Reduction Of Extracellular Fluid Volume Research Articles

Design and Baseline Characteristics of the Chlorthalidone in Chronic Kidney Disease (CLICK) Trial

Background: Hypertension often accompanies chronic kidney disease (CKD), and diuretics are widely prescribed to reduce blood pressure (BP). Chlorthalidone (CTD) is a thiazide-like diuretic and an effective antihypertensive drug, yet little data exist to support its use in treating hypertension in individuals with advanced CKD. Methods: Chlorthalidone in Chronic Kidney Disease (CLICK) is a phase II, single-institution, multicenter, double-blind randomized control trial to test the hypothesis that CTD improves BP, through reduction of extracellular fluid volume, and results in target organ protection in patients with stage 4 CKD and poorly controlled hypertension. After a single-blind placebo run-in for 2 weeks and confirmation of hypertension by 24-h ambulatory blood pressure (ABP), patients are randomized to either placebo or CTD 12.5 mg once daily (QD) followed by dose escalation. Randomization is stratified by prior loop diuretic use, and the double-blind phase lasts 12 weeks. With a total of 160 patients, the study will have ≥80% power to detect a 6 mm Hg difference in systolic 24-h ABP between the 2 treatment groups. Results: Between June 2016 and October 2019, 131 patients have been randomized. The baseline characteristics are as follows: average age 65.8 years, 79% men, 36% Black, 79% with diabetes, mean eGFR 23.2 mL/min/1.73 m², median urine albumin/creatinine ratio 923 mg/g, average number of BP medications 3.4, 60% on loop diuretics, and 24-h ABP averaged 141.7/73.8 mm Hg. Conclusion: Among patients with stage 4 CKD and uncontrolled hypertension, CLICK should answer the question whether CTD is safe and effective.

Effect of tolvaptan on renal handling of water and sodium, GFR and central hemodynamics in autosomal dominant polycystic kidney disease during inhibition of the nitric oxide system: a randomized, placebo-controlled, double blind, crossover study

BackgroundTolvaptan slows progression of autosomal dominant polycystic kidney disease (ADPKD) by antagonizing the vasopressin-cAMP axis. Nitric oxide (NO) stimulates natriuresis and diuresis, but its role is unknown during tolvaptan treatment in ADPKD.MethodsEighteen patients with ADPKD received tolvaptan 60 mg or placebo in a randomized, placebo-controlled, double blind, crossover study. L-NMMA (L-NG-monomethyl-arginine) was given as a bolus followed by continuous infusion during 60 min. We measured: GFR, urine output (UO), free water clearance (CH2O), fractional excretion of sodium (FENa), urinary excretion of aquaporin-2 channels (u-AQP2) and epithelial sodium channels (u-ENaCγ), plasma concentrations of vasopressin (p-AVP), renin (PRC), angiotensinII (p-AngII), aldosterone (p-Aldo), and central blood pressure (cBP).ResultsDuring tolvaptan with NO-inhibition, a more pronounced decrease was measured in UO, CH2O (61% vs 43%) and FENa (46% vs 41%) after placebo than after tolvaptan; GFR and u-AQP2 decreased to the same extent; p-AVP increased three fold, whereas u-ENaCγ, PRC, p-AngII, and p-Aldo remained unchanged. After NO-inhibition, GFR increased after placebo and remained unchanged after tolvaptan (5% vs −6%). Central diastolic BP (CDBP) increased to a higher level after placebo than tolvaptan. Body weight fell during tolvaptan treatment.ConclusionsDuring NO inhibition, tolvaptan antagonized both the antidiuretic and the antinatriuretic effect of L-NMMA, partly via an AVP-dependent mechanism. U-AQP2 was not changed by tolvaptan, presumeably due to a counteracting effect of elevated p-AVP. The reduced GFR during tolvaptan most likely is caused by the reduction in extracellular fluid volume and blood pressure.Trial registrationClinical Trial no: NCT02527863. Registered 18 February 2015.

Metabolic Complications Associated With Use of Diuretics

Diuretics are commonly used therapeutic agents that act to inhibit sodium transport systems along the length of the renal tubule. The most effective diuretics are inhibitors of sodium chloride transport in the thick ascending limb of Henle. Loop diuretics mobilize large amounts of sodium chloride and water and produce a copious diuresis with a sharp reduction of extracellular fluid volume. As the site of action of diuretics moves downstream (thiazide and potassium-sparing diuretics), their effectiveness declines because the transport systems they inhibit have low transport capacity. Depending on the site of action diuretics can influence the renal handling of electrolyte-free water, calcium, potassium, protons, sodium bicarbonate, and uric acid. As a result, electrolyte and acid-base disorders commonly accompany diuretic use. Glucose and lipid abnormalities also can occur, particularly with the use of thiazide diuretics. This review focuses on the biochemical complications associated with the use of diuretics. The development of these complications can be minimized with careful monitoring, dosage adjustment, and replacement of electrolyte losses.

Epidemiology of Interdialytic Ambulatory Hypertension and the Role of Volume Excess

Background: The epidemiology of hypertension among hemodialysis (HD) patients is difficult to describe accurately because of difficulties in the assessment of blood pressure (BP). Methods: Using 44-hour interdialytic ambulatory BP measurements, we describe the epidemiology of hypertension in a cohort of 369 patients. To seek correlates of hypertension control, antihypertensive agents were withdrawn among patients with controlled hypertension and ambulatory BP monitoring was repeated. Results: Hypertension (defined as an average ambulatory systolic BP ≧135 mm Hg or diastolic BP ≧85 mm Hg, or the use of antihypertensive medications) was prevalent in 82% of the patients and independently associated with epoetin use, lower body mass index and fewer years on dialysis. Although 89% of the patients were being treated, hypertension was controlled adequately in only 38%. Poor control was independently associated with greater antihypertensive drug use. Inferior vena cava (IVC) diameter in expiration was associated with increased risk of poorly controlled hypertension both in cross-sectional analysis and after withdrawal of antihypertensive drugs. Conclusions: Interdialytic hypertension is highly prevalent and difficult to control among HD patients. End-expiration IVC diameter is associated with poor control of hypertension in cross-sectional analyses as well as after washout of antihypertensive drugs. Among HD patients, an attractive target for improving hypertension control appears to be the reduction of extracellular fluid volume.

Vasopressin administration facilitates fluid removal during hemodialysis

Inadequate secretion of vasopressin during fluid removal by hemodialysis may contribute to the cardiovascular instability that complicates this therapy and administration of exogenous hormone, by supporting arterial pressure, may facilitate volume removal. To test this, we measured plasma vasopressin in patients with end-stage renal disease (ESRD) during hemodialysis and found that despite significant fluid removal, plasma vasopressin concentration did not increase. We further found that ESRD did not alter the endogenous removal rate of plasma vasopressin and that plasma hormone is not dialyzed. Finally, in a randomized, double-blinded, placebo-controlled trial in 22 hypertensive patients, we examined the effect of a constant infusion of a non-pressor dose of vasopressin on the arterial pressure response during a hemodialysis in which the target fluid loss was increased by 0.5 kg over the baseline prescription. We found that arterial pressure was more stable in the patients receiving vasopressin and that while only one patient (9%) in the vasopressin group had a symptomatic hypotensive episode, 64% of the patients receiving placebo had such an episode (P=0.024). Moreover, increased fluid removal was achieved only in the vasopressin group (520+/-90 ml vs 64+/-130 ml, P=0.01). Thus, administration of non-pressor doses of vasopressin to hypertensive subjects improves cardiovascular stability during hemodialysis and allows increased removal of excess extracellular fluid. Inadequate vasopressin secretion during hemodialysis-induced fluid removal is a likely contributor to the intradialytic hypotension that limits fluid removal.

An Observational Study On The Spectrum Of Heat-Related Illness, With A Proposal On Classification

During operations in subtropical areas over the summer months of 2001 and 2003 the authors audited 80 patients with heat-related illness, with the intention of defining the nature and distribution...

Can a reduction in extracellular fluid volume result in increased serum albumin in peritoneal dialysis patients?

Serum albumin predicts survival in end-stage renal failure. The literature has emphasized the dependence of albumin on inflammation. We previously proposed an independent relationship with overhydration. To date, there is no proven therapy that increases serum albumin in dialysis patients. We investigated whether decreasing dry weight increases serum albumin in peritoneal dialysis patients. Twenty-one subjects (15 continuous ambulatory peritoneal dialysis patients and 6 continuous cycled peritoneal dialysis patients) were assessed at 0 and 4 weeks. Body weight, blood pressure, 4-site skin-fold thickness, subjective global assessment score, and use of antihypertensive medication were recorded. Fluid samples were collected for estimation of serum albumin, C-reactive protein, and 24-hour dialysate and urine volume. The extracellular fluid volume was estimated by multiple-frequency bioelectric impedance. Between the 0- and 4-week assessments, dialysis prescription was altered to increase the daily ultrafiltrate volume (1.00 ± 0.71 L to 1.29 ± 0.75 L; P = 0.04). Significant decreases were seen in body weight (70.7 ± 12.1 kg to 69.9 ± 12.2 kg; P = 0.0002), extracellular fluid volume (16.2 ± 3.3 L to 15.5 ± 3.2 L; P = 0.0006), systolic blood pressure (147.7 ± 26.3 mm Hg to 124.2 ± 20.9 mm Hg; P < 0.0001), diastolic blood pressure (84.2 ± 14.5 mm Hg to 76.6 ± 11.7 mm Hg; P = 0.01), and number of antihypertensive drugs (1.9 ± 1.0 to 1.6 ± 1.1; P = 0.02). Serum albumin increased (34.6 ± 4.1 g/L to 35.9 ± 3.6 g/L; P = 0.01). C-reactive protein did not change. Decreasing dry weight in peritoneal dialysis by an increase in ultrafiltration volume results in a decreased extracellular fluid volume, which is reflected by an improvement in blood pressure control. This improvement in blood pressure was associated with an increase in serum albumin. This finding strengthens the argument that overhydration is a cause of hypoalbuminemia in peritoneal dialysis and offers a therapeutic option in management of this patient group. © 2002 by the National Kidney Foundation, Inc.

Randomised controlled trial of postnatal sodium supplementation on body composition in 25 to 30 week gestational age infants

AIMSTo compare the effects of early and delayed sodium supplementation on body composition and body water compartments during the first two weeks of postnatal life.METHODSPreterm infants of 25–30 weeks' gestation...

Renal and endocrine responses in humans to isotonic saline infusion during microgravity.

It was the purpose of this study to investigate how the endocrine and renal mechanisms of fluid volume control in humans (n = 4) adapt to microgravity by applying an intravenous isotonic saline infusion. The acute ground-based supine (Sup) and seated (Seat) positions were chosen as references. During microgravity, renal sodium excretion (UNaV) was doubled during the second and third hours after infusion compared with during Seat (P < 0.05) but blunted during the first hour after infusion compared with during Sup, leading to a reduction in cumulative UNaV (59 +/- 15 vs. 108 +/- 12 mmol/5 h; P < 0.05). Plasma norepinephrine (NE) attained the highest value 3 h after infusion during microgravity (31 +/- 5 x 10(-2) ng/ml vs. 19 +/- 1 and 13 +/- 3 x 10(-2) ng/ml for Seat and Sup, respectively; P < 0.05). Inflight levels of plasma renin and aldosterone were very similar to levels during Seat. In conclusion, 1) the microgravity-adapted renal responses to infusion reflected a condition in between that of ground-based Seat and Sup, respectively, and 2) the plasma levels of NE, renin, and aldosterone were elevated inflight and not related to the changes in UNaV and urinary flow rate. These observations are in contrast to results of ground-based simulation experiments and might partly have been caused by a prior inflight reduction in extracellular fluid volume. The high levels of NE during microgravity warrant further investigation.

Chapter 10: ANF-induced modulation of ADH-release in the rabbit and Pekin duck

The atrial natriuretic factor (ANF) as an osmoregulatory hormone causes a reduction of extracellular fluid volume primarily through stimulation of renal and extrarenal water and sodium elimination. Consequently, ANF counteracts the renin-angio-tensin II-aldosterone (RAAS) and the antidiuretic hormone (ADH) systems at their target organ level. The possible direct interaction of ANF with the hypothalamo-neurohypophyseal ADH system was investigated in conscious ducks and rabbits during conditions of eu- and dehydration. In euhydrated animals, the plasma concentration of ADH remained unchanged during the systemic infusion of species-specific ANF, whereas in dehydrated rabbits but not ducks, the plasma concentration of ADH was significantly decreased. These differences in ADH modulation were supported by the localization of binding sites for radiolabeled ANF at the sites of ADH release, the median eminence (ME) and neurohypophysis (NH) of the rabbit but not duck brain, using receptor-autoradiography. For both species, circumventricular organs lacking a functional blood-brain barrier (BBB) such as the subfornical organ (SFO), the organum vasculosum of the laminae terminalis (OVLT), the pineal and the choroid plexus (ChP), as well as the ependymal lining of the third ventricle (VIII) were labeled specifically. Within the BBB, binding sites for ANF could not be detected in the ADH-synthesizing paraventricular (PVN) and supraoptic nuclei (SON) of either species, however, sites were observed in the anterior median nucleus of the hypothalamus (AM) of the duck brain. In the AM as well as the PVN and ME, the existence of a brain-intrinsic ANF system could be demonstrated for the Pekin duck using immunocytochemistry.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased monoamine turnover in the region of the subfornical organ following reduction of extracellular fluid volume

Increased monoamine turnover in the region of the subfornical organ following reduction of extracellular fluid volume

Allergic Nephropathy Associated With Ciprofloxacin

We report a case of ciprofloxacin-related allergic tubulointerstitial nephritis, which manifested as nonoliguric renal failure, eosinophilia, and eosinophiluria. Our patient responded to discontinuation of ciprofloxacin therapy and oral administration of a brief course of corticosteroids. Although rare, allergic tubulointerstitial nephritis apparently can be caused by ciprofloxacin therapy. Clinicians should be aware of this entity.

Urine Electrolytes in the Assessment of Extracellular Fluid Volume Contraction

The purpose of this study was to determine which urine electrolytes should be measured to confirm that the extracellular fluid (ECF) volume is depleted. ECF volume contraction was induced by furosemide administration to rats consuming an electrolyte-free diet. An external potassium balance was achieved by replacing potassium losses with KHCO3 and KCl so that the sodium and chloride deficits were comparable (equivalent to a 30% reduction in ECF volume). As expected, the urine sodium and chloride concentrations fell to 2 +/- 0.3 mmol/l and 3 +/- 0.3 mmol/l, respectively. Rats were then randomized to receive 50-75% of their sodium or chloride deficit as either: NaCl (control group), NH4Cl or NaHCO3 to mimic clinical situations associated with ECF volume contraction. In the NaCl group, the urine sodium and chloride concentrations remained low (6 +/- 2 mmol/l and 7 +/- 2 mmol/l), consistent with persistent ECF volume contraction. Although the NH4Cl group continued to have a low urine sodium concentration (2 +/- 0.2 mmol/l), there was now a marked increase in the urine chloride concentration (51 +/- 7 mmol/l; p less than 0.01 vs. NaCl group). In contrast, although the NaHCO3 group continued to have a low urine chloride concentration (2 +/- 1 mmol/l), there was a significant increase in the urine sodium concentration (19 +/- 3 mmol/l; p less than 0.01 vs. NaCl group). We conclude that the clinical assessment of ECF volume by urine electrolytes requires an evaluation of both the urine sodium and chloride concentrations.

The antihypertensive effect of dietary potassium chloride loading in rats with adrenal regeneration hypertension.

Adrenal regeneration hypertension was induced in male Wistar rats by unilateral adrenal enucleation, contralateral adrenalectomy and the provision of a 1% (w/v) NaCl solution for drinking. A fivefold increase in dietary KCl content caused a significant reduction in the systolic blood pressure of hypertensive rats but not of control rats. During the increase in potassium intake there was a marked polydipsia. When 1% NaCl solution was the drinking fluid, the resultant increase in sodium intake was associated with an abolition of the antihypertensive effect of potassium loading, but when the sodium intake was held constant, the antihypertensive effect was maintained. In rats with adrenal regeneration hypertension, plasma volume was significantly higher, and packed cell volume and plasma protein concentrations were significantly lower than in control rats. These differences were abolished after 4 days of dietary KCl supplementation. Increased dietary potassium intake was associated with significantly lower serum aldosterone concentrations and significantly higher plasma potassium concentrations in adrenal enucleated rats compared with controls. The possibility that a reduction in extracellular fluid volume (due to a natriuresis) and/or a peripheral vasodilatation contributed to the antihypertensive effect of KCl loading is discussed.

Failure of sodium restriction to abolish exaggerated natriuresis in poststreptococcal glomerulonephritis.

Exaggerated natriuresis in response to hypertonic saline infusion occurs with great regularity in patients with documented previous attacks of poststreptococcal glomerulonephritis. Five patients were studied before and after 1 week of dietary sodium restriction in order to examine the possibility that increased extracellular fluid volume might play a role in the response to acute saline infusion. Plasma renin activity (PRA) and PRA responsiveness to sodium depletion were normal, suggesting that extracellular fluid volume was not increased. In all patients, extracellular fluid volume decreased during sodium restriction, as judged by weight loss, cumulative negative sodium balance, small decreases in measured plasma volume, and appropriate increases of PRA and plasma aldosterone concentration. Hypertonic saline infusion provoked exaggerated natriuresis in all patients equally as well after dietary sodium restriction as before. Exaggerated natriuresis in poststreptococcal glomerulonephritis occurs without evidence of chronic expansion of extracellular fluid volume and is not affected by reduction of extracellular fluid volume.

Factors influencing sodium and water excretion in uremic man

Urinary excretion of sodium and water was investigated in patients with chronic end-stage renal disease before and after three different experimental manipulations: reduction in urea solute load by dialysis while extracellular fluid volume (ECFV) was maintained, dialysis without alteration in urea solute load or ECFV and reduction in ECFV without alteration in urea solute load. Sodium and water excretion significantly declined in association with a reduction in both urea solute load and ECFV, but not during a dialysis when reduction on both of these indexes was prevented. The excretory changes occurred in the absence of any alteration in creatinine clearance. The studies suggest that both solute load and the degree of extracellular fluid volume expansion contribute independently to the rate of sodium and water excretion in chronic renal disease. It is concluded that in any given patient the overall excretion of sodium and water is directly influenced by a number of factors including the solute load, the degree of ECFV and the glomerular filtration rate.

Relationship between absolute body-fluid deficits and fluid intake in the rat.

Acute absolute body-fluid deficits were induced in rats by injection of the diuretic drug furosemide, which caused up to 20% reduction of extracellular fluid volume and up to 2% reduction of intracellular fluid volume. Water and .3 M NaCl were subsequently made available to allow the rats to replace their body fluids by drinking. The rats increased their intake of both fluids, but replaced less than half of the total deficit, thereby tolerating larger and larger voluntary body-fluid deficits as the size of the diuretic fluid loss increased. Plasma measures showed that the rats sustained hypovolemia after drinking, while intracellular fluid volume was apparently restored. Fluid-depleted rats drank normally in response to intracellular dehydration induced by a sodium chloride load. Incomplete restoration of body-fluid balance after body-fluid depletion is due to a failure to drink in response to extracellular dehydration.

The control of aldosterone secretion in nephrectomized man.

1. The adrenal response to a reduction in extracellular fluid volume (ECFV), sodium depletion, intravenous adrenocorticotrophic hormone (ACTH) and angiotensin II was assessed from changes in plasma aldosterone and plasma cortisol in eleven nephrectomized patients. Five patients were also studied before nephrectomy and six after successful renal transplantation. 2. Before nephrectomy, the resting concentrations of plasma aldosterone were usually raised. In the three patients out of five tested, the response to intravenous ACTH was marked. In two out of four patients, there was a good response to angiotensin II infusion. In one of two patients, there was a good response to a reduction in ECFV and sodium depletion. 3. After nephrectomy, the resting concentrations of plasma aldosterone were negligible or uniformly reduced and the response to ECFV reduction, sodium depletion, ACTH and angiotensin II was universally poor. 4. In all cases there was a normal plasma cortisol response to ACTH. 5. After renal transplantation in six patients, the four to whom an infusion of angiotensin II was given showed a return to a normal aldosterone response and all six showed a normal response to ACTH. 6. No clear correlation was shown between resting concentrations of plasma aldosterone and plasma potassium after nephrectomy. 7. It was concluded that the kidney, through the renin-angiotensin system, may play its main part by sensitizing the zona glomerulosa to other stimuli, but an alternative kidney-dependent mechanism cannot be excluded.

Treatment of Low-Renin Essential Hypertension

Seventeen patients with essential hypertension were studied in a double-blind comparison of the antihypertensive effect of spironolactone with that of a hydrochlorothiazide-triamterene combination. All 17 patients responded to spironolactone. The decrease in average mean blood pressure was 20.7 mm Hg accompanied by an average diuresis of —3.1 kg. Fourteen of the 17 patients had favorable responses to hydrochlorothiazide-triamterene. The average decrease in mean blood pressure was 17.0 mm Hg, and the average diuresis was —1.5 kg. The difference in mean blood pressure response was not statistically significant. The fact that both forms of therapy were effective, even though their mechanisms of action differ, suggests that extracellular fluid volume reduction may be the key factor in the amelioration of hypertension in patients with low-renin essential hypertension.

Physiological factors regulating secretion of neurophysin

A radioimmunoassay for serum neurophysin has been developed. In pigs serum neurophysin increased immediately following hemorrhage, and it increased threefold above basal concentration 4 minutes after removing 10 per cent of the total blood volume. It remained elevated for several hours, but after reinfusing the blood which had been with-drawn, serum neurophysin decreased gradually towards the basal concentration. No significant difference in serum concentration of neurophysin was observed in rats of different age, sex, or following ether anesthesia; but the concentration in hypophysectomized rats was one third normal. Serum neurophysin in the external jugular vein was fivefold greater than that in the inferior vena cava. Serum neurophysin increased progressively with the amount of blood removed by hemorrhage and increased more than tenfold upon removing 40 percent of the total blood volume. Prolonged dehydration, ingestion of hypertonic saline, and intravenous infusion of hypertonic solutions caused a significant increase in the concentration of serum neurophysin. An acute reduction in extracellular fluid volume also raised the concentration of serum neurophysin. Thirty minutes after suckling, no change in neurophysin was observed in rats. The rate of release of neurophysin in vitro increased by a factor of 10 when the potassium concentration in the incubation medium was raised from 5.6 mM K+ to 56 mM K+ solution.