Urinary Concentration and Dilution in the Aging Kidney

During normal aging, there is a decrease in maximal urine concentrating ability [1-3]. This physiological change was clearly demonstrated by the Baltimore Longitudinal Study of Aging [1]. Rowe and colleagues measured maximal urine concentrating ability in healthy individuals in three age groups: 20−39, 40−59, and 60−79. Individuals aged 60−79 had approximately a 20% reduction in maximum urine osmolality, a 50% decrease in the ability to conserve solute, and a 100% increase in minimal urine flow rate, when compared to the two younger age groups [1]. The change in urine concentrating ability could not be explained by a decrease in glomerular filtration rate [1]. Aged individuals do have a diminished thirst response, but the relationship between vasopressin (also named antidiuretic hormone) secretion and plasma osmolality is preserved and may even be enhanced [3]. Thus, neither a reduction in renal function, as measured by glomerular filtration rate, nor an abnormality in vasopressin secretion, appears to be the mechanism that explains the decrease in urine concentrating ability during aging [1;3;4]. The cloning (reviewed in [5-7]) of many of the key renal medullary water (aquaporins) and solute (sodium and urea) transport proteins that are involved in the urine concentrating mechanism, and the type 2 vasopressin receptor, have resulted in studies into the molecular mechanisms underlying the reduction in urine concentrating ability that occurs during aging.


Urine Concentrating Mechanism
The region of the kidney that is responsible for the generation of concentrated or dilute urine is the medulla (figure 1). To produce a concentrated urine, the collecting duct must be permeable to water and a hypertonic medullary interstitium must be generated by the nephron segments located in the loops of Henle (reviewed in [8;9]). To generate a hypertonic medullary interstitium, a small osmotic gradient is generated at each level of the medulla and then magnified down its length by countercurrent multiplication. In the thick ascending limb of the loop of Henle (in the outer medulla): the NKCC2/BSC1 cotransporter actively reabsorbs Na+, K+, and Cl− across the apical membrane; the K+ that is reabsorbed is secreted back into the lumen via the K+ secretory channel ROMK; resulting in net NaCl reabsorption.

Transport proteins involved in the urinary concentrating mechanism. In the outer medulla, active NaCl reabsorption via NKCC2/BSC1 in the thick ascending limb of the loop of Henle generates a hypertonic medullary interstitium. This concentrates NaCl in ...
In contrast to the outer medulla, NaCl is passively reabsorbed in the inner medulla across the thin ascending limb of the loop of Henle (reviewed in [8;9]). The thin ascending limb luminal fluid has a higher concentration of NaCl and a lower concentration of urea than inner medullary interstitial fluid, thereby establishing chemical gradients that favor NaCl reabsorption and urea secretion, provided that the interstitial urea concentration is sufficiently high. NaCl reabsorption exceeds urea secretion in the thin ascending limb, as it has a higher permeability to NaCl than urea, thereby resulting in dilution of the thin ascending limb luminal fluid as it ascends towards the outer medulla.

NaCl reabsorption in both ascending limb portions of the loop of Henle results in both: a hypertonic medullary interstitium; and delivery of a dilute fluid (relative to plasma) to the distal tubule since both ascending limb segments are water impermeable. The collecting duct is impermeable to water in the absence of vasopressin, resulting in excretion of this dilute fluid as dilute urine. However, the collecting duct becomes highly permeable to water in the presence of vasopressin, and if a hypertonic medulla is present, water is reabsorbed resulting in excretion of a concentrated urine (reviewed in [8;9]).

Vasopressin Receptors
There are two types of vasopressin receptors: type 1 and type 2 (reviewed in [10]). The V2-receptor is involved in urinary concentration. It is expressed in the collecting duct, is a G-protein coupled 7 transmembrane spanning receptor, and its activation results in the generation of the second messenger cyclic AMP. The V1-receptor is involved in increasing systemic blood pressure and has two subtypes: V1a and V1b (also called V3). It is expressed in vasculature, liver, and brain, and its activation results in the generation of the second messenger intracellular calcium.

Water reabsorption along the entire collecting duct is regulated by vasopressin binding to the V2-receptor and stimulating cAMP production (reviewed in [5;9;11]). When blood plasma osmolality becomes elevated by water deprivation (or other causes), hypothalamic osmoreceptors, which can sense an increase of as little as 2 mOsm/kg H2O, stimulate vasopressin secretion from the posterior hypothalamus. Vasopressin binds to V2-receptors in the basolateral plasma membrane of collecting duct principal cells and IMCD cells, which stimulates adenylyl cyclase to produce cAMP and in turn activates protein kinase A.

One potential mechanism for the aging-related decrease in urine concentrating ability would be a reduction in V2-receptors in the aged kidney. In rat, a decrease in V2-receptor mRNA abundance has been detected in one study [12] but no effect on V2-receptor mRNA abundance or vasopressin-stimulated cAMP production was detected in other studies [13-15]. Thus, there is conflicting data on the effect of aging on V2-receptor mRNA abundance (and no data on V2-receptor protein abundance).

Aquaporins
At present, there are 13 cloned water channels or aquaporins (AQPs), 6 of which are expressed in the kidney (reviewed in [5;9]). AQP1 is expressed in the proximal tubule and descending limb of the loop of Henle; AQP7 is also expressed in the proximal tubule. AQP2 is expressed in the apical plasma membrane and sub-apical vesicles of the collecting duct and is the “vasopressin-regulated” water channel. AQP3 and APQ4 are expressed in the basolateral plasma membrane of the collecting duct. AQP6 is expressed in intracellular vesicles in the collecting duct in association with H+-ATPase.

The primary mechanism by which vasopressin rapidly regulates water reabsorption in the collecting duct is by regulating the accumulation of AQP2 in the apical plasma membrane (reviewed in [5;9]). Vasopressin regulation involves both AQP2 phosphorylation at serines 256, 261, 264, and 269 [16-19], and regulated trafficking of AQP2 between sub-apical vesicles and the apical plasma membrane (reviewed in [5]). Wade and colleagues [20] originally proposed the “membrane shuttle hypothesis” in 1979, at a time when water channels had not been cloned or identified. They proposed that the (putative) water channels were stored in vesicles and inserted exocytically into the apical plasma membrane in response to vasopressin. After AQP2 was cloned, the “membrane shuttle hypothesis” was confirmed experimentally by Knepper and colleagues in rat inner medullary collecting ducts (reviewed in [5]). The water that is reabsorbed through AQP2 exits the collecting duct principal cells through AQP3 and AQP4. Water reabsorption is stopped when vasopressin-stimulation ends by endocytosing AQP2 back into the cell, where it is recycled into endosomes until the next stimulation by vasopressin (reviewed in [5;9]).

Several studies show that the protein abundance of some AQPs is reduced in the aged rat kidney [13;21], which could contribute to the reduction in concentrating ability during aging. These studies show that AQP2 protein abundance is reduced in 24−30 month-old rats (which are very old rats), when compared to 10 month-old rats, in both the outer and inner medulla [12;13;21]. The abundance of AQP2 that is phosphorylated at serine 256 is also markedly reduced in the older rats [21]; phosphorylation of serines 261, 264, and 269 has not been studied to date. AQP3 protein abundance is also reduced in the inner medulla of 30 month-old rats, compared to 10 month-old rats, but not in the outer medulla [13;21]. Transepithelial water reabsorption across the collecting duct of aged rats is likely to be reduced by the reductions in AQP2 and AQP3 protein abundances. These changes appear to be specific for AQP2 and AQP3 since neither AQP4 nor AQP1 protein abundances differ between 30 and 10 month-old rats [13;21;22].

The preceding studies pertain to the basal state, ie. rats receiving food and water ad libitum. An important clinical issue is the response of aged people to dehydration, as elderly individuals are more susceptible to dehydration than younger individuals. To model this situation in rats, we compared the ability of 30 month-old rats to respond to 3 days of water restriction, as compared to the response of 4 month-old rats [23]; 4 month-old rats are young adult animals (figure 2). Both the 30 and 4 month-old rats lost 8% of their body weight and had similar increases in hematocrit, but only the older rats became hypernatremic [23]. AQP2 protein abundance and urine osmolality increased significantly in the 4 month-old rats but not in the 30 month-old rats [12;23;24]. Somewhat surprisingly, AQP2 protein abundance did not increase in dehydrated 15 month-old rats, similar to the response in the 30 month-old rats [24]. AQP2 mRNA abundance also increased in dehydrated 2 month-old rats but not in dehydrated 7 month-old rats [14]. Thus, the age at which concentrating ability is lost in rats may be significantly younger than 24−30 months.

Water restriction does not increase AQP2 protein abundance in 30 or 15 month-old rats. Panel A: densitometic summary. There was no significant difference between hydrated (Hyd.) vs. dehydrated (Dehyd) in the 30 or 15 month-old rats. Asterisk indicates ...
The preceding studies suggest that an important mechanism that contributes to the reduction in urine concentrating ability in aging is a failure to increase AQP2 protein abundance in the collecting duct in response to vasopressin. To determine whether this defect could be corrected pharmacologically, supra-physiologic concentrations of dDAVP (Desmopressin), a selective V2-receptor agonist that does not increase blood pressure, were administered to 30 and 10 month-old rats [25]. dDAVP administration caused similar increases in urine osmolality and decreases in urine flow rate in 30 and 10 month-old rats, although the maximum urine osmolality in the older rats was lower than in the younger rats [25]. dDAVP administration also increased the protein abundances of both AQP2 and AQP3 [25], suggesting that the reduced maximal urine osmolality in the aged rats is related, at least in part, to the reduced level of these AQP proteins.


Sodium Transporters
NaCl reabsorption through the Na+-K+-2Cl− cotransporter NKCC2/BSC1 is critical for the establishment of the hypertonic medullary interstitium that is needed to concentrate urine (reviewed in [8;9]). NKCC2/BSC1 protein abundance is reduced in older rats in the outer medulla [26]. NKCC2/BSC1 protein abundance is increased by water restriction, but the increase is less than in younger rats [22;26]. The decrease in NKCC2/BSC1 protein will reduce active NaCl reabsorption across the thick ascending limb of the loop of Henle, thereby reducing the generation of a hypertonic medulla and urine concentrating ability.

The protein abundances of the Ǝ and subunits of the epithelial sodium channel ENaC are also reduced [26]. Water restriction resulted in either no increase, or a reduced increase, in the protein abundances of ENaC, the sodium-protein exchanger 3 (NHE3), the Na+-Cl− cotransporter (NCC/TSC), and the sodium pump Na+-K+-ATPase [22;26]. Thus, the reduced maximal urine osmolality in aged rats may also be related, at least in part, to the reduced level of these sodium transporter proteins.


Urea Transporters
Urea is the second major solute that contributes to medullary interstitial hyperosmolality, and hence to urine concentrating ability [27-29]. Protein malnutrition reduces urine concentrating ability [30-34]. Elderly individuals may be at risk for protein malnutrition, especially those on fixed incomes. Two human (and two rat) urea transporter genes have been cloned: UT-A, which has 6 protein isoforms; and UT-B, which has 2 protein isoforms (reviewed in [6;8;9;35]). UT-A1 protein is expressed in the apical plasma membrane of the inner medullary collecting duct [36]. UT-A3 protein is expressed in the same segment of the collecting duct as UT-A1 [37]. Vasopressin increases urea permeability in the perfused terminal inner medullary collecting duct by increasing UT-A1 and UT-A3 phosphorylation and UT-A1 and UT-A3 accumulation in the apical plasma membrane [37-41]. Vasopressin phosphorylates UT-A1 at serines 486 and 499 [42]. The abundance of both UT-A1 and UT-A3 proteins is significantly reduced in 30 month-old vs. 10 month-old rats [21;43]; phosphorylation of serines 486 and 499 has not been studied to date (figure 3).


Urea transporters are reduced in 30 month-old rats compared to 10 month-old rats. Panel A: UT-A1 protein abundance. Panel B: UT-B protein abundance. Panel C: UT-A3 protein abundance. Asterisk indicates a significant difference between 30 and 10 month-old ...
Administering a supra-physiologic concentration of dDAVP increases UT-A1 protein abundance in the 30 month-old rats, but to a lesser degree than in the 10 month-old rats [25]. Inner medullary interstitial urea concentration is increased by water restricting the 30 month-old rats, but to a lesser degree than in the 10 month-old rats [43]. The reduced levels of UT-A1 and UT-A3 proteins will decrease urea reabsorption and inner medullary interstitial urea accumulation, thereby reducing the hyperosmolality of the inner medulla and urine concentrating ability. Thus, the reductions in UT-A1 and UT-A3 protein abundances, along with the reductions in AQP and sodium transporter protein abundances (discussed above), likely contribute to the reduced urine concentrating ability in the aged rats.

Glucocorticoids may be a mechanism that contributes to the decrease in UT-A1 abundance in aged rats. Older (30 month-old) rats have elevated plasma corticosterone levels as compared to 10 month-old rats [25]. Glucocorticoids decrease UT-A1 transcription, mRNA abundance, and protein abundance [44;45]. These findings suggest the hypothesis that increased glucocorticoids in aged rats may contribute to the reduction in UT-A1 protein.

UT-B protein is expressed on erythrocytes and in the descending vasa recta. A reduction in UT-B would reduce urine concentrating ability by reducing the efficiency of counter-current exchange and/or decreasing intra-renal urea recycling. People who lack the Kidd blood group antigen, which is also UT-B, and knock-out mice lacking UT-B, are unable to concentrate their urine to normal levels [46;47]. Thus, UT-B protein expression on erythrocytes and/or in the descending vasa recta is necessary to produce maximally concentrated urine [46;48-50].

UT-B protein abundance is significantly reduced in aged rats [21;43], and administration of supra-physiological amounts of dDAVP increases it [25]. Thus, another factor that may contribute to reduced urine concentrating ability in aged rats is the reduced level of UT-B protein.


Summary
Aged people and rats have a reduced ability to maximally concentrate their urine. Many of the key transport proteins that contribute to urine concentrating ability, namely AQP2, serine-256-phosphorylated AQP2, AQP3, NKCC2/BSC1, UT-A1, UT-B, and the V2-receptor, are reduced in the medulla of aged rats. The reductions in the abundances of proteins, and their reduced response to administration of a supra-physiologic dose of dDAVP or water restriction, contributes to the reduced ability of aged rats to concentrate their urine and conserve water. If similar mechanisms occur in human kidneys, it would provide a molecular explanation for the reduced concentrating ability in aging and may provide opportunities for novel therapeutic approaches to improve urine concentrating ability.


ACKNOWLEDGMENT
This work was supported by National Institutes of Health grants R01-DK41707 and P01-DK61521.


Footnotes
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Thirst and hydration: Physiology and consequences of dysfunction

The constant supply of oxygen and nutriments to cells (especially neurons) is the role of the cardiovascular system. The constant supply of water (and sodium) for cardiovascular function is the role of thirst and sodium appetite and kidney function. This physiological regulation ensures that plasma volume and osmolality are maintained within set limits by initiating behaviour and release of hormones necessary to ingest and conserve water and sodium within the body. This regulation is separated into 2 parts; intracellular and extracellular (blood). An increased osmolality draws water from cells into the blood thus dehydrating specific brain osmoreceptors that stimulate drinking and release of anti diuretic hormone (ADH or vasopressin). ADH reduces water loss via lowered urine volume. Extracellular dehydration (hypovolaemia) stimulates specific vascular receptors that signal brain centres to initiate drinking and ADH release. Baro/volume receptors in the kidney participate in stimulating the release of the enzyme renin that starts a cascade of events to produce angiotensin II (AngII), which initiates also drinking and ADH release. This stimulates also aldosterone release which reduces kidney loss of urine sodium. Both AngII and ADH are vasoactive hormones that could work to reduce blood vessel diameter around the remaining blood. All these events work in concert so that the cardiovascular system can maintain a constant perfusion pressure, especially to the brain. Even if drinking does not take place ADH, AngII and aldosterone are still released. Furthermore, it has been observed that treatment of hypertension, obesity, diabetes and cancer can involve renin–AngII antagonists which could suggest that, in humans at least, there may be dysfunction of the thirst regulatory mechanism.

Angiotensin, thirst, and sodium appetite.

Abstract

Angiotensin (ANG) II is a powerful and phylogenetically widespread stimulus to thirst and sodium appetite. When it is injected directly into sensitive areas of the brain, it causes an immediate increase in water intake followed by a slower increase in NaCl intake. Drinking is vigorous, highly motivated, and rapidly completed. The amounts of water taken within 15 min or so of injection can exceed what the animal would spontaneously drink in the course of its normal activities over 24 h. The increase in NaCl intake is slower in onset, more persistent, and affected by experience. Increases in circulating ANG II have similar effects on drinking, although these may be partly obscured by accompanying rises in blood pressure. The circumventricular organs, median preoptic nucleus, and tissue surrounding the anteroventral third ventricle in the lamina terminalis (AV3V region) provide the neuroanatomic focus for thirst, sodium appetite, and cardiovascular control, making extensive connections with the hypothalamus, limbic system, and brain stem. The AV3V region is well provided with angiotensinergic nerve endings and angiotensin AT1 receptors, the receptor type responsible for acute responses to ANG II, and it responds vigorously to the dipsogenic action of ANG II. The nucleus tractus solitarius and other structures in the brain stem form part of a negative-feedback system for blood volume control, responding to baroreceptor and volume receptor information from the circulation and sending ascending noradrenergic and other projections to the AV3V region. The subfornical organ, organum vasculosum of the lamina terminalis and area postrema contain ANG II-sensitive receptors that allow circulating ANG II to interact with central nervous structures involved in hypovolemic thirst and sodium appetite and blood pressure control. Angiotensin peptides generated inside the blood-brain barrier may act as conventional neurotransmitters or, in view of the many instances of anatomic separation between sites of production and receptors, they may act as paracrine agents at a distance from their point of release. An attractive speculation is that some are responsible for long-term changes in neuronal organization, especially of sodium appetite. Anatomic mismatches between sites of production and receptors are less evident in limbic and brain stem structures responsible for body fluid homeostasis and blood pressure control. Limbic structures are rich in other neuroactive peptides, some of which have powerful effects on drinking, and they and many of the classical nonpeptide neurotransmitters may interact with ANG II to augment or inhibit drinking behavior. Because ANG II immunoreactivity and binding are so widely distributed in the central nervous system, brain ANG II is unlikely to have a role as circumscribed as that of circulating ANG II. Angiotensin peptides generated from brain precursors may also be involved in functions that have little immediate effect on body fluid homeostasis and blood pressure control, such as cell differentiation, regeneration and remodeling, or learning and memory. Analysis of the mechanisms of increased drinking caused by drugs and experimental procedures that activate the renal renin-angiotensin system, and clinical conditions in which renal renin secretion is increased, have provided evidence that endogenously released renal renin can generate enough circulating ANG II to stimulate drinking. But it is also certain that other mechanisms of thirst and sodium appetite still operate when the effects of circulating ANG II are blocked or absent, although it is not known whether this is also true for angiotensin peptides formed in the brain. Whether ANG II should be regarded primarily as a hormone released in hypovolemia helping to defend the blood volume, a neurotransmitter or paracrine agent with a privileged role in the neural pathways for thirst and sodium appetite of all kinds, a neural organizer especially in sodium appetite.

Role of brain angiotensin II in thirst and sodium appetite of sheep.

The contribution of brain angiotensin II (ANG II) to thirst and Na+ appetite of sheep was evaluated. Thirst was stimulated by water deprivation, intracarotid or intracerebroventricular infusion of ANG II, or intracarotid or intracerebroventricular infusion of hypertonic solution. Intracerebroventricular infusion, over 1-3 h, of the ANG II type 1 (AT1) receptor antagonist, losartan, decreased or abolished water intake caused by all of the stimuli tested. Intracerebroventricular infusion of ZD-7155, another AT1-receptor antagonist, blocked ANG II-induced water intake. Neither losartan nor ZD-7155 infused intracerebroventricularly altered the Na+ appetite of Na(+)-depleted sheep. Intracerebroventricular infusion of losartan over 3 h, however, did block the increase in water intake and the decrease in Na+ intake caused by intracerebroventricular infusion of hypertonic NaCl in Na(+)-depleted sheep. Intracerebroventricular infusion of the ANG II type 2 (AT2) receptor antagonist, PD-123319, over 1-3 h, did not alter ANG II-induced water intake or Na+ depletion-induced Na+ intake. These results are consistent with the proposition that brain ANG II, working via AT1 receptors, is involved in the neural system controlling some aspects of physiological thirst and Na+ appetite. A role for AT2 receptors in physiological thirst or Na+ appetite is not supported by the present results.


Conditions for secretion of vasopressin in pressor amounts in water-replete rats. By Iriuchijima J.
Abstract

Conditions for secretion of pressor amounts of vasopressin were sought in conscious, water-replete rats. The characteristic lowering of arterial pressure on injection of a vasopressin antagonist was used to detect vasopressin secretion in pressor amounts. The absence or marked abatement of both baroreceptor impulses and adrenomedullary secretion were found necessary for secretion of vasopressin in pressor amounts: the vasopressin antagonist lowered arterial pressure in rats with sinoaortic denervation and ganglion blockade or adrenalectomy. Besides baroreceptor activity and adrenomedullary secretion, anesthetics were also found inhibitory on vasopressin release in pressor amounts. The adrenomedullary hormone signaling the presence of adrenomedullary activity to the vasopressin releasing mechanism was identified as noradrenaline and not adrenaline. It is suggested that the vasopressin pressor mechanism is recruited to sustain arterial pressure when the sympathoadrenal system fails.

[Role of vasopressin in arterial hypertension].
[Article in French]
Thibonnier M, Sassano P, Daufresne S, Menard J.
Abstract

On isolated arteriole preparations vasopressin behaves as an extremely potent vasoconstrictor. In healthy animals and man its pressor effect is counteracted by several compensatory mechanisms, including stimulation of the baroreceptor reflex with reduction of sympathetic activity, decrease in renin secretion, sodium loss and reduction of vascular response to vasopressor agents. Alterations of these mechanisms unmask the hypertensive effect of vasopressin as shown by several experimental hypertension models in animals. In human pathology vasopressin has been shown to be a good indicator of the severity pf arterial hypertension, but its role in that disease will only be determined when vascular antagonists of vasopressin devoid of paryial agonistic activity become available.

[Cardiovascular effect of the antidiuretic hormone arginine vasopressin].
[Article in German]
Rascher W.
Abstract

The two major biological actions of vasopressin are antidiuresis and vasoconstriction. The antidiuretic action of low concentrations of vasopressin is well established and concentrations 10 to 100 times above those required for antidiuresis elevate arterial blood pressure. Antidiuresis is mediated by V2-receptors at the kidney, whereas vasopressin constricts arterioles by binding at V1-receptors. Pharmacological effects of specific antagonists of the vasoconstrictor activity of vasopressin (vascular or V1-receptor antagonists) are presented. Low concentrations of vasopressin do have significant hemodynamic effects. Physiological concentrations of vasopressin cause vasoconstriction and elevate systemic vascular resistance. In subjects with intact cardiovascular reflex activity, however, cardiac output falls concomitantly and blood pressure therefore does not change. In animals with baroreceptor deafferentation or in patients with blunted baroreceptor reflexes (autonomic insufficiency) a rise in plasma vasopressin causes vasoconstriction and an increase in blood pressure, because cardiac output does not fall under these conditions. Vasopressin contributes substantially via increase in systemic vascular resistance to maintain blood pressure during water deprivation. During hemorrhage and hypotension vasopressin has a major role to restore blood pressure. In experimental hypertension vasopressin contributes to the development and maintenance of high blood pressure in DOCA, but not in genetic hypertensive rats. The role of vasopressin in human hypertension is not yet clear. Vasopressin in extrahypothalamic areas of the brain affects circulatory regulation by interaction with central cardiovascular control centers. The exact mechanism of how vasopressin is involved in central regulation of blood pressure remains to be established. In contrast to our previous opinion vasopressin is a vasoactive hormone also at low plasma concentrations. Its cardiovascular action is more complex than previously assumed.


PHYSIOLOGY & BEHAVIOR
EDITORS-IN-CHIEF
Founding Editor, MATTHEW J. WAYNER

Editorial Advisory Board
MICHAEL BAUM, Boston University, Boston, MA
TIMOTHY J. BARTNESS, Georgia State University, Atlanta, GA
GARY K. BEAUCHAMP, Monell Chemical Senses Center, Philadelphia, PA
LARRY L. BELLINGER, Baylor College of Dentistry, Dallas, TX
D. CAROLINE BLANCHARD, University of Hawaii, Manoa, Honolulu, HI
RICHARD J. BODNAR, Queens College of the City University of New York,
Flushing, NY
THOMAS W. CASTONGUAY, University of Maryland, College Park, MD
LIQUE M. COOLEN, University of Cincinnati, Cincinnati, OH
WIM E. CRUSIO, Laboratoire de Neurosciences Cognitives, Talence, France
SIETSE F. DE BOER, University of Illinois at Urbana-Champaign, Urbana, IL
JUAN M. DOMINGUEZ, The University of Texas at Austin, Austin, Texas
DAVID A. EDWARDS, Emory University, Atlanta, GA
D.P. FIGLEWICZ LATTEMANN, VA Puget Sound Health Care System,
Seattle, WA
CHERYL A. FRYE, SUNY at Albany, Albany, NY
RONALD J. JANDACEK, University of Cincinnati, Cincinnati, OH
ROBIN B. KANAREK, Tufts University, Medford, MA
KEITH KENDRICK, AFRC Babraham Institute, Cambridge, England
SARAH F. LEIBOWITZ, The Rockefeller University, New York, NY
BRUCE S. McEWEN, The Rockefeller University, New York, NY
MARILYN Y. McGINNIS, University of Texas at San Antonio, San Antonio, TX
KLAUS A. MICZEK, Tufts University, Medford, MA
GUY MITTLEMAN, University of Memphis, Memphis, TN
PIERRE MORMEDE, University de Bordeaux, Bordeaux, France
RANDY J. NELSON, The Ohio State University, Columbus, OH
MELLY S. OITZL, Leiden/Amsterdam Center for Drug Research and Leiden
University Medical Center, Leiden, The Netherlands
JAMES G. PFAUS, Concordia University, Montréal, Québec, Canada
SUSAN RITTER, Washington State University, Pullman, WA
ROBERT J. RODGERS, University of Leeds, Leeds, UK
NEIL E. ROWLAND, University of Florida, Gainesville, FL
PAUL A. RUSHING, National Institute of Health, Bethesda, MD, USA
NORBERT SACHSER, Westfalische Wilhelms Universität,
Münster, Germany
GARY J. SCHWARTZ, The New York Hospital–Cornell Medical Center, White
Plains, NY
ANTHONY SCLAFANI, Brooklyn College, Brooklyn, NY
ANDREA SGOIFO, University of Parma Via Usberti, Parma, Italy
GERARD P. SMITH, The New York Hospital–Cornell Medical Center,
White Plains, NY
WILLIAM P. SMOTHERMAN, State University of New York, Binghamton, NY
VOLKER STEFANSKI, Dept. of Animal Physiology, Universitätsstr. 30, 95440
Bayreuth, Germany
URSULA STOCKHORST, Institute of Psychology, Osnabrueck, Germany
JOHN G. VANDENBERGH, North Carolina State University, Raleigh, NC
ZOE S. WARWICK, University of Maryland, Baltimore, MD
RICHARD S. WEISINGER, La Trobe University, Victoria, Australia
MARGRIET S. WESTERTERP-PLANTENGA, Maastricht University, Maastricht,
The Netherlands

STEPHEN WOODS, University of Cincinnati, Cincinnati, OH

CAFFEINATED DRINKS CAUSE DEHYDRATION

CAFFEINATED DRINKS CAUSE DEHYDRATION?

The hydrationist, Professor Armstrong from the University of Connecticut, talks about whether caffeinated drinks cause dehydration.

"It’s interesting that in the 1930’s there was a small study done on medical students that showed that when they consumed caffeinated drinks, their output of urine for a few hours increased. However, the researchers in that study did not investigate total body water and did not look at markers of hydration status. So, to counter that study, about eight years ago university students were studied in our laboratory in the United States. We looked at the question of what would happen if 500 mg of caffeine were consumed each day, or about half of that amount, roughly 250 mg. Or if 0 mg of caffeine were consumed each day. And indeed we found by looking at over 20 biomarkers of hydration state, that they were not dehydrated. This explains why we don’t see millions of people in emergency rooms of hospitals who are dehydrated because they consumed caffeinated beverages. So in my opinion, it is a myth that caffeinated drinks cause dehydration."

Urine Bubbly?

What does it mean when you have bubbles in your urine?
The presence of bubbles in urine or foamy urine is a common clinical symptom hinting at proteinuria in kidney failure patients. But urine with bubbles does not necessarily mean that you are suffering from kidney disease. Bubbly urine can be due to a relatively benign or harmless condition as well. Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine (bilirubinuria),retrograde ejaculation, pneumaturia (air bubbles in the urine) due to a fistula, or drugs such as pyridium.

What does it mean when your pee is foamy?

A full bladder can make your urine stream faster and more forceful, which can cause foam. The urine can also get foamy if it's more concentrated, which can occur due to dehydration or pregnancy. Sometimes, the problem is your toilet. ... Protein in the urine is another cause, and it's usually due to kidney disease.

What does it mean if you have foam in your urine?

This can be a sign of protein in your urine (proteinuria), which requires further evaluation. Increased amounts of protein in urine may indicate a serious kidney problem. If your urine seems unusually foamy most of the time, your doctor may recommend that your urine be checked for elevated levels of protein.

Why does my pee smell so strong?

Consumption of certain foods, such as asparagus (which can impart a characteristic odor to urine), and taking some medications may be causes for changes in the odor of urine. The presence of bacteria in the urine, such as with a urinary tract infection (UTI), can affect the appearance and smell of urine.

What does it mean if you have protein in your urine?

Protein in urine (proteinuria) Protein in the urine, also called proteinuria, is often a sign of kidney problems, or an overproduction of proteins by the body. Healthy kidneys only pass a small amount of protein through their filters.

How much is too much protein in the urine?
Here are some natural home remedies that can aid in treating proteinuria:

1.Eat plenty of fruits and vegetables, grains, and legumes.
2.Lean meats are better than red meat, as the latter is harder to break down.
3.Consume more fish.
4.Restrict salt intake.
5.Drink plenty of water and avoid soda/caffeine/coffee.

6.Exercise regularly.

Why would you have protein in your urine?

Both diabetes and high blood pressure can cause damage to the kidneys, which leads to proteinuria. Other types of kidney disease unrelated to diabetes or high blood pressure can also cause protein to leak into the urine. Examples of other causes include: Medications.

How do you get rid of protein in the urine?
1.Keep track of the amount of protein you are eating. ...
2.Help your kidneys flush out and remove excess proteins from your body by drinking plenty of extra water. ...
3.Make a permanent commitment to change your reduced protein diet. ...

4.Focus your diet on foods which are natural and lower in protein.

What does it mean when your urine is cloudy?

Cloudy urine can be caused by a variety of conditions, including vaginal discharge, sexually transmitted diseases, dehydration, certain autoimmune disorders, as well as infection, inflammation, or other conditions of the urinary tract (kidneys, ureters, bladder and urethra).

What are the main causes of kidney stones?

Kidney stones form when your urine contains more crystal-forming substances — such as calcium, oxalate and uric acid — than the fluid in your urine can dilute. At the same time, your urine may lack substances that prevent crystals from sticking together, creating an ideal environment for kidney stones to form.

What can cause your urine to smell?

Some foods and medications, such as asparagus or certain vitamins, can cause a noticeable urine odor, even in low concentrations. Sometimes, unusual urine odor indicates a medical condition or disease, such as: Bladder infection. Cystitis (bladder inflammation).

Why does my pee smell like ammonia?

Eating foods rich in protein can cause this smell, especially if you eat a lot of them. That's because the foods can lead to excess nitrogen in your body, and when that is released, it smells like ammonia. Dehydration. If you don't have enough water in your body, your urine becomes very concentrated.

Can proteinuria be cured completely?

In such cases, proteinuria is temporary and it can be completely reversed after the underlying cause is eliminated. However if proteinuria is caused by chronic kidney disease, diabetes or hypertension. ... Proteinuria is typical symptom of kidney disease which is one of the major causes of protein leakage in urine.

"Bad Cholesterol": A Myth and a Fraud

We in the medical profession, totally oblivious of the vital roles of cholesterol in the body, have been duped into thinking that it is this substance that causes arterial disease of the heart and the brain. The pharmaceutical industry has capitalized on the slogan of "bad cholesterol" and has produced toxic-to-the-body chemicals that minimally lower the level of cholesterol in the body and in the process cause liver damage to thousands of people, some who die as a result of using the medication.

It is surprising that none of the frequently quoted and media-popularized doctors has reflected on the fact that cholesterol levels are measured from blood taken from the veins, yet nowhere in medical literature is there a single case of cholesterol having caused obstruction of the veins. Venous blood moves far slower than arterial blood and thus would be more inclined to have cholesterol deposits if the assumption of "bad cholesterol" were accurate. This mistake by us in the medical community, and its capitalization by the pharmaceutical industry, has caused an ongoing fraud against society.

In truth, the so-called "bad" cholesterol is actually far more beneficial than is appreciated. The reason for its rise in the body is because of complications caused by chronic unintentional dehydration and insufficient urine production. Dehydration produces concentrated, acidic blood that becomes even more dehydrated during its passage through the lungs before reaching the heart - because of evaporation of water in the lungs during breathing. The membranes of the blood vessels of the heart and main arteries going up to the brain become vulnerable to the shearing pressure produced by the thicker, acidic blood. This shearing force of toxic blood causes abrasions and minute tears in the lining of the arteries that can peel off and cause embolisms of the brain, kidneys and other organs. To prevent the damaged blood vessel walls from peeling, low-density (so-called "bad") cholesterol coats and covers up the abrasions and protects the underlying tissue like a waterproof bandage until the tissue heals.

Thus, the vital, life-saving role of low-density cholesterol proves this substance is of utmost importance in saving the lives of those who do not adequately hydrate their bodies so that their blood can flow easily through the blood vessels without causing damage.

Cholesterol is an element from which many of our hormones are made. Vitamin D is made by the body from cholesterol in our skin that is exposed to sunlight. Cholesterol is used in the insulating membranes that cover our nerve systems. There is no such a thing as bad cholesterol. If all the primary ingredients are available for its normal functions, the human body does not engage in making things that are bad for its survival. Until now we did not know water was a vital nutrient that the body needed at all times - and in sufficient quantity.

Water itself - not caffeinated beverages that further dehydrate - is a better cholesterol-lowering medication than any chemical on the market. It is absolutely safe and is not harmful to the body like the dangerous medications now used. Please share this information with those you care for.

For more information about my medical breakthrough on the topic of chronic unintentional dehydration and the diseases it causes, other than what is posted on this site, refer to my books and tapes - products of over 20 years of fulltime research.

F. Batmanghelidj, M.D.

Frequent Urination

Google frequent urination cured with sea salt & water. Cut water consumption by 1/3 & increase sea salt to 1/8 tsp per 8 ounces of water & eat more wet food. Then do a little adjustment till you get it right. Google New York times salt we misjudged you. Researchers prove we aren't t getting enough salt.

These testimonials were sent to Jim Bolen who conceived the idea of Bagel Magic as many people are calling it. This idea was the result of people whose urine was literally running through them, having to urinate every half hour and weren't getting all the expected results from the water cure. The results have been amazing.
**************
Hi Jim,

I had to write and thank you for the bagel tip. Mom (81) was running to the bathroom every half hour all day and night. Your bagel trick really helped and things are back to normal.

As I told you, she had a chronic bowel problem all her life which had gotten worse over the last 6 years due to surgery to remove an adrenal gland. Whether from surgery or the steroids they put her on she spent each day in pain and was taken to the hospital twice for severe cramps and constipation. She no longer has any bowel problems, no cramps, no pain.

Thank you so much for your time and concern. What a wonderful way to get healthy.

Carlise.
***********************

Hi, I want to take a moment to share my experience with the water cure. My name is Richard, I first started the program in March of this year. Living in NYC,I was suffering from extreme anxiety,panic attacks etc...I started the program,and have since noticed a big difference in my stress levels(I'm much calmer) as well as energy levels and overall sense of well being. I've dropped a good 20 pounds as well! I was however still dealing with frequent urination, having to urinate every 30 minutes or so. I would also notice some ups and downs with my day to day feelings,somedays feeling quite good while other days having a return of some of the old anxiety. For the past few weeks or so Jim Bolen has been suggesting to me to try a bagel and then drink water/salt. This, Jim explained should help keep the water in the body for at least 2 hours and allowing the water enough time to top off the still somewhat dehydrated cells. After a few weeks of my resisting trying the bagels(for fear of putting excess weight on) I tried my first bagel yesterday at 4:00 followed by 16 ounces of water and a little sea salt.I did not urinate until 7:30!!! I then had dinner at 8:00 again with one whole bagel and 16oz's water/salt. I then did not urinate until 11:00!!! To top it off,I slept the entire night without awaking one time to urinate. A first in 20 years!!!!! If you are dealing with frequent urination,I urge you to try Jim Bolen's advice. Eat a Bagel with your water/salt A.K.A. The Magic Bullet!!!

Thank you Jim!!!!! 

In Health, Richard.

*****************

Piling on The Pressure

ENaC's (epithelial sodium channels) tasks do not end at birth.  It plays a vital role in regulating the amount of sodium in your blood and this, in turn, determines your blood pressure. If ENaC channels malfunction, your blood pressure can skyrocket, putting you at risk of a stroke.

Your kidneys are sophisticated organs that clean the blood, continuously filtering out toxins and waste products and flushing away excess water. Waste processing takes place in about a million individual units known as nephrons, where tufts of fine blood vessels, know as capillaries, are entwined with tiny tubules that act as urine-collecting devices.
Amazingly, the whole of your blood passes through the kidney twice every hour. The red blood cells and plasma proteins are retained in the capillary,  but the salts and water are forced out into the kidney tubule. Almost all of the sodium and much of the water that is filtered are subsequently reabsorbed as the fluid passes down the kidney tubules. What remains is stored in the bladder and excreted as urine.

ENaC channels in the membranes of the kidney tubule cells are responsible for reabsorption of sodium. As in the lung , sodium uptake is accompanied by water, which leads to an increase in blood volume and, because the circulation is a closed system, raises the blood pressure. A diet high in salt (sodium chloride) is bad for you because more sodium is taken up, which drags more water with it, increasing your blood volume and therefore your blood pressure.
Conversely, if blood sodium levels are low, insufficient water is retained by the body, leading to a fall in blood pressure. This is why it is important to ensure that you eat enough unrefined sea salt in a hot climate , where a lot of salt is lost through sweating.

Mutations in any of the three genes that make up the ENaC channel affect blood pressure.  Those that lead to increased ENaC activity cause a hereditary form of hypertension known as Liddle's disease, whereas those that reduce ENaC activity result in low blood pressure. The latter are particularly dangerous as they lead to a life-threatening salt-losing syndrome in newborns and infants.  Because sodium uptake is reduced, less water is reabsorbed, so that the child quickly becomes dehydrated and the blood concentration of other ions ( especially potassium ) becomes unbalanced.  The disease is fatal unless it is quickly recognised and treated.

Fortunately, mutations in ENaC are rare. However, it is thought that one reason for the greater incidence of high blood pressure and its attendant complications in black people than in Caucasians is because they have relatively common variants in their ENaC channels genes that predispose them to increased sodium uptake.
Why this is the case is uncertain, but one suggestion is that people living near the Sahara evolved very efficient mechanisms for absorbing salt as it was in such short supply. While this is advantage when salt is only rarely obtainable, it becomes a handicap in our present world where much processed food is very high in salt.

DON'T LISTEN TO THE NEGATIVE REVIEWS --- TRY IT YOURSELF!

I downloaded this testimonial from the review section of an Internet site. It was so poignant that I could not resist sharing it with you. I hope the author does not mind. I am sure he would want you to read it, too.

Don't listen to the negative reviews --- try it yourself !

March 5, 2004
Reviewer : aggressivepeace from San Francisco, CA

I think Mr. Urologist ( I won't use Dr.) has no clue what he  is talking about . I have no medical degree and can tell you that what he is saying is asinine. Water intoxication, in most cases is found in triathletes, marathoners, and military. It only happens when they have drunk excessive (generally over 200 ounces ) amounts in a small period of time . This caused  their sodium and mineral balances to go awry and they got sick or died. If the Pee Doctor  had actually read the book , he would see that Dr. Batman talks repeatedly about adding sea salt to your intake if you have concerns about water intoxication.


I have had the following benefit from increasing my water intake to half my body weight in ounces per day, plus an additional 1.5 ounces of water for every 1 ounce of caffeinated beverages.  (For me this is 128 ounces of water a day. I weigh 220 and drink one 12-ounce soda a day.)  Again, follows is a list of the benefits I have had, if you don't believe me you are foolish. I have no reason to lie.


* no depression


* more energy


* sleeping better


* skin more elastic and generally healthier ( I am getting compliments about my face)


* increased sense of well-being or doing something positive for myself 


* full, clean urine


* full, regular excrement


* no back pain ( lower)


* reduced knee / joint pain


* less pain in my damaged ulnar nerve


* eat less


* feel tired less


* awareness of thirst has  returned ) I don't eat or do something else instead)


* less heartburn


The absolute most positive and main effect is no depression. I am entirely astounded at the positive effect this has had on my life . I have gotten off meds and will never return, for now I know the true answer. Meds are good to get you through a bad spot, but they will not relieve your depression effectively over a long period of time. This doesn't even consider the horrible negative side effects.


It is so clear that this is the healthiest thing that you can ever do for yourself ( a close #2 is regular cardiovascular and muscle-building  exercise). I personally commit that you will have increased health and mentality if you drink the correct amount of water for yourself. Also, consult Dr.Weil regarding the power of your mind toward your health.

Peace and good hydration to you all.

Thanks Dr. Batman !!!!!! You are a life saver. I hope your message gets to more and more people . I am now having friends come back to me stating  how they are noticing differences for themselves No one really believes it until it happens to them, and when my friends saw the sincerity I had about my improvement they tried it themselves.

Thanks again. You have truly made the world a better place.

**************************************

Following Watercure Protocol

Whatever your health condition is, you stand to gain more IF you follow this watercure protocol.

0. Find out your correct daily hydration need. (your body weight in kilogram) x (31.42 ) ml = (your daily water quota) ml. 10% of this daily water quota is your personal 'glass of water'.
1. Drink 2 'glasses of water' , first thing in the morning upon rising.

2. Half hour before meal, drink 1 ' glass of water' .

3. Two and a half hour after meal, drink 1 'glass of water'.

4. Drink 1 'glass of water' before going to bed at night.

NOTE: For every 1250 ml of water intake , use 1/4 teaspoon of sea salt. Average body weight of 30 kg will need this 1250 ml water and 1/4 teaspoon salt, daily. 

CRYSTAL CLEAR :What's My Pee Telling Me?

Sometimes after a tinkle, you may glance unto the toilet only to see a bowl of crystal clear water, leaving you to wonder, "Where did my yellow go?" Clear pee reflects an excess of water in the urine. Good sign. This dilutes the concentration of urobilinogen and makes urine seems like nothing more than lukewarm (if you feel it with your hand) H2O. The most likely explanation for clear urine is the consumption of large amounts of water. Good for the body. Our urine tends to be darkest when we wake up (our kidneys retain water to keep our bodies hydrated at night) and progressively lightens as we replenish our water stores. In general, clear urine is a positive sign telling you that you are well hydrated.

Clear urine can also be one of the first signs that you are well on the path toward inebriation. Within twenty minutes of your first alcoholic beverage, the body's level of anti-diuretic hormone (ADH) decreases. This hormone normally functions to prevent urination and allows the body to conserve water. As you continue to toss back drink after drink, levels of ADH in the body plummet, effectively making the kidneys nothing more than conduits for the massive amounts of liquid you are ingesting. The end result is large amounts of dilute urine, which leads to dehydration, hangovers, and the well-known admonition against "breaking the seal."

When drinking alcohol ... you feel the urge to go to the toilet.... the longer you hold on...... the less you'll need to go to the toilet as you continue to drink.
The earlier you break the seal, the more you'll need to go to the toilet.

Girl: "I needa go to the toilet real bad guys"
Group of Friends: "DONT BREAK THE SEAL"
Girl: "awww....."

How Dehydration cause Obesity

 To simplify complications is the FIRST essential of success. (Click here)

In general, body mass index (BMI)above 27 is considered obese.

Losing weight through proper hydration of the human body, some natural salt intake, and exercise like casual walking is more prudent than drastic dieting. Complications of drastic dieting and of focusing only on the readings of the weight scale can cause an unbalance intake of essential ingredients and precipitate deficiency diseases.

The good thing about water, yes, plain water as the primary source of clean energy is the fact that any excess is passed out in the form of urine. Fat, on the other hand, has to be burned through many steps until it is converted to carbon dioxide and passed out in the lungs.

It is prudent to slim down before trying to run; not trying to run to slim down.
Finola Hughes, star of the television series All My Children , who lost thirty (30) pound without dieting. A radio talk-show host lost forty(40) pounds without effort and has gone down from a size 20 to a size 14. She not only lost her flab, she also got rid of her hot flashes, fatigue, aching joints, and sinus headaches, all in one sweep. Children in affluent societies showing an astounding tendency to gain weight and very fast too. These fat citizens turn obese has become an issue in the media and within the government.

The reason is twofold. One, they are being pushed into overeating by the food industry's constant advertising that promotes different fast foods. Two, these children are pushed to drink sweetened drinks instead of plain water. Any form of sweetness sensed by the tongue will stimulate the pancreas to secrete insulin. Insulin is a weight-gain-promoting (anabolic) hormone; it promotes fat cells to convert sugar and carbohydrates in the diet into fat.

The importance of natural salt to weight loss. When the human body becomes dehydrated and needs to increase its water reserves, it can do so only if salt (sodium chloride) is available to expand the extracellular water content of the body. In dehydration, the human body seeks natural salt in the foods that are eaten. This search for salt is another reason for overeating. The salt found in the fast food chains are not natural salt, hence, the human body cannot use it, compare to natural unrefined salt, as sea salt.

To simplify complications is the FIRST essential of success. (Click here)

If ever you wonder about the validity of plain water as the natural "preventive" medication in staying slim and fit and rugged and in avoiding the many diseases today, remember: DEHYDRATION MEANS SHORTAGE OF WATER IN THE BODY. It means that a rationing system goes into effect for the available water in the human body to determine when, why, and where water should reach various parts or organs of the human body. Naturally, the area that become comparatively dry cannot function normally. These regional or local abnormally functioning areas often produce pain and, eventually, the degenerative disease condition. Water cure: drugs kills, in short. Obesity :The Deadly Disease of Dehydration.


It is never too late or too early to revise and be wise again for the rest of our journey.......

Use Water-cure. Rather be thankful for the timely warning, and do something about it.

Drink at least 10% of your own daily water-quota (31.42 ml multiply by your present body weight(kg), every 90 minutes. Use 1/4 teaspoon of sea-salt in your daily diet, for every 1250 ml water drank.

Pain is a sign/signal produced by dehydration in the human body. Pain may be common but it is not normal.

To simplify complications is the FIRST essential of success.
 To simplify complications is the FIRST essential of success. (Click here)