment and genetic testing, especially in cases deviating from the typical RTT phenotype. Our findings contribute valuable insights into the early diagnosis and management of atypical RTT presentations.

Loss of the Secretin Receptor Impairs Renal Bicarbonate Excretion and Aggravates Metabolic Alkalosis in Mice during Acute Base-Loading.

SIGNIFICANCE STATEMENT: During acute base excess, the renal collecting duct ß -intercalated cells ( ß -ICs) become activated to increase urine base excretion. This process is dependent on pendrin and cystic fibrosis transmembrane regulator (CFTR) expressed in the apical membrane of ß -ICs. The signal that leads to activation of this process was unknown. Plasma secretin levels increase during acute alkalosis, and the secretin receptor (SCTR) is functionally expressed in ß -ICs. We find that mice with global knockout for the SCTR lose their ability to acutely increase renal base excretion. This forces the mice to lower their ventilation to cope with this challenge. Our findings suggest that secretin is a systemic bicarbonate-regulating hormone, likely being released from the small intestine during alkalosis. BACKGROUND: The secretin receptor (SCTR) is functionally expressed in the basolateral membrane of the ß -intercalated cells of the kidney cortical collecting duct and stimulates urine alkalization by activating the ß -intercalated cells. Interestingly, the plasma secretin level increases during acute metabolic alkalosis, but its role in systemic acid-base homeostasis was unclear. We hypothesized that the SCTR system is essential for renal base excretion during acute metabolic alkalosis. METHODS: We conducted bladder catheterization experiments, metabolic cage studies, blood gas analysis, barometric respirometry, perfusion of isolated cortical collecting ducts, immunoblotting, and immunohistochemistry in SCTR wild-type and knockout (KO) mice. We also perfused isolated rat small intestines to study secretin release. RESULTS: In wild-type mice, secretin acutely increased urine pH and pendrin function in isolated perfused cortical collecting ducts. These effects were absent in KO mice, which also did not sufficiently increase renal base excretion during acute base loading. In line with these findings, KO mice developed prolonged metabolic alkalosis when exposed to acute oral or intraperitoneal base loading. Furthermore, KO mice exhibited transient but marked hypoventilation after acute base loading. In rats, increased blood alkalinity of the perfused upper small intestine increased venous secretin release. CONCLUSIONS: Our results suggest that loss of SCTR impairs the appropriate increase of renal base excretion during acute base loading and that SCTR is necessary for acute correction of metabolic alkalosis. In addition, our findings suggest that blood alkalinity increases secretin release from the small intestine and that secretin action is critical for bicarbonate homeostasis.

Severe Multifactorial Metabolic Alkalosis in the Emergency Department: A Case Report.

BACKGROUND: Metabolic alkalosis is an uncommon clinical entity resulting from a wide variety of underlying etiologies including gastrointestinal, renal, endocrine, and metabolic causes. It is a typically clinically silent condition; however, severe cases can be life-threatening, mandating both a systematic investigative approach and an early aggressive management strategy. CASE REPORT: We present a case of a 58-year-old man with severe, multifactorial metabolic alkalosis (pH 7.72, HCO3- 42 mmol/L, pCO2 31 mm Hg) resulting from refractory vomiting, severe hypokalemia (2.0 mmol/L), and hypoalbuminemia (albumin 20 g/L). WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Severe metabolic alkalosis is associated with significant morbidity and mortality. Clinicians need to be aware of the potential underlying causes in these cases, as well as how to delineate between chloride- and non-chloride-depleted states, which dictates initial treatment. We provide a pragmatic summary of the evaluation, pertinent investigations, and early management of these cases.

Bicarbonate is the primary inducer of KCC3a expression in renal cortical B-type intercalated cells.

A primary function of intercalated cells in the distal tubule of the kidney is to maintain pH homeostasis. For example, type B intercalated cells secrete bicarbonate largely through the action of the apical Cl-/HCO3- exchanger, pendrin, which helps correct metabolic alkalosis. Since both the K-Cl cotransporter, KCC3a and pendrin colocalize to the apical region of type B and non-A, non-B intercalated cells and since both are upregulated in models of metabolic alkalosis, such as with dietary NaHCO3 loading, we raised the possibility that apical KCC3a facilitates pendrin-mediated bicarbonate secretion, such as through apical Cl- recycling. The purpose of this study was to determine if KCC3a abundance changes through intake of bicarbonate alone or through bicarbonate plus its accompanying cation, and if it requires a direct interaction with pendrin or the renin-angiotensin-aldosterone system. We observed that KCC3a protein abundance, but not mRNA, increases in a mouse model of metabolic alkalosis, achieved with dietary NaHCO3 or KHCO3 intake. Bicarbonate ion increases KCC3a abundance, both in vivo and in vitro, independently of the accompanying cation. Moreover, bicarbonate intake upregulates KCC3a independently of aldosterone or angiotensin II. Since NaHCO3 intake increased KCC3a abundance in wild-type as well as in pendrin knockout mice, this KCC3a upregulation by bicarbonate does not depend on a direct interaction with pendrin. We conclude that increased extracellular bicarbonate, as observed in models of metabolic alkalosis, directly raises KCC3a abundance independently of angiotensin II, aldosterone, or changes in KCC3a transcription and does not involve a direct interaction with pendrin.NEW & NOTEWORTHY KCC3a expression is stimulated in alkalemia. This paper shows that bicarbonate itself is mediating this effect through a posttranscriptional mechanism. The paper also shows that this phenomenon is not mediated by aldosterone or angiotensin II.

Alkaline-sensitive two-pore domain potassium channels form functional heteromers in pancreatic ß-cells.

Two-pore domain K+ channels (K2P channels), active as dimers, produce inhibitory currents regulated by a variety of stimuli. Among them, TWIK1-related alkalinization-activated K+ channel 1 (TALK1), TWIK1-related alkalinization-activated K+ channel 2 (TALK2), and TWIK1-related acid-sensitive K+ channel 2 (TASK2) form a subfamily of structurally related K2P channels stimulated by extracellular alkalosis. The human genes encoding these proteins are clustered at chromosomal region 6p21 and coexpressed in multiple tissues, including the pancreas. The question whether these channels form functional heteromers remained open. By analyzing single-cell transcriptomic data, we show that these channels are coexpressed in insulin-secreting pancreatic ß-cells. Using in situ proximity ligation assay and electrophysiology, we show that they form functional heterodimers both upon heterologous expression and under native conditions in human pancreatic ß-cells. We demonstrate that heteromerization of TALK2 with TALK1 or with TASK2 endows TALK2 with sensitivity to extracellular alkalosis in the physiological range. We further show that the association of TASK2 with TALK1 and TALK2 increases their unitary conductance. These results provide a new example of heteromerization in the K2P channel family expanding the range of the potential physiological and pathophysiological roles of TALK1/TALK2/TASK2 channels, not only in insulin-secreting cells but also in the many other tissues in which they are coexpressed.

Pendrin regulation is prioritized by anion in high-potassium diets.

The Cl-/[Formula: see text] exchanger pendrin in the kidney maintains acid-base balance and intravascular volume. Pendrin is upregulated in models associated with high circulating aldosterone concentration, such as dietary NaCl restriction or an aldosterone infusion. However, it has not been established if pendrin is similarly regulated by aldosterone with a high-K+ diet because the effects of accompanying anions have not been considered. Here, we explored how pendrin is modulated by different dietary potassium salts. Wild-type (WT) and aldosterone synthase (AS) knockout (KO) mice were randomized to control, high-KHCO3, or high-KCl diets. Dietary KCl and KHCO3 loading increased aldosterone in WT mice to the same extent but had opposite effects on pendrin abundance. KHCO3 loading increased pendrin protein and transcript abundance. Conversely, high-KCl diet feeding caused pendrin to decrease within 8 h of switching from the high-KHCO3 diet, coincident with an increase in plasma Cl- and a decrease in [Formula: see text]. In contrast, switching the high-KCl diet to the high-KHCO3 diet caused pendrin to increase in WT mice. Experiments in AS KO mice revealed that aldosterone is necessary to optimally upregulate pendrin protein in response to the high-KHCO3 diet but not to increase pendrin mRNA. We conclude that pendrin is differentially regulated by different dietary potassium salts and that its regulation is prioritized by the dietary anion, providing a mechanism to prevent metabolic alkalosis with high-K+ base diets and safeguard against hyperchloremic acidosis with consumption of high-KCl diets.NEW & NOTEWORTHY Regulation of the Cl-/[Formula: see text] exchanger pendrin has been suggested to explain the aldosterone paradox. A high-K+ diet has been proposed to downregulate a pendrin-mediated K+-sparing NaCl reabsorption pathway to maximize urinary K+ excretion. Here, we challenged the hypothesis, revealing that the accompanying anion, not K+, drives pendrin expression. Pendrin is downregulated with a high-KCl diet, preventing acidosis, and upregulated with an alkaline-rich high-K+ diet, preventing metabolic alkalosis. Pendrin regulation is prioritized for acid-base balance.

Dietary anions control potassium excretion: it is more than a poorly absorbable anion effect.

The urinary potassium (K+) excretion machinery is upregulated with increasing dietary K+, but the role of accompanying dietary anions remains inadequately characterized. Poorly absorbable anions, including [Formula: see text], are thought to increase K+ secretion through a transepithelial voltage effect. Here, we tested if they also influence the K+ secretion machinery. Wild-type mice, aldosterone synthase (AS) knockout (KO) mice, or pendrin KO mice were randomized to control, high-KCl, or high-KHCO3 diets. The K+ secretory capacity was assessed in balance experiments. Protein abundance, modification, and localization of K+-secretory transporters were evaluated by Western blot analysis and confocal microscopy. Feeding the high-KHCO3 diet increased urinary K+ excretion and the transtubular K+ gradient significantly more than the high-KCl diet, coincident with more pronounced upregulation of epithelial Na+ channels (ENaC) and renal outer medullary K+ (ROMK) channels and apical localization in the distal nephron. Experiments in AS KO mice revealed that the enhanced effects of [Formula: see text] were aldosterone independent. The high-KHCO3 diet also uniquely increased the large-conductance Ca2+-activated K+ (BK) channel ß4-subunit, stabilizing BKα on the apical membrane, the Cl-/[Formula: see text] exchanger, pendrin, and the apical KCl cotransporter (KCC3a), all of which are expressed specifically in pendrin-positive intercalated cells. Experiments in pendrin KO mice revealed that pendrin was required to increase K+ excretion with the high-KHCO3 diet. In summary, [Formula: see text] stimulates K+ excretion beyond a poorly absorbable anion effect, upregulating ENaC and ROMK in principal cells and BK, pendrin, and KCC3a in pendrin-positive intercalated cells. The adaptive mechanism prevents hyperkalemia and alkalosis with the consumption of alkaline ash-rich diets but may drive K+ wasting and hypokalemia in alkalosis.NEW & NOTEWORTHY Dietary anions profoundly impact K+ homeostasis. Here, we found that a K+-rich diet, containing [Formula: see text] as the counteranion, enhances the electrogenic K+ excretory machinery, epithelial Na+ channels, and renal outer medullary K+ channels, much more than a high-KCl diet. It also uniquely induces KCC3a and pendrin, in B-intercalated cells, providing an electroneutral KHCO3 secretion pathway. These findings reveal new K+ balance mechanisms that drive adaption to alkaline and K+-rich foods, which should guide new treatment strategies for K+ disorders.

Acetazolamide for metabolic alkalosis complicating respiratory failure with chronic obstructive pulmonary disease or obesity hypoventilation syndrome: a systematic review.

BACKGROUND: Metabolic alkalosis may lead to respiratory inhibition and increased need for ventilatory support or prolongation of weaning from ventilation for patients with chronic respiratory disease. Acetazolamide can reduce alkalaemia and may reduce respiratory depression. METHODS: We searched Medline, EMBASE and CENTRAL from inception to March 2022 for randomised controlled trials comparing acetazolamide to placebo in patients with chronic obstructive pulmonary disease, obesity hypoventilation syndrome or obstructive sleep apnoea, hospitalised with acute respiratory deterioration complicated by metabolic alkalosis. The primary outcome was mortality and we pooled data using random-effects meta-analysis. Risk of bias was assessed using the Cochrane RoB 2 (Risk of Bias 2) tool, heterogeneity was assessed using the I2 value and χ2 test for heterogeneity. Certainty of evidence was assessed using GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) methodology. RESULTS: Four studies with 504 patients were included. 99% of included patients had chronic obstructive pulmonary disease. No trials recruited patients with obstructive sleep apnoea. 50% of trials recruited patients requiring mechanical ventilation. Risk of bias was overall low to some risk. There was no statistically significant difference with acetazolamide in mortality (relative risk 0.98 (95% CI 0.28 to 3.46); p=0.95; 490 participants; three studies; GRADE low certainty) or duration of ventilatory support (mean difference -0.8 days (95% CI -7.2 to 5.6); p=0.36; 427 participants; two studies; GRADE: low certainty). CONCLUSION: Acetazolamide may have little impact on respiratory failure with metabolic alkalosis in patients with chronic respiratory diseases. However, clinically significant benefits or harms are unable to be excluded, and larger trials are required. PROSPERO REGISTRATION NUMBER: CRD42021278757.

Respiratory Acidosis and Respiratory Alkalosis: Core Curriculum 2023.

The respiratory system plays an integral part in maintaining acid-base homeostasis. Normal ventilation participates in the maintenance of an open buffer system, allowing for excretion of CO2 produced from the interaction of nonvolatile acids and bicarbonate. Quantitatively of much greater importance is the excretion of CO2 derived from volatile acids produced from the complete oxidation of fat and carbohydrate. A primary increase in CO2 tension of body fluids is the cause of respiratory acidosis and develops most commonly from one or more of the following: (1) disorders affecting gas exchange across the pulmonary capillary, (2) disorders of the chest wall and the respiratory muscles, and/or (3) inhibition of the medullary respiratory center. Respiratory alkalosis or primary hypocapnia is most commonly caused by disorders that increase alveolar ventilation and is defined by an arterial partial pressure of CO2 <35 mm Hg with subsequent alkalization of body fluids. Both disorders can lead to life-threatening complications, making it of paramount importance for the clinician to have a thorough understanding of the cause and treatment of these acid-base disturbances.

Intravenous or Oral Acetazolamide for Treatment of Diuretic-Induced Alkalosis in Patients With Heart Failure.

BACKGROUND: Acetazolamide has been used for diuretic-induced metabolic alkalosis, but the preferred dose, route, and frequency of administration remain unknown. OBJECTIVE: The purpose of this study was to characterize dosing strategies and determine the effectiveness of intravenous (IV) and oral (PO) acetazolamide for patients with heart failure (HF) with diuretic-induced metabolic alkalosis. METHODS: This was a multicenter, retrospective cohort study comparing the use of IV versus PO acetazolamide in patients with HF receiving at least 120 mg of furosemide for the treatment of metabolic alkalosis (serum bicarbonate CO2 ≥32). The primary outcome was the change in CO2 on the first basic metabolic panel (BMP) within 24 hours of the first dose of acetazolamide. Secondary outcomes included laboratory outcomes, such as change in bicarbonate, chloride, and incidence of hyponatremia and hypokalemia. This study was approved by the local institutional review board. RESULTS: IV acetazolamide was given in 35 patients and PO acetazolamide was given in 35 patients. Patients in both groups were given a median of 500 mg of acetazolamide in the first 24 hours. For the primary outcome, there was a significant decrease in CO2 on the first BMP within 24 hours after patients received the IV acetazolamide (-2 [interquartile range, IQR: -2, 0] vs 0 [IQR: -3, 1], P = 0.047). There were no differences in secondary outcomes. CONCLUSION AND RELEVANCE: IV acetazolamide resulted in significantly decreased bicarbonate within 24 hours of administration. IV acetazolamide may be preferred to treat diuretic-induced metabolic alkalosis in patients with HF.

Metabolic alkalosis in hemodialysis patients.

BACKGROUND: Hemodialysis solutions typically contain a high alkali concentration designed to counter interdialytic acidosis, but this could result in persistent alkalosis in some patients. The prevalence and significance of persistent alkalosis were therefore examined at four outpatient centers over a 10-year period. METHODS: Alkalosis was defined as a pre-dialysis serum [HCO3 ] ≥ 26 meq/L in >6 months of a 12-month period and was persistent if present in a majority of months thereafter. Control patients had a serum [HCO3 ] of 19-23 meq/L > 6 of every 12 months. Standard, citrate-containing dialysate was used in all patients without adjustment of bicarbonate concentration. RESULTS: 444 of 1271 patients had alkalosis that persisted in 73. Compared to control patients, persistently alkalotic patients were older, but gender, race, starting weight, comorbidities, and mortality did not differ. Dialysis dose was 7% greater, protein catabolic rate was 11% lower, and interdialytic weight gain was 29% lower, all p < 0.001. Persistently alkalotic patients had double the incidence of cardiac arrhythmias (p = 0.07) and a 20% greater intradialytic blood pressure decrease (p < 0.001). CONCLUSIONS: Alkalosis is common in hemodialysis patients and can be persistent, likely due to decreased protein catabolic rate and increased dialysis dose, and may have detrimental cardiovascular effects.

Arterial Blood Gases and Acid-Base Regulation.

Disorders of acid-base status are common in the critically ill and prompt recognition is central to clinical decision making. The bicarbonate/carbon dioxide buffer system plays a pivotal role in maintaining acid-base homeostasis, and measurements of pH, PCO2, and HCO3 - are routinely used in the estimation of metabolic and respiratory disturbance severity. Hypoventilation and hyperventilation cause primary respiratory acidosis and primary respiratory alkalosis, respectively. Metabolic acidosis and metabolic alkalosis have numerous origins, that include alterations in acid or base intake, body fluid losses, abnormalities of intermediary metabolism, and renal, hepatic, and gastrointestinal dysfunction. The concept of the anion gap is used to categorize metabolic acidoses, and urine chloride excretion helps define metabolic alkaloses. Both the lungs and kidneys employ compensatory mechanisms to minimize changes in pH caused by various physiologic and disease disturbances. Treatment of acid-base disorders should focus primarily on correcting the underlying cause and the hemodynamic and electrolyte derangements that ensue. Specific therapies under certain conditions include renal replacement therapy, mechanical ventilation, respiratory stimulants or depressants, and inhibition of specific enzymes in intermediary metabolism disorders.

Renal fluid and acid/base balance during refeeding in restrictive eating disorders.

BACKGROUND AND OBJECTIVES: Fluid shifts have been ascribed to central diabetes insipidus in patients with anorexia nervosa hospitalized for refeeding. Recent data, however, suggest that vasopressin production is not dysregulated in this population. Our objective was to describe the trajectory of fluid imbalances in relationship to kidney function, electrolyte disturbances, and acid/base balance during refeeding. METHODS: A retrospective review of daily fluid balance and biochemical values was performed in 70 sequential unique patients admitted to University of California at Los Angeles Hospital Medical Stabilization Program for Eating Disorders from December 2018 to November 2020. RESULTS: Participants (2 males/68 females) were between 10 and 24 years of age and with a median body mass index of 16.1 (14.3, 18.1) kg/m2 . A severe negative fluid balance (>-900 ml/day) was observed in 80% of patients at some point during hospitalization. Serum sodium concentrations were normal on admission and remained stable during refeeding. Serum bicarbonate concentrations were 25 ± 1 mEq/dl on admission and increased above the normal range in 31% of patients. Metabolic alkalosis was inversely associated with the development of a negative fluid balance. Estimated glomerular filtration rate was impaired in 54% of patients, improved with refeeding, and was not associated with the development of a severe negative fluid balance or metabolic alkalosis. DISCUSSION: Chronic energy deprivation alters the physiology of renal fluid and bicarbonate handling in ways that are independent of vasopressin and glomerular filtration. Further studies are warranted to understand the renal adaptations that occur during energy restriction and subsequent refeeding. PUBLIC SIGNIFICANCE: Massive urinary fluid losses occur in patients with restrictive eating disorders hospitalized for refeeding. In addition, many patients have impaired renal bicarbonate excretion. These findings suggest that chronic energy deprivation impairs the kidney's ability to handle the shifts in fluid and acid/base balance that occur when appropriate oral nutrition is re-introduced.

Cystic fibrosis and CFTR-related disorder with electrolyte imbalance at diagnosis: clinical features and outcome in an Italian cohort.

There is limited information available on the clinical data, sweat test trends, and outcomes of individuals with cystic fibrosis (CF) who present with an isolated episode of hypoelectrolytemia with metabolic alkalosis (HMA). This study describes a cohort of Italian individuals with HMA as presenting symptom. The study is a retrospective multicenter analysis of individuals who presented with HMA as an initial symptom and was followed at 8 Italian CF Centers, from March 1988 to March 2022. Demographic, clinical, microbiological, biochemical, and genetic data were extracted from local health records. Ninety-three individuals were enrolled in the study. At first evaluation, 82 (88.2%) were diagnosed with CF, and 11 received a CFTR-Related Disorder (CFTR-RD) diagnostic label. Twenty-three (85.1%) out of the 27 subjects who underwent CF neonatal screening (NBS) resulted falsely negative. After a mean observational period of 11.5 years, most of subjects had a mild pulmonary phenotype, pancreatic sufficiency, and rarely CF-related complications. Four CFTR-RD changed to a CF diagnosis during the study period, resulting in 86 (92.4%) subjects classified as CF. CONCLUSIONS:  Most CF patients presenting with isolated HMA have a mild course of disease and rarely CF-related complications. WHAT IS KNOWN: • Isolated episode of hypoelectrolytemia with metabolic alkalosis is a well-known onset symptom of Cystic Fibrosis in infancy. • There is limited information available on the clinical data and outcomes of individuals with Cystic Fibrosis who present with electrolyte imbalance at diagnosis. WHAT IS NEW: • Most patients with Cystic Fibrosis presenting with isolated hypoelectrolytemia and metabolic alkalosis have a mild course of disease and rarely CF-related complications. • Electrolyte imbalance at diagnosis of Cystic Fibrosis is a common symptom in children not screened for CF at birth, or in those who received a false negative result from newborn screening.

The effect of changing dialysate bicarbonate concentration on serum bicarbonate, body weight and normalized nitrogen appearance rate.

INTRODUCTION: Most hemodialysis machines deliver a fixed bicarbonate concentration. Higher concentrations may improve acidosis, but risk post-hemodialysis alkalosis, whereas lower concentrations potentially increase acidosis but reduce alkalosis. We reviewed the effects of lowering dialysate bicarbonate. METHODS: We reviewed peri-dialysis chemistries in patients switching to a lower bicarbonate dialysate at 4 time points over 19 months. RESULTS: We studied 126 patients, mean age 63.7 ± 16.3 years, 57.9% males. Post-hemodialysis alkalosis fell from 1.6 to 0.3% sessions, but pre-hemodialysis acidosis increased from 11.9 to 23.8% sessions (p = 0.005) reducing dialysate bicarbonate from 32 to 28 mmol/L. After 3 months, pre-hemodialysis serum bicarbonate fell (21.1 ± 2.3 to 19.8 ± 2.2 mmol/L), and post-hemodialysis (24.9 ± 2.1 to 22.5 ± 2.0 mmol/L, p < 0.001) with a fall in pre-hemodialysis weight from 74.6 ± 20.7 to 71.7 ± 18.2 kg, normalized protein nitrogen accumulation rate 0.8 ± 0.28 to 0.77 ± 0.2 g/kg/day, p < 0.05, and serum albumin 39.7 ± 4.2 to 37.7 ± 4.9 g/L, p < 0.001. Thereafter, apart from pre- and post-hemodialysis serum bicarbonate, weight and normalized protein nitrogen accumulation stabilized, although albumin remained lower (37.6 ± 4.0 g/L, p < 0.001). On multivariate logistic analysis, serum bicarbonate increased more with lower pre-hemodialysis bicarbonate standardized coefficient ß 0.5 (95% confidence interval -0.6 to -0.42), increased normalized protein nitrogen accumulation ß 0.2 (0.96 to 2.38), p < 0.001, and session time ß 0.09, (0.47 to 5.98), p < 0.022, and less with lower dialysate bicarbonate 0.0-0.23 (-1.54 to -0.74), p < 0.001. CONCLUSION: Increases in SE-Bic with hemodialysis, depend on the bicarbonate gradient, session time and nPNA. Lower D-Bic reduces post-hemodialysis alkalosis but increases pre-hemodialysis acidosis and may initially have adverse effects on weight and normalized protein nitrogen accumulation.