Fluid-induced harm in the hospital: look beyond volume and start considering sodium. From physiology towards recommendations for daily practice in hospitalized adults

Purpose Iatrogenic fluid overload is a potential side effect of intravenous fluid therapy in the hospital. Little attention has been paid to sodium administration as a separate cause of harm. With this narrative review, we aim to substantiate the hypothesis that a considerable amount of fluid-induced harm is caused not only by fluid volume, but also by the sodium that is administered to hospitalized patients. Methods We show how a regular dietary sodium intake is easily surpassed by the substantial amounts of sodium that are administered during typical hospital stays. The most significant sodium burdens are caused by isotonic maintenance fluid therapy and by fluid creep, defined as the large volume unintentionally administered to patients in the form of dissolved medication. In a section on physiology, we elaborate on the limited renal handling of an acute sodium load. We demonstrate how the subsequent retention of water is an energy-demanding, catabolic process and how free water is needed to excrete large burdens of sodium. We quantify the effect size of sodium-induced fluid retention and discuss its potential clinical impact. Finally, we propose preventive measures, discuss the benefits and risks of low-sodium maintenance fluid therapy, and explore options for reducing the amount of sodium caused by fluid creep. Conclusion The sodium burdens caused by isotonic maintenance fluids and fluid creep are responsible for an additional and avoidable derailment of fluid balance, with presumed clinical consequences. Moreover, the handling of sodium overload is characterized by increased catabolism. Easy and effective measures for reducing sodium load and fluid retention include choosing a hypotonic rather than isotonic maintenance fluid strategy (or avoiding these fluids when enough free water is provided through other sources) and dissolving as many medications as possible in glucose 5%.

Cisplatin Decreases ENaC Activity Contributing to Renal Salt Wasting Syndrome

Cisplatin (CDDP) is an important anticancer drug. A common side effect of CDDP is renal salt and water-wasting syndrome (RSWS). The origin of RSWS is obscure. Emerging evidence, though, suggests that broad inhibition of sodium transport proteins by CDDP may result in decreases in tubular reabsorption, causing increases in sodium and water excretion. In this sense, CDDP would be acting like a diuretic. The effect of CDDP on the epithelial Na+ channel (ENaC), which is the final arbiter fine-tuning renal Na+ excretion, is unknown. We test here whether CDDP affects ENaC to promote renal salt and water excretion. The effects of CDDP and benzamil (BZM), a blocker of ENaC, on excretion of a sodium load were quantified. Similar to BZM, CDDP facilitated renal Na+ excretion. To directly quantify the effects on ENaC, principal cells in split-open tubules were patch clamped. CDDP, at doses comparable to those used for chemotherapy (1.5 µM), significantly decreased ENaC activity in native tubules. To further elaborate on this mechanism, the dose-dependent effects of CDDP on mouse ENaC (mENaC) heterologously expressed in Chinese Hamster Ovary (CHO) cells were tested using patch clamping. As in native tubules, CDDP significantly decreased the activity of mENaC expressed in CHO cells. Dose–response curves and competition with amiloride identified CDDP as a weak inhibitor of ENaC (apparent IC50 = 1 µM) that competes with amiloride for inhibition of the channel, weakening the inhibitory actions of the latter. Such observations are consistent with CDDP being a partial modulator of ENaC, which possibly has a binding site that overlaps with that of amiloride. These findings are consistent with inhibition of ENaC by CDDP contributing to the RSWS caused by this important chemotherapy drug.

Effects of a didpeptidyl peptidase-4 inhibitor on urinary sodium and water excretion in rats with water-salt disbalance

Желудочно-кишечный тракт секретирует широкий спектр пептидов, регулирующих метаболические процессы и влияющих на функции почек и водно-солевой баланс. Эффекты данных биологически активных веществ можно усилить увеличением их периода полужизни путем угнетения фермента дипептидилпептидазы-4. Цель исследования - изучение экскреции ионов натрия и воды при угнетении дипептидилпептидазы-4 вилдаглиптином у крыс с различным состоянием водно-солевого баланса. Методика. Состояния гипернатриемии, гиперосмии или гипоосмии моделировали пероральным введением гипертонического и изотонического растворов NaCl и воды. Результаты. Вилдаглиптин вызвал дозозависимое снижение активности фермента дипептидилпептидазы-4 с максимумом эффекта при дозе 1 мг на 100 г массы тела. Его введение перед гипертонической натриевой нагрузкой увеличивало экскрецию натрия на 56%, усилило реабсорбцию осмотически свободной и свободной от натрия воды. Введение ингибитора дипептидилпептидазы-4 перед изотонической натриевой нагрузкой усиливало экскрецию натрия в той же степени, но не влияло на реабсорбцию воды. Инъекция вилдаглиптина, предваряющая водную нагрузку, вызвала антидиуретическую реакцию почек. Заключение. Блокада дипептидилпептидазы-4 вилдаглиптином способствует выведению из организма избыточного количества натрия и изменению реабсорбции воды в зависимости от концентрации ионов натрия в сыворотке крови, вероятно, за счет увеличения периода циркуляции кишечных регуляторных пептидов, секретирующихся в ответ на пероральные нагрузочные пробы NaCl. Данные процессы ускоряют восстановление водно-солевого гомеостаза в условиях поступления избытка натрия через желудочно-кишечный тракт. The gastrointestinal tract secretes multiple peptides that regulate metabolic processes and influence the kidney function and water-salt balance. The effects of these biologically active substances can be intensified by increasing their half-life through inhibition of the dipeptidyl peptidase-4 (DPP-4) enzyme. The aim of the study was investigation of sodium and water excretion after inhibition of DPP-4 with vildagliptin in rats with different states of the water-salt balance. Methods. The hypernatremic, hyperosmotic and hypoosmotic states were modeled by oral administration of hypertonic and isotonic NaCl solutions or water. Results. Vildagliptin induced a dose-dependent decrease in the DPP-4 activity with a maximum effect of 1 mg per 100 g of body weight. Vildagliptin administration prior to the hypertonic sodium load increased sodium excretion by 56% and stimulated reabsorption of solute-free and sodium-free water. Administration of the DPP-4 inhibitor before the isotonic sodium load increased sodium excretion to the same degree without affecting the water reabsorption. A vildagliptin injection prior to the water load resulted in an antidiuretic response of the kidneys. Conclusion. The inhibition of DPP-4 activity with vildagliptin promoted removal of excessive sodium from the body and changed the water reabsorption depending on the sodium concentration in the blood serum, presumably by prolonging circulation of the intestinal regulatory peptides secreted in response to oral NaCl load tests. These processes accelerate restoration of the water-salt homeostasis in the conditions of excessive sodium delivery through the gastrointestinal tract.

Sodium Prescription in the Prevention of Intradialytic Hypotension: New Insights into an Old Concept

Background: Sodium prescription in patients with intradialytic hypotension remains a challenge for the attending nephrologist, as it increases dialysate conductivity in hypotension-prone patients, thereby adding to dietary sodium levels. Methods: New sodium prescription strategies are now available, including the use of a mathematical model to compute the sodium mass to be removed during dialysis as a physiological controller. Results: This review describes the sodium load of patients with end-stage renal disease on chronic hemodialysis (HD) and discusses 2 strategies to remove excess sodium in patients prone to intradialytic hypotension, namely, Profiled HD and the hemodiafiltration Aequilibrium System. Conclusion: The Profiled HD and Aequilibrium System trial both proved effective in counteracting intradialytic hypotension.

Abstract P324: Reduction in Excreted Sodium Load in Obese Sheep: Role of Antenatal Betamethasone and Sex

Our previous studies have demonstrated the programmed impairment of sodium excretion in lean antenatal betamethasone exposed sheep whereby the males exhibited blunted excretion of a sodium load when compared to control males or control or antenatal betamethasone exposed females. Obesity has been recognized as a risk factor for developing early stage kidney failure in individuals exposed to unfavorable intrauterine conditions by virtue of fetal programming. We hypothesize that obesity (second hit) can accentuate the impairment of sodium excretion in antenatal betamethasone exposed offspring in a sex specific manner. Pregnant ewes received either betamethasone or vehicle at 80-81 days gestation. The male (n=6 per group) or female (n=5 per group) offspring were overfed to become obese (40% weight gain over a course of 3 months) at age of 1.5 years. Acute sodium load (sodium chloride: 0.13g/kg) was administrated intravenously. Sodium excretion (excreted sodium load), blood pressure (BP), renal plasma flow (RPF), and glomerular filtration rate (GFR) were measured. Data for sodium excretion are expressed as percentage of excreted sodium load. ANOVA and Student’s t test were used for data analysis. The excreted sodium load was lower in obese male antenatal betamethasone exposed offspring (OMB) than in obese male vehicle exposed offspring (OMV) (13.5±3.1% vs. 33.2±9.9% p=0.04). However, the excreted sodium load was not significantly different between obese female antenatal betamethasone exposed offspring (OFB) and obese female vehicle exposed offspring (OFV) (60.4±6.2% vs. 72.0±8.2%, p=0.31). Compared male offspring with female offspring, the excreted sodium load was lower in male offspring (33.2±9.9% vs. 72.0±8.2%, p=0.001, OMV vs. OFV; 13.5±3.2% vs. 60.4±6.2%, p<0.0001, OMB vs. OFB). During the experiments BP, RPF and GFR did not change significantly. . These data suggest that obesity, acting as a second hit, accentuates impairment of sodium excretion in antenatal betamethasone exposed male but not female offspring. Thus the sex specific effect of antenatal betamethasone on sodium excretion persists in in animals experiencing a secondary insult of obesity in adulthood.

Aging-related impairment of urine-concentrating mechanisms correlates with dysregulation of adrenocortical angiotensin type 1 receptors in male Fischer rats

To investigate age-associated impairments in fluid homeostasis, 4-mo (young) and 32-mo (old) Fischer 344/BN male rats were studied before and after a dietary sodium load. Transferring young rats from a low-sodium (LS) to a high-sodium (HS) diet increased water intake and urine volume by 1.9- and 3.0-fold, respectively, while urine osmolality and plasma aldosterone decreased by 33 and 98%. Concomitantly, adrenocortical angiotensin type 1 receptor (AT1R) density decreased by 35%, and AT1bR mRNA decreased by 39%; no changes were observed in AT1aR mRNA. In contrast, the increase in water intake (1.4-fold) was lower in the old rats, and there was no effect of the HS diet on urine volume or urine osmolality. AT1R densities were 29% less in the old rats before transferring to the HS diet, and AT1R densities were not reduced as rapidly in response to a HS diet compared with the young animals. After 6 days on the HS diet, plasma potassium was lowered by 26% in the old rats, whereas no change was detected in the young rats. Furthermore, while plasma aldosterone was substantially decreased after 2 days on the HS diet in both young and old rats, plasma aldosterone was significantly lower in the old compared with the young animals after 2 wk on the LS diet. These findings suggest that aging attenuates the responsiveness of the adrenocortical AT1R to a sodium load through impaired regulation of AT1bR mRNA, and that this dysregulation contributes to the defects in water and electrolyte homeostasis observed in aging.