Edelman Revisited: Concepts, Achievements, and Challenges.

The key message from the 1958 Edelman study states that combinations of external gains or losses of sodium, potassium and water leading to an increase of the fraction (total body sodium plus total body potassium) over total body water will raise the serum sodium concentration ([Na]S), while external gains or losses leading to a decrease in this fraction will lower [Na]S. A variety of studies have supported this concept and current quantitative methods for correcting dysnatremias, including formulas calculating the volume of saline needed for a change in [Na]S are based on it. Not accounting for external losses of sodium, potassium and water during treatment and faulty values for body water inserted in the formulas predicting the change in [Na]S affect the accuracy of these formulas. Newly described factors potentially affecting the change in [Na]S during treatment of dysnatremias include the following: (a) exchanges during development or correction of dysnatremias between osmotically inactive sodium stored in tissues and osmotically active sodium in solution in body fluids; (b) chemical binding of part of body water to macromolecules which would decrease the amount of body water available for osmotic exchanges; and (c) genetic influences on the determination of sodium concentration in body fluids. The effects of these newer developments on the methods of treatment of dysnatremias are not well-established and will need extensive studying. Currently, monitoring of serum sodium concentration remains a critical step during treatment of dysnatremias.

Dialysis-associated hyperglycemia: manifestations and treatment.

PURPOSE: Dialysis-associated hyperglycemia (DAH), is associated with a distinct fluid and electrolyte pathophysiology. The purpose of this report was to review the pathophysiology and provide treatment guidelines for DAH. METHODS: Review of published reports on DAH. Synthesis of guidelines based on these reports. RESULTS: The following fluid and solute abnormalities have been identified in DAH: (a) hypoglycemia: this is a frequent complication of insulin treatment and its prevention requires special attention. (b) Elevated serum tonicity. The degree of hypertonicity in DAH is lower than in similar levels of hyperglycemia in patients with preserved renal function. Typically, correction of hyperglycemia with insulin corrects the hypertonicity of DAH. (c) Extracellular volume abnormalities ranging from pulmonary edema associated with osmotic fluid shift from the intracellular into the extracellular compartment as a consequence of gain in extracellular solute (glucose) to hypovolemia from osmotic diuresis in patients with residual renal function or from fluid losses through extrarenal routes. Correction of DAH by insulin infusion reverses the osmotic fluid transfer between the intracellular and extracellular compartments and corrects the pulmonary edema, but can worsen the manifestations of hypovolemia, which require saline infusion. (d) A variety of acid-base disorders including ketoacidosis correctable with insulin infusion and no other interventions. (e) Hyperkalemia, which is frequent in DAH and is more severe when ketoacidosis is also present. Insulin infusion corrects the hyperkalemia. Extreme hyperkalemia at presentation or hypokalemia developing during insulin infusion require additional measures. CONCLUSIONS: In DAH, insulin infusion is the primary management strategy and corrects the fluid and electrolyte abnormalities. Patients treated for DAH should be monitored for the development of hypoglycemia or fluid and electrolyte abnormalities that may require additional treatments.

Hyperglycemic Crisis in an Anuric Peritoneal Dialysis Patient with Profound and Symptomatic Hypertonicity.

An anuric peritoneal dialysis patient with diabetes mellitus, congestive heart failure, and anasarca developed severe hyperglycemia with hypertonicity causing profound neurological manifestations after prolonged and continuous use of hypertonic (4.25%) dextrose dialysate. She expired with hypotensive shock from a new myocardial infarction soon after completion of treatment with insulin infusion. The degree of the presenting hypertonicity far exceeded the value expected from the degree of hyperglycemia. We identified prolonged peritoneal dialysis with hypertonic solutions and profound extracellular volume expansion as the causes of the excessive hypertonicity. Hyperglycemia developing in diabetic patients treated for anasarca by peritoneal dialysis after continuous use of hypertonic dextrose dialysate is associated with the risk of excessive hypertonicity with severe clinical manifestations.

Fluid balance concepts in medicine: Principles and practice.

The regulation of body fluid balance is a key concern in health and disease and comprises three concepts. The first concept pertains to the relationship between total body water (TBW) and total effective solute and is expressed in terms of the tonicity of the body fluids. Disturbances in tonicity are the main factor responsible for changes in cell volume, which can critically affect brain cell function and survival. Solutes distributed almost exclusively in the extracellular compartment (mainly sodium salts) and in the intracellular compartment (mainly potassium salts) contribute to tonicity, while solutes distributed in TBW have no effect on tonicity. The second body fluid balance concept relates to the regulation and measurement of abnormalities of sodium salt balance and extracellular volume. Estimation of extracellular volume is more complex and error prone than measurement of TBW. A key function of extracellular volume, which is defined as the effective arterial blood volume (EABV), is to ensure adequate perfusion of cells and organs. Other factors, including cardiac output, total and regional capacity of both arteries and veins, Starling forces in the capillaries, and gravity also affect the EABV. Collectively, these factors interact closely with extracellular volume and some of them undergo substantial changes in certain acute and chronic severe illnesses. Their changes result not only in extracellular volume expansion, but in the need for a larger extracellular volume compared with that of healthy individuals. Assessing extracellular volume in severe illness is challenging because the estimates of this volume by commonly used methods are prone to large errors in many illnesses. In addition, the optimal extracellular volume may vary from illness to illness, is only partially based on volume measurements by traditional methods, and has not been determined for each illness. Further research is needed to determine optimal extracellular volume levels in several illnesses. For these reasons, extracellular volume in severe illness merits a separate third concept of body fluid balance.

Establishing the presence or absence of chronic kidney disease: Uses and limitations of formulas estimating the glomerular filtration rate.

The development of formulas estimating glomerular filtration rate (eGFR) from serum creatinine and cystatin C and accounting for certain variables affecting the production rate of these biomarkers, including ethnicity, gender and age, has led to the current scheme of diagnosing and staging chronic kidney disease (CKD), which is based on eGFR values and albuminuria. This scheme has been applied extensively in various populations and has led to the current estimates of prevalence of CKD. In addition, this scheme is applied in clinical studies evaluating the risks of CKD and the efficacy of various interventions directed towards improving its course. Disagreements between creatinine-based and cystatin-based eGFR values and between eGFR values and measured GFR have been reported in various cohorts. These disagreements are the consequence of variations in the rate of production and in factors, other than GFR, affecting the rate of removal of creatinine and cystatin C. The disagreements create limitations for all eGFR formulas developed so far. The main limitations are low sensitivity in detecting early CKD in several subjects, e.g., those with hyperfiltration, and poor prediction of the course of CKD. Research efforts in CKD are currently directed towards identification of biomarkers that are better indices of GFR than the current biomarkers and, particularly, biomarkers of early renal tissue injury.

Hypertonicity: Clinical entities, manifestations and treatment.

Hypertonicity causes severe clinical manifestations and is associated with mortality and severe short-term and long-term neurological sequelae. The main clinical syndromes of hypertonicity are hypernatremia and hyperglycemia. Hypernatremia results from relative excess of body sodium over body water. Loss of water in excess of intake, gain of sodium salts in excess of losses or a combination of the two are the main mechanisms of hypernatremia. Hypernatremia can be hypervolemic, euvolemic or hypovolemic. The management of hypernatremia addresses both a quantitative replacement of water and, if present, sodium deficit, and correction of the underlying pathophysiologic process that led to hypernatremia. Hypertonicity in hyperglycemia has two components, solute gain secondary to glucose accumulation in the extracellular compartment and water loss through hyperglycemic osmotic diuresis in excess of the losses of sodium and potassium. Differentiating between these two components of hypertonicity has major therapeutic implications because the first component will be reversed simply by normalization of serum glucose concentration while the second component will require hypotonic fluid replacement. An estimate of the magnitude of the relative water deficit secondary to osmotic diuresis is obtained by the corrected sodium concentration, which represents a calculated value of the serum sodium concentration that would result from reduction of the serum glucose concentration to a normal level.

Hypertonicity: Pathophysiologic Concept and Experimental Studies.

Disturbances in tonicity (effective osmolarity) are the major clinical disorders affecting cell volume. Cell shrinking secondary to hypertonicity causes severe clinical manifestations and even death. Quantitative management of hypertonic disorders is based on formulas computing the volume of hypotonic fluids required to correct a given level of hypertonicity. These formulas have limitations. The major limitation of the predictive formulas is that they represent closed system calculations and have been tested in anuric animals. Consequently, the formulas do not account for ongoing fluid losses during development or treatment of the hypertonic disorders. In addition, early comparisons of serum osmolality changes predicted by these formulas and observed in animals infused with hypertonic solutions clearly demonstrated that hypertonicity creates new intracellular solutes causing rises in serum osmolality higher than those predicted by the formulas. The mechanisms and types of intracellular solutes generated by hypertonicity and the effects of the solutes have been studied extensively in recent times. The solutes accumulated intracellularly in hypertonic states have potentially major adverse effects on the outcomes of treatment of these states. When hypertonicity was produced by the infusion of hypertonic sodium chloride solutions, the predicted and observed changes in serum sodium concentration were equal. This finding justifies the use of the predictive formulas in the management of hypernatremic states.

Respiratory failure in diabetic ketoacidosis.

Respiratory failure complicating the course of diabetic ketoacidosis (DKA) is a source of increased morbidity and mortality. Detection of respiratory failure in DKA requires focused clinical monitoring, careful interpretation of arterial blood gases, and investigation for conditions that can affect adversely the respiration. Conditions that compromise respiratory function caused by DKA can be detected at presentation but are usually more prevalent during treatment. These conditions include deficits of potassium, magnesium and phosphate and hydrostatic or non-hydrostatic pulmonary edema. Conditions not caused by DKA that can worsen respiratory function under the added stress of DKA include infections of the respiratory system, pre-existing respiratory or neuromuscular disease and miscellaneous other conditions. Prompt recognition and management of the conditions that can lead to respiratory failure in DKA may prevent respiratory failure and improve mortality from DKA.

Indices of serum tonicity in clinical practice.

Although disturbances of serum tonicity (effective osmolality) may have dire consequences, only surrogate indices of tonicity are available in practice. This report identifies the appropriate index for expressing clinical states of dystonicity. Serum sodium concentration ([Na]S) and osmolality ([Osm]S) may be incongruent. When the tonicity state shown by [Osm]S is higher than [Na]S and the difference between the 2 indices is caused by an excess of solute that distributes in total body water, tonicity is described by [Na]S. When this difference results from a gain of solute with extracellular distribution like mannitol or a decrease in serum water content, causing a falsely low measurement of [Na]S, [Osm]S accurately reflects tonicity. Two indices of tonicity are applicable during hyperglycemia: the tonicity formula (2 ·[Na]S + [Glucose]S/18) and the corrected [Na]S ([Na]S corrected to a normal [Glucose]S using an empirically derived coefficient). Clinicians should understand the uses and limitations of the tonicity indices.

The renal concentrating mechanism and the clinical consequences of its loss.

The integrity of the renal concentrating mechanism is maintained by the anatomical and functional arrangements of the renal transport mechanisms for solute (sodium, potassium, urea, etc) and water and by the function of the regulatory hormone for renal concentration, vasopressin. The discovery of aquaporins (water channels) in the cell membranes of the renal tubular epithelial cells has elucidated the mechanisms of renal actions of vasopressin. Loss of the concentrating mechanism results in uncontrolled polyuria with low urine osmolality and, if the patient is unable to consume (appropriately) large volumes of water, hypernatremia with dire neurological consequences. Loss of concentrating mechanism can be the consequence of defective secretion of vasopressin from the posterior pituitary gland (congenital or acquired central diabetes insipidus) or poor response of the target organ to vasopressin (congenital or nephrogenic diabetes insipidus). The differentiation between the three major states producing polyuria with low urine osmolality (central diabetes insipidus, nephrogenic diabetes insipidus and primary polydipsia) is done by a standardized water deprivation test. Proper diagnosis is essential for the management, which differs between these three conditions.

The renal concentrating mechanism and the clinical consequences of its loss

The integrity of the renal concentrating mechanism is maintained by the anatomical and functional arrangements of the renal transport mechanisms for solute (sodium; potassium; urea; etc) and water and by the function of the regulatory hormone for renal concentration; vasopressin. The discovery of aquaporins (water channels) in the cell membranes of the renal tubular epithelial cells has elucidated the mechanisms of renal actions of vasopressin. Loss of the concentrating mechanism results in uncontrolled polyuria with low urine osmolality and; if the patient is unable to consume (appropriately) large volumes of water; hypernatremia with dire neurological consequences. Loss of concentrating mechanism can be the consequence of defective secretion of vasopressin from the posterior pituitary gland (congenital or acquired central diabetes insipidus) or poor response of the target organ to vasopressin (congenital or nephrogenic diabetes insipidus). The differentiation between the three major states producing polyuria with low urine osmolality (central diabetes insipidus; nephrogenic diabetes insipidus and primary polydipsia) is done by a standardized water deprivation test. Proper diagnosis is essential for the management; which differs between these three conditions

Abnormalities of serum potassium concentration in dialysis-associated hyperglycemia and their correction with insulin: review of published reports.

The main difference between dialysis-associated hyperglycemia (DH) and diabetic ketoacidosis (DKA) or nonketotic hyperglycemia (NKH) occurring in patients with preserved renal function is the absence of osmotic diuresis in DH, which eliminates the need for large fluid and solute (including potassium) replacement. We analyzed published reports of serum potassium (K(+)) abnormalities and their treatment in DH. Hyperkalemia was often present at presentation of DH with higher frequency and severity than in hyperglycemic syndromes in patients with preserved renal function. The frequency and severity of hyperkalemia were higher in DH episodes with DKA than those with NKH in both hemodialysis and peritoneal dialysis. For DKA, the frequency and severity of hyperkalemia were similar in hemodialysis and peritoneal dialysis. For NKH, hyperkalemia was more severe and frequent in hemodialysis than in peritoneal dialysis. Insulin infusion corrected the hyperkalemia of DH in most cases. Additional measures for the management of hyperkalemia or modest potassium infusions for hypokalemia were needed in a few DH episodes. The predictors of the decrease in serum K(+) during treatment of DH with insulin included the starting serum K(+) level, the decreases in serum values of glucose concentration and tonicity, and the increase in serum total carbon dioxide level. DH represents a risk factor for hyperkalemia. Insulin infusion is the only treatment for hyperkalemia usually required.

Age, race, diabetes, blood pressure, and mortality among hemodialysis patients.

Observational studies involving hemodialysis patients suggest a U-shaped relationship between BP and mortality, but the majority of these studies followed large, heterogeneous cohorts. To examine whether age, race, and diabetes status affect the association between systolic BP (SBP; predialysis) and mortality, we studied a cohort of 16,283 incident hemodialysis patients. We constructed a series of multivariate proportional hazards models, adding age and BP to the analyses as cubic polynomial splines to model potential nonlinear relationships with mortality. Overall, low SBP associated with increased mortality, and the association was more pronounced among older patients and those with diabetes. Higher SBP associated with increased mortality among younger patients, regardless of race or diabetes status. We observed a survival advantage for black patients primarily among older patients. Diabetes associated with increased mortality mainly among older patients with low BP. In conclusion, the design of randomized clinical trials to identify optimal BP targets for patients with ESRD should take age and diabetes status into consideration.

Abnormalities of serum potassium concentration in dialysis-associated hyperglycemia and their correction with insulin: a unique clinical/physiologic exercise in internal potassium balance.

The absence of significant losses of potassium in the urine makes dialysis-associated hyperglycemia (DH) a model for the study of the internal potassium balance. Studies of DH have revealed that hyperkalemia is frequent at presentation, insulin infusion is usually the only treatment required, and the magnitude of the decrease in serum potassium concentration (K(+)) during treatment of DH with insulin depends on the starting serum K(+) level, the decreases in serum glucose concentration and tonicity, and the increase in serum total carbon dioxide level. We present an analysis of these findings based on previously studied actions of insulin. Calculations of transcellular potassium shifts based on the combined effects of insulin-the increase in the electrical potential differences (hyperpolarization) of the cell membranes and the correction of the hyperglycemic intracellular dehydration through decrease in serum glucose concentration-produced quantitative predictions of the decrease in serum K(+) similar to the reported changes in serum K(+) during treatment of DH with insulin. The lessons from analyzing serum K(+) changes during treatment of DH with insulin are applicable to other conditions where internal potassium balance is called upon to protect serum K(+), such as the postprandial state. The main questions related to internal potassium balance in DH that await clarification include the structure and function of cell membrane potassium channels, the effect of insulin on these channels, and the mechanisms of feedforward potassium regulation.

Left ventricular diastolic function in patients on hemodialysis.

BACKGROUND: Previous studies have shown that the assessment of Doppler mitral flow velocity (DMFV) curves can be used to predict prognosis owing to left ventricular (LV) diastolic dysfunction in certain specific diseases. Our aim was to study whether the prognostic value of DMFV curves is affected by the many end-stage renal disease factors, such as chronic uremia and long-term hemodialysis (HD), which cause LV diastolic dysfunction and death. METHODS: Retrospective echo Doppler studies obtained 10 to 12 hours after HD in 90 patients (52 males; mean age, 56 years) were analyzed to determine changes in deceleration time (DT) of the early mitral filling wave (E) and the ratio of E to the atrial velocity (A). The study findings (n = 83) showed 2 groups of DT: long DT (DT > 240 milliseconds) and normal/short DT (DT

Anemia management and association of race with mortality and hospitalization in a large not-for-profit dialysis organization.

BACKGROUND: The optimal hemoglobin target and possible toxicity of epoetin therapy in hemodialysis patients are controversial. Previous studies suggest that African American patients use higher doses of epoetin and have better survival compared with white hemodialysis patients. STUDY DESIGN: Retrospective longitudinal cohort. SETTING & PARTICIPANTS: Epoetin-exposed incident hemodialysis patients (N = 12,733; African Americans, n = 4,801; white, n = 7,386) treated in Dialysis Clinic Inc facilities during 2000 to 2006. PREDICTORS: Hemoglobin, epoetin, iron. OUTCOMES: Mortality, hospitalization. MEASUREMENTS: Proportional hazards models with time-varying covariates. RESULTS: Hemoglobin concentrations less than 10 g/dL in whites and less than 11 g/dL in African Americans were associated with increased mortality and hospitalization versus the referent hemoglobin level of 11 to 11.9 g/dL. Hemoglobin levels of 13 g/dL or greater in whites were associated with decreased noncardiovascular mortality. Six-month cumulative epoetin doses of 20,000 U/wk or greater were associated with increased mortality and hospitalization versus the referent group (8,000 to 12,499 U/wk). Epoetin doses less than 8,000 U/wk were associated with decreased risk. Higher epoetin doses were associated with increased mortality at hemoglobin concentrations of 10 to 12.9 g/dL and with increased hospitalization at all hemoglobin concentrations of 10 g/dL or greater. Higher epoetin doses were associated with increased mortality and hospitalization within each tertile of serum albumin concentration. These patterns did not differ by race. LIMITATIONS: Treatment-by-indication bias and unidentified confounders cannot be excluded. Small sample sizes in the highest and lowest hemoglobin strata decrease statistical power. CONCLUSIONS: Relationships between hemoglobin concentration and mortality differed between African Americans and whites. Additionally, the relationship of lower mortality with greater achieved hemoglobin concentration seen in white patients was observed for all-cause, but not cardiovascular, mortality. A higher cumulative epoetin dose was associated with worse outcomes, even in patients with albumin levels greater than 4 g/dL. There were no statistically significant interactions between race and epoetin dose. Further studies are needed to confirm and to define the mechanism of these findings.

Extreme hyperglycemia with ketoacidosis and hyperkalemia in a patient on chronic hemodialysis.

A patient on hemodialysis for end-stage renal disease secondary to diabetic nephropathy was admitted in a coma with Kussmaul breathing and hypertension (232/124 mmHg). She had extreme hyperglycemia (1884 mg/dL), acidosis (total CO(2) 4 mmol/L), hyperkalemia (7.2 mmol/L) with electrocardiographic abnormalities, and hypertonicity (330.7 mOsm/kg). Initial treatment with insulin drip resulted in a decrease in serum potassium to 5.3 mmol/L, but no significant change in mental status or other laboratory parameters. Hemodialysis of 1.75 hours resulted in rapid decline in serum glucose and tonicity and rapid improvement of the acidosis, but no change in mental status, which began to improve slowly after the hemodialysis was stopped, but with ongoing treatment with continuous insulin infusion. The rate of decline in tonicity during hemodialysis (14.5 mOsm/kg/h) was high, raising concerns about neurological complications. In this case, extreme hyperglycemia with ketoacidosis, hyperkalemia, and coma developing in a hemodialysis patient responded to insulin infusion. Monitoring of the clinical status and the pertinent laboratory values is required to assess the need for other therapeutic measures including volume and potassium replacement and emergency dialysis. The indications for and risks of emergency dialysis in this setting are not clearly defined.