Electrolyte and Acid-Base Disorders Associated with Cancer Immunotherapy.

Novel immunotherapy drugs have changed the landscape of cancer medicine. Immune checkpoint inhibitors and chimeric antigen receptor T cells are being used and investigated in almost all types of cancers. Immune-related adverse events have been associated with immunotherapies. AKI has been the most commonly associated kidney adverse event. In this review, we showcase the several associated electrolyte disorders seen with immunotherapy. Immune checkpoint inhibitors can lead to hyponatremia by several mechanisms, with the syndrome of inappropriate antidiuresis being the most common. Endocrine causes of hyponatremia are rare. Hypokalemia is not uncommon and is associated with both proximal and distal renal tubular acidosis. Hypercalcemia associated with immune checkpoint inhibitors has led to some interesting observations, including immune checkpoint inhibitor-induced parathyroid hormone-related peptide production, sarcoid-like granulomas, and hyperprogression of the disease. Hypocalcemia and hyperphosphatemia may be seen with immune checkpoint inhibitor-induced tumor lysis syndrome. Chimeric antigen receptor T cell therapy-associated electrolyte disorders are also common. This is associated chiefly with hyponatremia, although other electrolyte abnormalities can occur. Early recognition and prompt diagnosis may help providers manage the mechanistically varied and novel electrolyte disorders associated with immunotherapy.

Impact of a new balanced gelatine on electrolytes and pH in the perioperative care.

INTRODUCTION: Balanced fluid replacement solutions can possibly reduce the risks for electrolyte imbalances, for acid-base imbalances, and thus for renal failure. To assess the intraoperative change of base excess (BE) and chloride in serum after treatment with either a balanced gelatine/electrolyte solution or a non-balanced gelatine/electrolyte solution, a prospective, controlled, randomized, double-blind, dual centre phase III study was conducted in two tertiary care university hospitals in Germany. MATERIAL AND METHODS: 40 patients of both sexes, aged 18 to 90 years, who were scheduled to undergo elective abdominal surgery with assumed intraoperative volume requirement of at least 15 mL/kg body weight gelatine solution were included. Administration of study drug was performed intravenously according to patients need. The trigger for volume replacement was a central venous pressure (CVP) minus positive end-expiratory pressure (PEEP) <10 mmHg (CVP <10 mmHg). The crystalloid:colloid ratio was 1:1 intra- and postoperatively. The targets for volume replacement were a CVP between 10 and 14 mmHg minus PEEP after treatment with vasoactive agent and mean arterial pressure (MAP) > 65 mmHg. RESULTS: The primary endpoints, intraoperative changes of base excess -2.59 ± 2.25 (median: -2.65) mmol/L (balanced group) and -4.79 ± 2.38 (median: -4.70) mmol/L (non-balanced group)) or serum chloride 2.4 ± 1.9 (median: 3.0) mmol/L and 5.2 ± 3.1 (median: 5.0) mmol/L were significantly different (p = 0.0117 and p = 0.0045, respectively). In both groups (each n = 20) the investigational product administration in terms of volume and infusion rate was comparable throughout the course of the study, i.e. before, during and after surgery. DISCUSSION: Balanced gelatine solution 4% combined with a balanced electrolyte solution demonstrated significant smaller impact on blood gas analytic parameters in the primary endpoints BE and serum chloride when compared to a non-balanced gelatine solution 4% combined with NaCl 0.9%. No marked treatment differences were observed with respect to haemodynamics, coagulation and renal function. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01515397) and clinicaltrialsregister.eu, EudraCT number 2010-018524-58.

Carbonic anhydrase inhibitors modify intracellular pH transients and contractions of rat middle cerebral arteries during CO2/HCO3- fluctuations.

The CO2/HCO3- buffer minimizes pH changes in response to acid-base loads, HCO3- provides substrate for Na+,HCO3--cotransporters and Cl-/HCO3--exchangers, and H+ and HCO3- modify vasomotor responses during acid-base disturbances. We show here that rat middle cerebral arteries express cytosolic, mitochondrial, extracellular, and secreted carbonic anhydrase isoforms that catalyze equilibration of the CO2/HCO3- buffer. Switching from CO2/HCO3--free to CO2/HCO3--containing extracellular solution results in initial intracellular acidification due to hydration of CO2 followed by gradual alkalinization due to cellular HCO3- uptake. Carbonic anhydrase inhibition decelerates the initial acidification and attenuates the associated transient vasoconstriction without affecting intracellular pH or artery tone at steady-state. Na+,HCO3--cotransport and Na+/H+-exchange activity after NH4+-prepulse-induced intracellular acidification are unaffected by carbonic anhydrase inhibition. Extracellular surface pH transients induced by transmembrane NH3 flux are evident under CO2/HCO3--free conditions but absent when the buffer capacity and apparent H+ mobility increase in the presence of CO2/HCO3- even after the inhibition of carbonic anhydrases. We conclude that (a) intracellular carbonic anhydrase activity accentuates pH transients and vasoconstriction in response to acute elevations of pCO2, (b) CO2/HCO3- minimizes extracellular surface pH transients without requiring carbonic anhydrase activity, and (c) carbonic anhydrases are not rate limiting for acid­base transport across cell membranes during recovery from intracellular acidification.

Is Bicarbonate Therapy Useful?

Despite concerns about the negative effects of metabolic acidosis, there is minimal evidence that sodium bicarbonate administration is an effective treatment. In addition, sodium bicarbonate therapy is associated with many adverse effects, including paradoxic intracellular acidosis, hypokalemia, hypocalcemia, hypernatremia, and hyperosmolality. Definitive recommendations regarding bicarbonate therapy are challenging as there is little high-quality evidence available. In most clinical scenarios of metabolic acidosis, treatment efforts should focus on resolution of the underlying cause, and sodium bicarbonate therapy should be used with caution, if at all. An exception to this is kidney disease, wherein sodium bicarbonate therapy may have a valuable role.

[MODERN APPROACHES TO CORRECTION OF HYPERNATREMIA IN NEUROSURGICAL PATIENTS].

The article presents the analysis of the intensive therapy through the correction of persistent hypernatremia in neurosurgical patients after removal of brain tumors. The aim of this work was to evaluate the effectiveness of Sterofundin in the framework of complex therapy of hypernatremia in neurosurgical patients after removal of brain tumors. We analyzed the dynamics of the concentrations of sodium, potassium, chorus of the plasma, anion gap and buffer bases in the postoperative period of these patients. For obtaining reliable results, the patients were divided into groups according to the nature of the treatment: Sterofundin and symptomatic correction of hypotonic solution of sodium chloride, saluretic and Verospiron respectively. In a comparison between the groups, a distinct difference in the speed of regression of hypernatremia and durability of the achieved effect was observed. In case of treatment with Sterofundin there was a significant decrease of hypernatremia by the end of the second day of the postoperative period without tendency to re-raise. The prevalence of hypotonic solutions of sodium chloride and potassium-sparing saluretics in intensive care allowed reducing the sodium concentration non-persistently to the fourth day on the background of significant fluctuations in its concentration. The use of Sterofundin in complex therapy of electrolyte disturbances, particularly of hypernatremia in neurosurgical patients after removal of brain tumors, is reflected in the form of significant regression of increased sodium concentration in plasma compared with the method of use "hypotonic" hemodilution, saluretics and potassium-sparing diuretics.

American Society of Nephrology Quiz and Questionnaire 2015: Electrolytes and Acid-Base Disorders.

The Nephrology Quiz and Questionnaire remains an extremely popular session for attendees of the annual Kidney Week meeting of the American Society of Nephrology. During the 2015 meeting the conference hall was once again overflowing with eager quiz participants. Topics covered by the experts included electrolyte and acid-base disorders, glomerular disease, end-stage renal disease and dialysis, and kidney transplantation. Complex cases representing each of these categories together with single-best-answer questions were prepared and submitted by the panel of experts. Before the meeting, training program directors of nephrology fellowship programs and nephrology fellows in the United States answered the questions through an internet-based questionnaire. During the live session members of the audience tested their knowledge and judgment on the same series of case-oriented questions in a quiz. The audience compared their answers in real time using a cell-phone app containing the answers of the nephrology fellows and training program directors. The results of the online questionnaire were displayed, and then the quiz answers were discussed. As always, the audience, lecturers, and moderators enjoyed this highly educational session. This article recapitulates the session and reproduces selected content of educational value for theClinical Journal of the American Society of Nephrologyreaders. Enjoy the clinical cases and expert discussions.

Oral sodium and potassium binders in heart failure.

Significant improvements in the morbidity and mortality associated with chronic heart failure have been gained with the use ACE inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and diuretics. However, the use of these agents is often limited by their propensity to precipitate worsening renal function and hyperkalemia, particularly in patients with chronic kidney disease. Several pharmacologic agents have been developed in recent years that utilize the gastrointestinal tract as an alternate route for drug absorption, electrolyte exchange, and drug and electrolyte elimination. The existing data establishing the safety and efficacy of these novel agents will be the focus of this review.

Magnesium physiology and clinical therapy in veterinary critical care.

OBJECTIVE: To review magnesium physiology including absorption, excretion, and function within the body, causes of magnesium abnormalities, and the current applications of magnesium monitoring and therapy in people and animals. ETIOLOGY: Magnesium plays a pivotal role in energy production and specific functions in every cell in the body. Disorders of magnesium can be correlated with severity of disease, length of hospital stay, and recovery of the septic patient. Hypermagnesemia is seen infrequently in people and animals with significant consequences reported. Hypomagnesemia is more common in critically ill people and animals, and can be associated with platelet, immune system, neurological, and cardiovascular dysfunction as well as alterations in insulin responsiveness and electrolyte imbalance. DIAGNOSIS: Measurement of serum ionized magnesium in critically or chronically ill veterinary patients is practical and provides information necessary for stabilization and treatment. Tissue magnesium concentrations may be assessed using nuclear magnetic resonance spectroscopy as well as through the application of fluorescent dye techniques. THERAPY: Magnesium infusions may play a therapeutic role in reperfusion injury, myocardial ischemia, cerebral infarcts, systemic inflammatory response syndromes, tetanus, digitalis toxicity, bronchospasms, hypercoagulable states, and as an adjunct to specific anesthetic or analgesic protocols. Further veterinary studies are needed to establish the frequency and importance of magnesium disorders in animals and the potential benefit of magnesium infusions as a therapeutic adjunct to specific diseases. PROGNOSIS: The prognosis for most patients with magnesium disorders is variable and largely dependent on the underlying cause of the disorder.

[Old age--neither sour nor bitter]. / Starosc--ani kwasna, ani gorzka.

The development of medicine involves prolongation of human life. In many cases, however, chronic diseases, quite common in the elderly, make the quality of life very poor. We put the question: why we--the doctors--are not able to cope with the problem and whether the pharmacological treatment actually helps? A common medical practice is the use of proton pump inhibitors for various, often nonspecific disorders of the gastrointestinal tract. Statistics point to the overuse of the drugs from this group, also in the elderly. Despite the belief in the safety of such proceedings, proton pump inhibitors may pose a significant threat to older patients contributing to the symptoms worsening, and significantly affecting the mechanisms of acid-base balance. Inhibition of gastric acid secretion in the stomach is not a golden receipt in the case of dyspeptic symptoms, especially in people with the elderly. In many of them achlorhydria or hipochlorhydria is diagnosed. In others, such treatment, may not bring an expected relief in symptoms, while contributing to disturbances of acid-base balance, and--indirectly--have an adverse effect on renal function. We suggest moderation in the use of proton pump inhibitors to bring patients to a real, and not quasi wellness.

[Controversy in the treatment of acid-base abnormalities].

Sodium bicarbonate has been standard therapy for the treatment of acidosis. In lactic acidosis and hypercapnic acidosis, however, there is no clinical data supporting its effectiveness. We reviewed the literature of the efficacy of sodium bicarbonate on lactic acidosis and hypercapnic acidosis. On both conditions, we have no solid evidence supporting its beneficial effect. Conversely, acidosis or hypercapnia might be protective in acute lung and systemic organ injury. Therefore, the unprepared use of bicarbonate might be harmful in terms of fluid and sodium overload and excess lactate concentrations. According to current literature, we cannot recommend sodium bicarbonate administration for patients with lactic acidosis and hypercapnic acidosis.

The effects of water replacement by oral rehydration fluids with or without betaine supplementation on performance, acid-base balance, and water retention of heat-stressed broiler chickens.

Exposing broilers to a high temperature increases water and electrolyte K(+) and Na(+) excretion, which negatively affects the heat dissipation capacity and acid-base homeostasis, resulting in losses in growth performance. In this experiment, the efficacy of providing oral rehydration therapy and betaine on growth performance, acid-base balance, and water and electrolyte retention was evaluated. A total of 432 one-day-old broiler chicks (Cobb) were allocated to 72 metabolic cages and reared to 31 d of age under standard conditions. From 32 to 41 d of age, chicks were exposed to heat stress (ambient temperature, 32°C) and high RH (80 to 100% RH) for 9 h daily. The ameliorative effects of a 3 × 3 factorial array of treatments administered via drinking water were evaluated in 8 replicates of 6 chicks per cage for each treatment. Two oral rehydration therapy (ORT) fluids, based on either citrate or bicarbonate salts, were added to tap water. In addition, betaine was added to tap water at an inclusion rate of 0, 500, or 1,000 mg/L to complete the array of 9 liquid-based treatments. Growth performance was assessed at 32, 35, and 41 d of age. From 32 to 35 d of age, chicks receiving ORT fluids exhibited improved growth performance, water balance, and electrolyte (K(+), Na(+)) retention. In addition, the physiological response to stress was attenuated, as indicated by lower heterophil-to-lymphocyte ratios and blood glucose concentrations relative to the negative controls. The addition of betaine at an inclusion rate of 500 mg/L improved BW gain. From d 36 to 41, treatments did not significantly influence growth performance, which suggests that chicks receiving tap water were able to compensate and adapt to the heat-stress conditions. The results demonstrate that the beneficial effects of providing ORT fluids and 500 mg of betaine/L were observed only during the first 4 d of heat exposure. After this period, adaptation to the heat appears to occur, and none of the treatments was successful in improving growth performance.

[Infusion therapy for neonates, infants and children]. / Infusionstherapie bei Neugeborenen, Säuglingen und Kindern.

Intravenous administration of fluids, electrolytes and glucose are the most common interventions in hospitalized pediatric patients. Parenteral fluid administration can be life-saving, however, if used incorrectly it also carries substantial risks. Perioperatively, adequate hydration, prevention of electrolyte imbalances and maintenance of normoglycemia are the main goals of parenteral fluid therapy. Conceptionally, the distinction between maintenance requirements, deficits and ongoing loss is helpful. Although the pathophysiological basis for parenteral fluid therapy was clarified in the first half of the 20th century, some aspects still remain controversial. In newborn infants, rational parenteral fluid therapy must take into account large insensible fluid losses, adaptive changes of renal function in the first days of life and the fact that neonates do not tolerate prolonged periods of fasting. In older infants the occurrence of iatrogenic hyponatremia with the use of hypotonic solutions has led to a critical reappraisal of the validity of the Holliday-Segar method for calculating maintenance fluid requirements in the postoperative period. Pragmatically, only isotonic solutions should be used in clinical situations which are known to be associated with increases in antidiuretic hormone (ADH) secretion. In this context, it is important to realize that in contrast to lactated Ringer's solution, the use of normal saline can lead to hyperchloremic acidosis in a dose-dependent fashion. Although there is no convincing evidence that colloids are better than crystalloids, there are clinical situations where the use of the more expensive colloids seems justified. It may be reasonable to choose a solution for fluid replacement which has a composition comparable to the composition of the fluid which must be replaced. Although hypertonic saline can reduce an elevated intracranial pressure, this therapy cannot be recommended as a routine procedure because there is currently no evidence that this intervention improves long-term outcome in pediatric patients with traumatic brain injury.

Diuretics in clinical practice. Part II: electrolyte and acid-base disorders complicating diuretic therapy.

IMPORTANCE OF THE FIELD: As with all potent therapeutic agents, the use of diuretic compounds has been linked with several adverse effects that may reduce quality of life and patient compliance and, in some cases, may be associated with considerable morbidity and mortality. Among the various types of adverse effects, disturbances of electrolyte and acid-base balance are perhaps the most common, and some of them are the aetiological factors of other side effects (i.e., hypokalaemia causing ventricular arrhythmias or glucose intolerance). The mechanism and site of action and, therefore, the pharmacological effects of each diuretic class largely determine the specific electrolyte or acid-base abnormalities that will accompany the use of each diuretic agent. AREAS COVERED IN THE REVIEW: This article reviews the major electrolyte disturbances (hypokalaemia, hyperkalaemia, hyponatraemia, disorders of magnesium and calcium balance), as well as the acid-base abnormalities complicating the use of the various diuretic agents. WHAT THE READER WILL GAIN: The reader will gain insights into the pathogenesis of the diuretic-induced electrolyte and acid-base disorders together with considerations for their prevention and treatment. TAKE HOME MESSAGE: Knowledge of the pharmacologic properties of each diuretic class and appropriate monitoring of patients under diuretic treatment represent the most important strategies to prevent the development of diuretic-related adverse events and their consequences.

Transient type 1 pseudo-hypoaldosteronism: report on an eight-patient series and literature review.

Eight boys aged 2-12 weeks with urinary tract malformations (UTMs) exhibited features of transient type 1 pseudo-hypoaldosteronism (TPHA1) in the course of urinary tract infection (UTI). Hyponatremia (120.9+/-5.8 mmol/l), hyperkalemia (6.9+/-0.9 mmol/l), metabolic acidosis (plasma bicarbonate 11+/-1.4 mmol/l), and a rise in serum creatinine levels (145+/-101 micromol/l) were associated with high urinary sodium (Na) and low potassium (K) excretion. Tubular resistance to aldosterone was indicated by high plasma aldosterone concentrations (170.4+/-100.5 ng/dl), high levels of the plasma aldosterone to potassium ratio (25.2+/-15.6), and diminished urinary K/Na values (0.31+/-0.19). With appropriate therapy, serum electrolytes, creatinine, and acid-base balance normalized within 2 weeks. A Medline search revealed another 85 cases of TPHA1 reported to date. All of the 93 patients were less than 7 months of age and 90% were less than 3 months of age, 90.3% suffered from UTM, with associated UTI in 89% of them, 11% had UTMin the absence of UTI, and 9.7% showed isolated UTI. These findings indicate that early infancy is the main contributing factor for TPHA1 to occur and that UTI and UTMare additional factors, with at least one being required for its development.

[Electrolyte and acid-base balance disorders in advanced chronic kidney disease]. / Alteraciones electroliticas y del equilibrio acido-base en la enfermedad renal cronica avanzada.

1. The kidneys are the key organs to maintain the balance of the different electrolytes in the body and the acid-base balance. Progressive loss of kidney function results in a number of adaptive and compensatory renal and extrarenal changes that allow homeostasis to be maintained with glomerular filtration rates in the range of 10-25 ml/min. With glomerular filtration rates below 10 ml/min, there are almost always abnormalites in the body's internal environment with clinical repercussions. 2. Water Balance Disorders: In advanced chronic kidney disease (CKD), the range of urine osmolality progressively approaches plasma osmolality and becomes isostenuric. This manifests clinically as symptoms of nocturia and polyuria, especially in tubulointerstitial kidney diseases. Water overload will result in hyponatremia and a decrease in water intake will lead to hypernatremia. Routine analyses of serum Na levels should be performed in all patients with advanced CKD (Strength of Recommendation C). Except in edematous states, a daily fluid intake of 1.5-2 liters should be recommended (Strength of Recommendation C). Hyponatremia does not usually occur with glomerular filtration rates above 10 ml/min (Strength of Recommendation B). If it occurs, an excessive intake of free water should be considered or nonosmotic release of vasopressin by stimuli such as pain, anesthetics, hypoxemia or hypovolemia, or the use of diuretics. Hypernatremia is less frequent than hyponatremia in CKD. It can occur because of the provision of hypertonic parenteral solutions, or more frequently as a consequence of osmotic diuresis due to inadequate water intake during intercurrent disease, or in some circumstance that limits access to water (obtundation, immobility). 3. Sodium Balance Disorders: In CKD, fractional excretion of sodium increases so that absolute sodium excretion is not modified until glomerular filtration rates below 15 ml/min (Strength of Recommendation B). Total body content of sodium is the main determinant of extracellular volume and therefore disturbances in sodium balance will lead to clinical situations of volume depletion or overload: Volume depletion due to renal sodium loss occurs in abrupt restrictions of salt intake in advanced CKD. It occurs more frequently in certain tubulointerstitial kidney diseases (salt losing nephropathies). Volume overload due to sodium retention can occur with glomerular filtration rates below 25 ml/min and leads to edema, arterial hypertension and heart failure. The use of diuretics in volume overload in CKD is useful to force natriuresis (Strength of Recommendation B). Thiazides have little effect in advanced CKD. Loop diuretics are effective and should be used in higher than normal doses (Strength of Recommendation B). The combination of thiazides and loop diuretics can be useful in refractory cases (Strength of Recommendation B). Weight and volume should be monitored regularly in the hospitalized patient with CKD (Strength of Recommendation C). 4. Potassium Balance Disorders: In CKD, the ability of the kidneys to excrete potassium decreases proportionally to the loss of glomerular filtration. Stimulation of aldosterone and the increase in intestinal excretion of potassium are the main adaptive mechanisms to maintain potassium homeostasis until glomerular filtration rates of 10 ml/min. The main causes of hyperkalemia in CKD are the following: Use of drugs that alter the ability of the kidneys to excrete potassium: ACEIs, ARBs, NSAIDs, aldosterone antagonists, nonselective beta-blockers, heparin, trimetoprim, calcineurin inhibitors. Determination of serum potassium two weeks after the initiation of treatment with ACEIs/ARBs is recommended (Strength of Recommendation C). Routine use of aldosterone antagonists in advanced CKD is not recommended (Strength of Recommendation C). Abrupt reduction in glomerular filtration rate: Constipation. Prolonged fasting. Metabolic acidosis. A low-potassium diet is recommended with GFR less than 20 ml/min, or GFR less than 50 ml/min if drugs that raise serum potassium are taken (Strength of Recommendation C). In the absence of symptoms or electrocardiographic abnormalities, review of medications, restriction of dietary potassium and use of oral ion exchange resins are usually sufficient therapeutic measures (Strength of Recommendation C). If symptoms and/or electrocardiographic abnormalities are present, the usual parenteral pharmacological measures should be used (10% calcium gluconate, insulin and glucose, salbutamol, resins, diuretics) (Strength of Recommendation A). Parenteral bicarbonate and ion exchange resins in enemas are not recommended as first-line treatment (Strength of Recommendation C). Hemodialysis should be considered in patients with glomerular filtration rates below 10 ml/min (Strength of Recommendation C). 5. Acid-Base Disorders in CKD: Moderate metabolic acidosis (Bic 16-20) mEq/L is common with glomerular filtration rates below 20 ml/min, and favors bone demineralization due to the release of calcium and phosphate from the bone, chronic hyperventilation, and muscular weakness and atrophy. Its treatment consists of administration of sodium bicarbonate, usually orally (0.5-1 mEq/kg/day), with the goal of achieving a serum bicarbonate level of 22-24 mmol/L (Strength of Recommendation C). Limitation of daily protein intake to less than 1 g/kg/day is also useful (Strength of Recommendation C). Use of sevelamer as a phosphate binder aggravates metabolic acidosis since it favors endogenous acid production and therefore acidosis should be monitored and corrected if it occurs (Strength of Recommendation C). Hypocalcemia should always be corrected before metabolic acidosis in CKD (Strength of Recommendation B). Metabolic acidosis is an infrequent disorder and requires exogenous alkali administration (bicarbonate, phosphate binders) or vomiting.