Jeffrey A. Kraut

Toxic Alcohol Ingestions: Clinical Features, Diagnosis, and Management

Alcohol-related intoxications, including methanol, ethylene glycol, diethylene glycol, and propylene glycol, and alcoholic ketoacidosis can present with a high anion gap metabolic acidosis and increased serum osmolal gap, whereas isopropanol intoxication presents with hyperosmolality alone. The effects of these substances, except for isopropanol and possibly alcoholic ketoacidosis, are due to their metabolites, which can cause metabolic acidosis and cellular dysfunction. Accumulation of the alcohols in the blood can cause an increment in the osmolality, and accumulation of their metabolites can cause an increase in the anion gap and a decrease in serum bicarbonate concentration. The presence of both laboratory abnormalities concurrently is an important diagnostic clue, although either can be absent, depending on the time after exposure when blood is sampled. In addition to metabolic acidosis, acute renal failure and neurologic disease can occur in some of the intoxications. Dialysis to remove the unmetabolized alcohol and possibly the organic acid anion can be helpful in treatment of several of the alcohol-related intoxications. Administration of fomepizole or ethanol to inhibit alcohol dehydrogenase, a critical enzyme in metabolism of the alcohols, is beneficial in treatment of ethylene glycol and methanol intoxication and possibly diethylene glycol and propylene glycol intoxication. Given the potentially high morbidity and mortality of these intoxications, it is important for the clinician to have a high degree of suspicion for these disorders in cases of high anion gap metabolic acidosis, acute renal failure, or unexplained neurologic disease so that treatment can be initiated early.

Serum Anion Gap: Its Uses and Limitations in Clinical Medicine

The serum anion gap, calculated from the electrolytes measured in the chemical laboratory, is defined as the sum of serum chloride and bicarbonate concentrations subtracted from the serum sodium concentration. This entity is used in the detection and analysis of acid-base disorders, assessment of quality control in the chemical laboratory, and detection of such disorders as multiple myeloma, bromide intoxication, and lithium intoxication. The normal value can vary widely, reflecting both differences in the methods that are used to measure its constituents and substantial interindividual variability. Low values most commonly indicate laboratory error or hypoalbuminemia but can denote the presence of a paraproteinemia or intoxication with lithium, bromide, or iodide. Elevated values most commonly indicate metabolic acidosis but can reflect laboratory error, metabolic alkalosis, hyperphosphatemia, or paraproteinemia. Metabolic acidosis can be divided into high anion and normal anion gap varieties, which can be present alone or concurrently. A presumed 1:1 stoichiometry between change in the serum anion gap (DeltaAG) and change in the serum bicarbonate concentration (DeltaHCO(3)(-)) has been used to uncover the concurrence of mixed metabolic acid-base disorders in patients with high anion gap acidosis. However, recent studies indicate variability in the DeltaAG/DeltaHCO(3)(-) in this disorder. This observation undercuts the ability to use this ratio alone to detect complex acid-base disorders, thus emphasizing the need to consider additional information to obtain the appropriate diagnosis. Despite these caveats, calculation of the serum anion gap remains an inexpensive and effective tool that aids detection of various acid-base disorders, hematologic malignancies, and intoxications.

Metabolic acidosis: pathophysiology, diagnosis and management

Metabolic acidosis is characterized by a primary reduction in serum bicarbonate (HCO3−) concentration, a secondary decrease in the arterial partial pressure of carbon dioxide (PaCO2) of ∼1 mmHg for every 1 mmol/l fall in serum HCO3− concentration, and a reduction in blood pH. Acute forms (lasting minutes to several days) and chronic forms (lasting weeks to years) of the disorder can occur, for which the underlying cause/s and resulting adverse effects may differ. Acute forms of metabolic acidosis most frequently result from the overproduction of organic acids such as ketoacids or lactic acid; by contrast, chronic metabolic acidosis often reflects bicarbonate wasting and/or impaired renal acidification. The calculation of the serum anion gap, calculated as [Na+] – ([HCO3−] + [Cl−]), aids diagnosis by classifying the disorders into categories of normal (hyperchloremic) anion gap or elevated anion gap. These categories can overlap, however. Adverse effects of acute metabolic acidosis primarily include decreased cardiac output, arterial dilatation with hypotension, altered oxygen delivery, decreased ATP production, predisposition to arrhythmias, and impairment of the immune response. The main adverse effects of chronic metabolic acidosis are increased muscle degradation and abnormal bone metabolism. Using base to treat acute metabolic acidosis is controversial because of a lack of definitive benefit and because of potential complications. By contrast, the administration of base for the treatment of chronic metabolic acidosis is associated with improved cellular function and few complications.

Role of N-glycosylation in trafficking of apical membrane proteins in epithelia

Polarized distribution of plasma membrane transporters and receptors in epithelia is essential for vectorial functions of epithelia. This polarity is maintained by sorting of membrane proteins into apical or basolateral transport containers in the trans-Golgi network and/or endosomes followed by their delivery to the appropriate plasma membrane domains. Sorting depends on the recognition of sorting signals in proteins by specific sorting machinery. In the present review, we summarize experimental evidence for and against the hypothesis that N-glycans attached to the membrane proteins can act as apical sorting signals. Furthermore, we discuss the roles of N-glycans in the apical sorting event per se and their contribution to folding and quality control of glycoproteins in the endoplasmic reticulum or retention of glycoproteins in the plasma membrane. Finally, we review existing hypotheses on the mechanism of apical sorting and discuss the potential roles of the lectins, VIP36 and galectin-3, as putative apical sorting receptors.

Acid-base analysis : a critique of the Stewart and bicarbonate-centered approaches

When approaching the analysis of disorders of acid-base balance, physical chemists, physiologists, and clinicians, tend to focus on different aspects of the relevant phenomenology. The physical chemist focuses on a quantitative understanding of proton hydration and aqueous proton transfer reactions that alter the acidity of a given solution. The physiologist focuses on molecular, cellular, and whole organ transport processes that modulate the acidity of a given body fluid compartment. The clinician emphasizes the diagnosis, clinical causes, and most appropriate treatment of acid-base disturbances. Historically, two different conceptual frameworks have evolved among clinicians and physiologists for interpreting acid-base phenomena. The traditional or bicarbonate-centered framework relies quantitatively on the Henderson-Hasselbalch equation, whereas the Stewart or strong ion approach utilizes either the original Stewart equation or its simplified version derived by Constable. In this review, the concepts underlying the bicarbonate-centered and Stewart formulations are analyzed in detail, emphasizing the differences in how each approach characterizes acid-base phenomenology at the molecular level, tissue level, and in the clinical realm. A quantitative comparison of the equations that are currently used in the literature to calculate H(+) concentration ([H(+)]) is included to clear up some of the misconceptions that currently exist in this area. Our analysis demonstrates that while the principle of electroneutrality plays a central role in the strong ion formulation, electroneutrality mechanistically does not dictate a specific [H(+)], and the strong ion and bicarbonate-centered approaches are quantitatively identical even in the presence of nonbicarbonate buffers. Finally, our analysis indicates that the bicarbonate-centered approach utilizing the Henderson-Hasselbalch equation is a mechanistic formulation that reflects the underlying acid-base phenomenology.

Metabolic Acidosis Suppresses 25-Hydroxyvitamin D3-1α-Hydroxylase in the Rat Kidney: DISTINCT SITE AND MECHANISM OF ACTION

: Effect of metabolic acidosis on two distinct 25-hydroxyvitamin D(3)-1alpha-hydroxylase (1alpha-hydroxylase) systems was studied in the kidneys of vitamin D-deficient rats; one is localized in the proximal convoluted tubule (PCT), is activated in vitamin D deficiency, and is regulated primarily by parathyroid hormone (PTH) via cyclic AMP; the other is localized in the proximal straight tubule (PST), is latent in vitamin D deficiency, and is selectively stimulated by calcitonin via a cyclic AMP-independent mechanism. The 1alpha-hydroxylase activities were measured in the PCT and PST microdissected from the kidney of vitamin D-deficient rats with or without metabolic acidosis of varying duration. The 1alpha-hydroxylase activity decreased in the PCT from 0.74+/-0.07 fmol/mm per h to 0.24+/-0.02 at day 3 of metabolic acidosis without a further decline at day 7. Neither metabolic acidosis of 16 h duration nor reduction of the incubation medium pH from 7.4 to 7.0 affected the enzyme activity in the PCT. To examine the underlying mechanism for the suppression of 1alpha-hydroxylase activity, PTH, cyclic AMP, or calcitonin was given to rats with metabolic acidosis of 3 d duration. Although PTH failed to augment the suppressed 1alpha-hydroxylase activity in the PCT, cyclic AMP restored it to the level of control rats. The 1alpha-hydroxylase activity in the PST remained undetectable in control rats and in acidotic rats with or without PTH or cyclic AMP treatments. However, calcitonin stimulated the 1alpha-hydroxylase activity in the PST equally from undetectable to 0.75+/-0.09 fmol/mm per h in control and to 0.78+/-0.10 in acidotic rats. The data suggests that metabolic acidosis suppresses 1alpha-hydroxylase only in the PCT by inhibiting PTH-dependent adenylate cyclase, and that cellular events beyond cyclic AMP in the PCT and the events responsive to calcitonin in the PST are unaffected. The results show the definite advantage of using defined single nephron segments to study the hormonal and ionic control of the 1alpha-hydroxylase system in the kidney.

Treatment of acute metabolic acidosis: a pathophysiologic approach

Acute metabolic acidosis is associated with increased morbidity and mortality because of its depressive effects on cardiovascular function, facilitation of cardiac arrhythmias, stimulation of inflammation, suppression of the immune response, and other adverse effects. Appropriate evaluation of acute metabolic acidosis includes assessment of acid–base parameters, including pH, partial pressure of CO2 and HCO3− concentration in arterial blood in stable patients, and also in central venous blood in patients with impaired tissue perfusion. Calculation of the serum anion gap and the change from baseline enables the physician to detect organic acidoses, a common cause of severe metabolic acidosis, and aids therapeutic decisions. A fall in extracellular and intracellular pH can affect cellular function via different mechanisms and treatment should be directed at improving both parameters. In addition to supportive measures, treatment has included administration of base, primarily in the form of sodium bicarbonate. However, in clinical studies of lactic acidosis and ketoacidosis, bicarbonate administration has not reduced morbidity or mortality, or improved cellular function. Potential explanations for this failure include exacerbation of intracellular acidosis, reduction in ionized Ca2+, and production of hyperosmolality. Administration of tris(hydroxymethyl)aminomethane (THAM) improves acidosis without producing intracellular acidosis and its value as a form of base is worth further investigation. Selective sodium–hydrogen exchanger 1 (NHE1) inhibitors have been shown to improve haemodynamics and reduce mortality in animal studies of acute lactic acidosis and should also be examined further. Given the important effects of acute metabolic acidosis on clinical outcomes, more intensive study of the pathogenesis of the associated cellular dysfunction and novel methods of treatment is indicated.

Isometric Exercise Increases the Size of Forearm Veins in Patients with Chronic Renal Failure

ObjectivesDelay in maturation or failure of maturation of Cimino-Brescia fistulae contributes to the significant vascular access-related morbidity of chronic hemodialysis patients. Increased size and capacitance of native veins before the formation of vascular access has been considered an important variable in the success rate of native fistulae. We evaluated whether a formal exercise program might alter the size of native veins. MethodsThe effect of exercise on venous size was evaluated in 5 patients with severe chronic renal failure [glomerular filtration rate, 30.6 ± 5.3 mL/min (mean ± SD)]. Five male patients with a mean age of 57 ± 9 years underwent a 6-week forearm exercise training program, involving nondominant arms, that included isometric hand-grip contractions to 25 to 35% of MVC lasting 40 to 120 seconds and repetitive squeezing of squash and racquet balls. Both the volume and intensity of exercise training was increased weekly based on strength measured by hand-grip dynamometer and on the patients’ indicated level of comfort. Cephalic vessel size in both the nondominant (trained) and dominant (control) arms, with and without a tourniquet, were obtained using Doppler ultrasound before and after the 6-week exercise training program. ResultsThe size of the cephalic vein of the exercised arm increased significantly (P < 0.05) compared with the control arm when measured in both the absence (048 ± 0.016 versus 0.024 ± 0.023 cm2) and the presence of a tourniquet (0.056 ± 0.022 versus 028 ± 0.027 cm2). ConclusionsThese findings indicate that a simple, incremental resistance, exercise-training program can cause a significant increase in the size of the cephalic vein commonly used in the creation of an arteriovenous fistula. The increase in size and resultant probable increase in blood flow might accelerate the maturation of native arteriovenous fistulae, thereby lessening the morbidity associated with vascular access.

ACID-BASE IN RENAL FAILURE: Disturbances of Acid-Base Balance and Bone Disease in End-Stage Renal Disease

Bone disease in patients with chronic renal failure (CRF) is thought to be the consequence primarily of the interplay of several factors, including the serum levels of parathyroid hormone (PTH), vitamin D, calcium, and phosphorus, and exposure to bone toxins such as aluminum or amyloid. Recently the metabolic acidosis noted with CRF has been implicated as an additional factor contributing to the genesis of bone disease. Although metabolic acidosis might be the dominant factor in the cause of bone disease in some instances, more commonly this acid‐base disturbance interacts with other factors contributing to the development of bone disease. The following article summarizes the data in support of an important role for metabolic acidosis in the genesis of bone disease in patients with CRF and presents our recommendations for treatment of uremic acidosis to prevent or treat the bone disease.

Use of base in the treatment of acute severe organic acidosis by nephrologists and critical care physicians: results of an online survey

BackgroundAcute severe metabolic acidosis associated with lactic acidosis or ketoacidosis can have severe detrimental effects on organ function, and might contribute to mortality. A general consensus exists that elimination of the cause of the acidosis is essential for treatment, but there is controversy concerning the use of base for the treatment of these disorders. Some physicians advocate administration of base when the acidosis is severe to prevent a decrease in cardiac output, whereas others oppose administration of base even when the acidosis is severe given the potential compromise of cardiac function. Nephrologists and critical care specialists are often the physicians developing recommendations for the treatment of severe acid-base disorders.MethodsA short online survey of 20 questions was developed to assess the approach to the treatment of acute metabolic acidosis of program directors of fellowship programs and experts from the specialties of critical care and nephrology.ResultsAlthough there was variability among individual physicians from both specialties, a larger percentage of nephrologists than critical care physicians queried recommended administration of base for the treatment of lactic acidosis (86% vs 67%) and ketoacidosis (60% vs 28%). Also, critical care physicians in general used a lower level of blood pH when deciding when to initiate treatment. Of the physicians who gave base, most utilized sodium bicarbonate as the form of base given.ConclusionsThe results of this survey indicate that the decisions whether to use base for the treatment of acute severe metabolic acidosis, and under which circumstances, vary among physicians, and indicate the need for further studies to develop evidence-based guidelines for therapy.