ENaC activity in the cortical collecting duct of HKα1 H+,K+-ATPase knockout mice is uncoupled from Na+ intake.

Modulation of the epithelial Na+ channel (ENaC) activity in the collecting duct (CD) is an important mechanism for normal Na+ homeostasis. ENaC activity is inversely related to dietary Na+ intake, in part due to inhibitory paracrine purinergic regulation. Evidence suggests that H+,K+-ATPase activity in the CD also influences Na+ excretion. We hypothesized that renal H+,K+-ATPases affect Na+ reabsorption by the CD by modulating ENaC activity. ENaC activity in HKα1 H+,K+-ATPase knockout (HKα1-/-) mice was uncoupled from Na+ intake. ENaC activity on a high-Na+ diet was greater in the HKα1-/- mice than in WT mice. Moreover, dietary Na+ content did not modulate ENaC activity in the HKα1-/- mice as it did in WT mice. Purinergic regulation of ENaC was abnormal in HKα1-/- mice. In contrast to WT mice, where urinary [ATP] was proportional to dietary Na+ intake, urinary [ATP] did not increase in response to a high-Na+ diet in the HKα1-/- mice and was significantly lower than in the WT mice. HKα1-/- mice fed a high-Na+ diet had greater Na+ retention than WT mice and had an impaired dipsogenic response. These results suggest an important role for the HKα1 subunit in the regulation of purinergic signaling in the CD. They are also consistent with HKα1-containing H+,K+-ATPases as important components for the proper regulation of Na+ balance and the dipsogenic response to a high-salt diet. Such observations suggest a previously unrecognized element in Na+ regulation in the CD.

Dysnatremias in patients with kidney disease.

Dysnatremias are among the most common electrolyte disorders in clinical medicine. Recent studies have shown that individuals with chronic kidney disease also are afflicted by these electrolyte disorders. Furthermore, their presence imparts an increased risk of mortality. In this review, we discuss studies in experimental animals and in humans that have attempted to establish the mechanisms responsible for limiting urinary dilution and urinary concentration in progressive kidney disease. The clinical implications of these disorders in water excretion are discussed in the setting of optimal water intake as kidney disease progresses. This review emphasizes the management of patients with chronic kidney disease who have marked abnormalities in serum sodium concentrations and gives specific recommendations for modifications in renal replacement therapy prescription in hyponatremic patients with end-stage renal disease.

Hypervolemic hypernatremia in patients recovering from acute kidney injury in the intensive care unit.

BACKGROUND: A high incidence of hypernatremia is often observed in patients recovering from acute kidney injury (AKI) in intensive care units. METHODS: An unselected cohort of 20 adult patients recovering from AKI in the intensive care unit of a single institution during a 1-year period, were investigated. Serum and urine electrolytes, osmolality, urea nitrogen and creatinine were measured in an attempt to determine the cause of the hypernatremia. RESULTS: Eighty-eight percent of patients who could not drink fluids were found to have hypernatremia (serum Na >145 mEq/L). Even though the hypernatremia was mild in most patients (146-160 mEq/L), the average rise in serum sodium concentration was 17.4 mEq/L. The average urine osmolality was 384 mmol/kg of which 47.6 and 32.8 mmol/kg were contributed by sodium and potassium, respectively. The patients had hypervolemia as evidenced by the presence of edema and an average weight gain of 21.5 kg at the onset of the hypernatremia. The rise in serum sodium level coincided with an increase in urine output. CONCLUSION: The hypernatremia is believed to be due to post-AKI diuresis in the face of inability to maximally concentrate the urine because of renal failure. The diuresis caused a disproportionate loss of water in excess of that of sodium in the absence of replenishment of the water loss. Additionally, the patients were hypervolemic due to the retention of large quantities of sodium and water as a result of infusion of substantial volumes of physiological saline prior to the development of hypernatremia.

Electrolyte-free water clearance versus modified electrolyte-free water clearance: do the results justify the effort?

BACKGROUND: Calculation of electrolyte-free water clearance (EFWC) allows for quantification of renal losses of free water and was shown to be helpful in the differential diagnosis of dysnatremias and might help in the correction of the electrolyte disorders. A modified EFWC formula (MEFWC) was described to be more accurate than the conventional one; however, it has never been evaluated clinically. METHODS: In order to evaluate the performance of MEFWC compared to EFWC under clinical circumstances, we gathered data from a total of 912 patient days of 138 critically ill patients. EFWC and MEFWC were calculated on the basis of these data. Additionally, from data of critically ill patients, we calculated a prediction of serum sodium based on the Edelman equation using either EFWC or MEFWC and compared results. RESULTS: Altogether, 343 normonatremic, 124 hyponatremic and 445 hypernatremic days were analyzed. Results for EFWC and MEFWC correlated significantly (R = 0.98). In patients with hyponatremia, the absolute difference between EFWC and MEFWC was significantly larger than in patients with normonatremia (437 vs. 256 ml, p < 0.01). The absolute difference between EFWC and MEFWC correlated significantly with the level of serum sodium (R = -0.41). The mean difference in the prediction of serum sodium change as calculated based on the Edelman equation between the formula using EFWC and the formula using MEFWC was 0.7 mmol/l (SD 0.68) and was highest in hyponatremia and lowest in hypernatremia. CONCLUSION: Results of EFWC and MEFWC were comparable in critically ill patients. Under normal circumstances, the use of the more complicated MEFWC is not justified. In hyponatremia, the difference between EFWC and MEFWC is larger and thus might justify the use of the more complicated formula.

Approach to and management of abnormalities in plasma sodium.

The differential diagnosis between hypertonic, isotonic and hypotonic hyponatremia are presented. The help of some usual serum (urea, uric acid and TCO2) and urine parameters (mainly osmolality and sodium concentration) are discussed and help to determine the best treatment. Morbidity associated with untreated hyponatremia and with the different treatment available is also discussed. Who to prevent and treat ODS (osmotic demyelating syndrome) is recalled. The pathophysiology and treatment of hypernatremia are also discussed.

Addition of indapamide to frusemide increases natriuresis and creatinine clearance, but not diuresis, in fluid overloaded ICU patients.

BACKGROUND: Fluid and sodium overload are a common problem in critically ill patients. Frusemide may result in diuresis in excess of natriuresis. The addition of indapamide may achieve a greater natriuresis, and also circumvent some of the problems associated with frusemide. The objective of this study was to examine the effect of adding indapamide to frusemide on diuresis, natriuresis, creatinine clearance and serum electrolytes. METHODS: Fluid overloaded ICU patients were randomised to either intravenous frusemide (Group F) or intravenous frusemide and enteral indapamide (Group F + I). Comprehensive exclusion criteria were applied to address confounders. 24 hour urine was analysed for electrolytes and creatinine. Serum electrolytes were measured before and 24 hours after administration of diuretics. RESULTS: Forty patients (20 in each group) were included in the study. The groups were similar in their baseline characteristics. Over the 24 h study period, patients in Group F + I, had a larger natriuresis (P = 0.01), chloride loss (P = 0.01) and kaliuresis (P = 0.047). Patients in Group F + I also had a greater 24 hour urinary creatinine clearance (P = 0.01). The 24 hour urine volume and fluid balance was similar between the groups. Patients in Group F had an increase in serum sodium (P = 0.04), while patients in Group F + I had a decrease in both serum chloride (P = 0.01) and peripheral oedema (P < 0.001) during the study duration. CONCLUSION: In fluid overloaded ICU patients, addition of indapamide to frusemide led to a greater natriuresis and creatinine clearance. Such a strategy might be utilised in optimising sodium balance in ICU patients.

Hypernatremia with edema.

Hypernatremia is usually associated with water depletion. Seven very ill patients developed hypernatremia in association with marked edema during therapy in the hospital. All patients had hypoalbuminemia and azotemia. At the time of hypernatremia, urine output averaged 1880 mL/24 h and urine sodium concentration averaged 59 mmol/L, suggesting that low levels of antidiuretic hormone and/or a diminished effect of this hormone on the nephron may contribute to the pathophysiological mechanism of the hypernatremia. Recognition of this salt- and water-overloaded state should guide therapy.

[Hypernatraemia, increased protein intake and progression of renal insufficiency in a patient with polycystic renal degeneration]. / Hypernatrémie, zvýsený príjem proteinu a progrese renální insuficience u nemocného s polycystickou degenerací ledvin.

The authors submit the case of a patient with polycystic degeneration of the kidneys where after haemorrhage from the anterior cerebral artery hypernatraemia developed and concurrently significant acceleration in the progression of renal insufficiency to failure developed. Hypernatraemia was caused by non-natrium osmotic diuresis conditioned by increased urea excretion. In chronological association with increased dietary protein intake renal insufficiency was hastened.

Electrolyte-free water clearance: a key to the diagnosis of hypernatremia in resolving acute renal failure.

Hypernatremia usually results from the loss of water from the body in excess of loss of electrolytes. Although urinary loss of free water is usually thought of when the urine is dilute, it can also occur when the urine is relatively concentrated, for example after administration of osmotic diuretics. We present a case of hypernatremia in the setting of resolving acute renal failure. Quantitative analysis of urinary losses and the concept of electrolyte-free water clearance help to explain the development and persistence of hypernatremia in this case. Urine in such cases is typically rich in urea (an irrelevant osmole from the perspective of plasma sodium) with low concentrations of sodium and potassium (osmoles that determine plasma sodium concentration). So from the perspective of plasma sodium-determining osmoles (sodium and potassium) this hyperosmolar urine is actually "dilute", resulting in loss of free water and a rise in the plasma sodium concentration. This case illustrates the utility of the electrolyte-free water concept in understanding the development of hypernatremia in resolving acute renal failure. We discuss the evolution of these concepts and how they can be applied to typical clinical situations.

Increased insensible water loss in newborn infants nursed under radiant heaters.

Urine osmolality was studied in 38 babies nursed in conventional incubators or cots and 18 nursed under an overhead radiant heat shield. Among 50 babies receiving a similar fluid intake in the first 48 hours of life mean urinary osmolality was significantly higher in the radiant heater group. In babies weighing less than 1500 g a trend towards higher urinary osmolalities was recorded in those nursed under radiant heaters even though they had received amost double the fluid intake of the incubator group. Severe hypernatraemia occurred in four of the five babies weighing less than 1000 g who were nursed under radiant heaters but in none of the seven babies of similar birth weight nursed in incubators. These findings are consistent with previous observations of an increase in insensible water loss in babies nursed under radiant heaters and emphasise the importance of providing enough extra water for these infants and the need for close monitoring of their fluid balance. The latter may be done at the bedside by measuring urinary specific gravity with a hand refractometer.

Enhanced end-organ responsiveness of the uremic kidney to the natriuretic factor.

In chronic renal disease, the addition of a fixed quantity of Na to the extracellular fluid (ECF) will evoke a natriuretic response per nephron which is inversely proportional to the glomerular filtration rate (GFR). One factor that could contribute to this "magnification" phenomenon is an increased sensitivity of residual nephrons to physiologic natriuretic forces. The present studies were designed to examine this possibility. Natriuretic urine fractions from uremic patients, infused into one renal artery of normal rats, produced a small but significant unilateral natriuresis. Infusion of the same fractions in identical amount into remnant kidneys of stage II nonuremic rats (i.e., rats with a contralateral normal kidney in situ) produced a natriuresis in the remnant kidney only which was equivalent to that observed in the normal kidneys. The i.v. infusion of natriuretic fractions into stage II rats produced comparable increments in the fractional excretion of sodium (FENa) bilaterally. However, when the natriuretic fractions were infused into remnant kidneys of stage III rats (no contralateral kidney), deltaFENa was significantly greater than in the foregoing groups. Because stage III rats have increased control values for FENa, baseline FENa was increased to an equivalent level in normal rats by unilateral renal denervation. Natriuretic factor was administered into the ipsilateral renal artery. Although the natriuretic response was increased, it was significantly less than in the stage III remnant kidneys. The data support the view that the uremic state per se is associated with an enhanced responsiveness of the residual nephrons to the natriuretic factor found in the urine (and blood) of uremic patients.

Recurrent hypernatremia; a proposed mechanism in a patient with absence of thirst and abnormal excretion of water.

A 7-year-old girl twice developed severe hypernatremia (serum sodium values up to 194 mEq/l) without obvious cause. The ability of her kidneys to conserve water was normal, and increasing her plasma osmolality stimulated an appropriate ADH response. Unable to excrete a water load, her kidneys continued to conserve water even with a serum sodium concentration of 133 mEq/l. She was never thirsty and did not ingest sufficient fluid by choice. Although there was no demonstrable anatomic lesion, we postulate a localized defect of her thirst center. This may have modified release of ADH and resulted in an inability to dilute the urine by interrupting a pathway that could exist from the thirst center to the supraoptic nuclei. A therapeutic regimen based on these studies has prevented further hypernatremia.

Influence of hypernatraemia and urea excretion on the ability to excrete a maximally hypertonic urine in the rat.

Rats normally excrete 20-25 mmol of sodium (Na+) + potassium (K+) per kilogram per day. To minimize the need for a large water intake, they must excrete urine with a very high electrolyte concentration (tonicity). Our objective was to evaluate two potential factors that could influence the maximum urine tonicity, hypernatraemia and the rate of urea excretion. Balance studies were carried out in vasopressin-treated rats fed a low-electrolyte diet. In the first series, the drinking solution contained an equivalent sodium chloride (NaCl) load at 150 or 600 mmol l(-1). In the second series, the maximum urine tonicity was evaluated in rats consuming 600 mmol l(-1) NaCl with an 8-fold range of urea excretion. Hypernatraemia (148 +/- 1 mmol l(-1)) developed in all rats that drank 600 mmol l(-1) saline. Although the rate of Na+ + K+ excretion was similar in both saline groups, the maximum urine total cation concentration was significantly higher in the hypernatraemic group (731 +/- 31 vs. 412 +/- 37 mmol l(-1)). Only when the rate of excretion of urea was very low, was there a further increase in the maximum urine total cation concentration (1099 +/- 118 mmol l(-1)). Thus hypernatraemia was the most important factor associated with a higher urine tonicity.

Myelodysplastic syndrome with central diabetes insipidus manifesting hypodipsic hypernatremia and dehydration.

Central diabetes insipidus (DI) is a rare but recognized complication of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) that is caused by leukemic infiltration to the hypothalamo-neurohypophyseal system. In rare patients in whom a wide region of the hypothalamus is involved, central DI results in hypodipsic hypernatremia and dehydration. Typical DI symptoms such as polydipsia, polyuria, and marked thirst are concealed in these cases, because the hypothalamic "thirst center" cannot send thirst stimuli to the cerebral cortex. Herein we describe a patient with MDS developing into AML, who presented with hypodipsic hypernatremia and dehydration. A diagnosis of central DI was made on the ground of a low level of serum anti-diuretic hormone (ADH) despite high serum osmolality. A magnetic resonance imaging study revealed attenuation of a physiological "bright spot" of the neurohypophysis. An induction course chemotherapy including regular-dose cytarabine and daunorubicin produced a rapid improvement of hypernatremia. The bone marrow aspirate after two courses of chemotherapy showed complete remission. At that point, ADH release and the "bright spot" were recovered. In order to correctly diagnose central DI in association with hematological malignancies, we should not overlook this atypical type of DI.