Solute Excretion Research Articles

Interpreting common hydration biomarkers on the basis of solute and water excretion

This investigation evaluated 12 hydration biomarkers, to determine which represent 24-h whole-body water balance (that is, measured as water retention or clearance (WR-C) by the kidneys). Healthy males (n=59; body mass, 75.1±7.9 kg; height, 178±6 cm; age, 22±3 years; body mass index, 23.9±2.4 kg/m(2)) met with a registered dietitian each morning (days 1-11) to optimize completeness and accuracy of food and fluid records, then went about ordinary daily activities. These men visited the laboratory for blood samples and collected all urine produced on days 1, 3, 6, 9 and 12. The reference standard (WR-C) was calculated using 24-h urine volume, 24-h urine osmolality, and serum osmolality (single morning venous sample). Statistical regression analyses indicated that, among the 12 hydration biomarkers, only 24-h urine osmolality (r(2)=0.60, P<0.0001) and 24-h urine specific gravity (r(2)=0.52, P<0.0001) strongly predicted WR-C. The 24-h fluid intake, 24-h body mass change, 24-h urine color and 24-h urine volume were weak (P>0.05) predictors of WR-C, similar to serum osmolality and other single measurements (range of r(2) values, 0.19-0.0001). These observations of healthy, active young men demonstrate that WR-C is strongly related to the 24-h concentration of urine, which in turn reflects the excretion of total solids in the diet. Although morning urine assessments provided information about a single time point, 24-h urine osmolality and 24-h urine specific gravity were the best predictors of 24-h body water balance.

Urinary incontinence – a challenge to the physiologist Joint symposium for the EU/FP7 networks INComb and TRUST in collaboration with the Swedish Enuresis Academy (SEA), Stockholm 2011

Urinary incontinence – a challenge to the physiologist Joint symposium for the EU/FP7 networks <scp>INC</scp>omb and <scp>TRUST</scp> in collaboration with the <scp>S</scp>wedish <scp>E</scp>nuresis <scp>A</scp>cademy (<scp>SEA</scp>), <scp>S</scp>tockholm 2011

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Case Reports: A 40 year female presented with nausea, vomiting and diarrhea for 2 weeks. She also had diagnoses of fibromyalgia, chronic fatigue and depression. She complained of “dizziness” and a 3-day history of increasing lethargy. In the ED, initial electrolyte evaluation showed severe derangements including Na 97, K 2.0, Cl 55, bicarbonate 33, iCa 3.89, Mg 1.9. Her urine osmolality was <40 mOsm/kg and urine Na was <10 mmol/L. Hemodynamics and respiratory status were unremarkable. On further asking, she revealed she had been drinking lot of fluids at home as she was not able to keep solid food down. The liquid she had been ingesting was predominantly iced tea in excess of 6 L/day. She was started on iv fluid supplementation along with multiple electrolyte abnormality correction. On day 3, her Na was 125 and she was more ataxic. MRI of the brain was done and it revealed presence of subtle increased T2 signal in the caudate head and minimally within the putamen bilaterally along with mild hyperintensity on T2 weighted imaging in the hippocampi bilaterally, without any pontine abnormalities. Findings were suggestive of early osmotic demyelination syndrome. Subsequently the symptoms resolved and she did not have any sequelae. This case highlights the phenomenon which is better known as beer potomania – contributed by limited solute intake in combination with excess liquid consumption. Iced tea, like beer, has no protein and very limited to nil Na content. The limit on how much free water excretion can be achieved in a day is dependent on urine osmolality (urine flow rate = rate of solute excretion / urine osmolality). For an individual drinking predominantly iced tea, they are taking in very limited solute per day, which is then eliminated in the urine. This puts a cap of only about 4-5 Liters of electrolyte-free water excretion per day. Thus, if an individual drinks more than the foresaid quantity of liquid in a day, in the absence of additional solute, he/she will become hyponatremic. On top of this mechanism, the patient described also may have non-osmotic secretion of ADH as a result of nausea, vomiting and diarrhea. All of these seem to have contributed to her severely depressed sodium levels.

Sodium challenge does not support an acute gastrointestinal–renal natriuretic signaling axis in humans

A gastrointestinal-renal natriuretic signaling axis has been proposed to regulate sodium excretion in response to acute sodium ingestion. Such an axis is thought to be regulated by a gastrointestinal sodium sensor coupled to the activation/release of a natriuretic signal and could have important clinical and scientific implications. Here we systematically tested for this putative axis and the potential involvement of the gastrointestinal-derived natriuretic prohormones prouroguanylin and proguanylin in 15 healthy volunteers. There was no difference in sodium excretion following equivalent oral or intravenous sodium loads during either high- or low-sodium diets. Furthermore, serum concentrations of prouroguanylin and proguanylin did not increase, did not differ following oral or intravenous sodium, and did not correlate with sodium excretion. Thus, our results do not support an acute gastrointestinal-renal natriuretic axis or a central role for prouroguanylin or proguanylin in humans. If such an axis does exist, it is not characterized by a significant difference in the pattern of sodium excretion following either an oral or intravenous sodium load.

Discovery and pharmacological study of a novel diuretic

Diuretics are used widely to raise renal salt and water clearance in a variety of conditions, such as oedema, as well in non-edematous states such as hypertension, which can reduce morbidity and mortality of cardiovascular and cerebrovascular diseases, especially the frequency of stroke and congestive heart failure. However, long-term use of conventional diuretics has several adverse effects including electrolyte disorders, hyperuricemia, hyperlipidemia, and glucose tolerance decrease. Electrolyte abnormalities can induce cardiac arrythmias and sudden death. Therefore, discovering a new diuretic that does not cause electrolyte disturbance becomes a hot issue. Phenotype analysis of knockout mice lacking urea transporter UT-B or various UT-A isoforms has provided evidence for the involvement of UTs in the urinary concentrating mechanism. Functional deletion of UT-B or UT-A isoforms markedly caused polyuria and urea selective low urine concentrating ability. However, deletion of UT-B or UT-As did not affect GFR and clearance rate of the principal solutes (Na+, K+, Cl-) in urine except for urea. Therefore, we suggested a hypothesis that UT inhibitors might be novel diuretics to excrete water without disturbing electrolyte metabolism. Present study discovered a potent small-molecular urea transporter inhibitor, UT-A4, using an erythrocyte osmotic lysis assay. Stopped flow light scattering experiment, a classical assay for measuring water and urea permeability, confirmed that UT-A4 reversibly inhibited UT-B activity. The experiments also showed that UT-A4 targeted the intracellular part of UT-B protein and had the same inhibition activity on influx and efflux of urea across membrane. UTinh-14 has inhibition activity on human, rabbit, rat and mouse UT-B. We used rats as an in vivo test model for determining the diuretic activity of UT-A4. Interestingly, UT-A4 caused dose-dependent polyuria, low urinary osmolality and urea concentration in rats. 18-h water deprivation raised urine concentrating ability in rats with or without UT-A4 treatment. However, urine osmolality and urea concentration remained significantly less in UT-A4 treated rats than that in control rats, except of unchanged non-urea solutes. Osmolality and urea concentration was significantly decreased in inner medullary tissue of UTinh-14 treated rats, but not in HCTZ treated rats. All these results suggest that UTinh-14 caused urea selective diuresis. The excretion of osmoles, urea and non-urea solutes had no significant difference between control and UTinh-14 treated rats. However, HCTZ treated rats had significant higher excretion of osmole and non-urea solutes than control and UTinh-14 treated rats, which made lower blood Na+, K+ and Cl-. These results indicate that UT-A4 is a selective UT inhibitor and has urea selective diuretic activity without disturbing excretion of electrolytes. It might have potential value on drug discovery as a new diuretic without electrolyte imbalance and metabolic disorder. It might also be used as a tool drug to study the physiological roles of UTs in big animal models.

The added-up albumin enhances the diuretic effect of furosemide in patients with hypoalbuminemic chronic kidney disease: a randomized controlled study

BackgroundChronic kidney disease (CKD) with edema is a common clinical problem resulting from defects in water and solute excretion. Furosemide is the drug of choice for treatment. In theory, good perfusion and albumin are required for the furosemide to be secreted at the tubular lumen. Thus, in the situation of low glomerular filtration rate (GFR) and hypoalbuminemia, the efficacy of furosemide alone might be limited. There has been no study to validate the effectiveness of the combination of furosemide and albumin in this condition.MethodsWe conducted a randomized controlled crossover study to compare the efficacy of diuretics between furosemide alone and the combination of furosemide plus albumin in stable hypoalbuminemic CKD patients by measuring urine output and sodium. The baseline urine output/sodium at 6 and 24 hours were recorded. The increment of urine output/sodium after treatment at 6 and 24 hours were calculated by using post-treatment minus baseline urine output/sodium at the corresponding period.ResultsTwenty-four CKD patients (GFR = 31.0 ± 13.8 mL/min) with hypoalbuminemia (2.98 ± 0.30 g/dL) were enrolled. At 6 hours, there were significant differences in the increment of urine volume (0.47 ± 0.40 vs 0.67 ± 0.31 L, P < 0.02) and urine sodium (37.5 ± 29.3 vs 55.0 ± 26.7 mEq, P < 0.01) between treatment with furosemide alone and with furosemide plus albumin. However, at 24 hours, there were no significant differences in the increment of urine volume (0.49 ± 0.47 vs 0.59 ± 0.50 L, P = 0.46) and urine sodium (65.3 ± 47.5 vs 76.1 ± 50.1 mEq, P = 0.32) between the two groups.ConclusionThe combination of furosemide and albumin has a superior short-term efficacy over furosemide alone in enhancing water and sodium diuresis in hypoalbuminemic CKD patients.Trial registrationThe Australian New Zealand Clinical Trials Registration (ANZCTR12611000480987)

Effects of tap water, electrolyte solution, and spontaneous and furosemide-stimulated urinary excretion on thirst

To contrast the effects of various modifications of body fluid volumes on thirst as reported by healthy volunteers. Ten male volunteers aged between 19 and 37 years (mean 22 years) underwent four experiments each, which comprised infusion of 400-800 mL of acetated Ringer's solution and intake of 600 mL of tap water. Half of the experiments were preceded by volume depletion (median 1.7 L) with furosemide. A visual analogue scale (0-100 mm) was used to assess perceived thirst during each experiment. Volume depletion (P < 0.001) and tap water (P < 0.03) both affected thirst by 13 mm per L of fluid, whereas spontaneous diuresis and infusion of Ringer's acetate did not significantly change the thirst rating (multiple regressions). More detailed analyses showed that the volume depletion increased the median (25th-75th percentiles) thirst rating from 28 mm (21-43) to 59 mm (46-72, P < 0.001) while no change occurred in those who were only slightly thirsty (< 30 mm) before the volume depletion began. Ringer's solution alleviated thirst in those who were very thirsty, but tended to increase thirst in the volunteers who were not thirsty before the infusion. Similarly, hydration with tap water decreased thirst (by 24 mm, P < 0.04) in those who were thirsty (> 60 mm) while the others reported no change. The change in thirst rating during volume depletion, administration of Ringer's acetate, and ingestion of tap water were all dependent on the thirst rating obtained when the manipulation of the body fluid volume was initiated.

Effect of nebivolol, a novel beta 1-selective adrenoceptor antagonist with vasodilating properties, on kidney function.

Nebivolol (CAS 99200-09-6) is a novel beta 1-selective adrenoceptor antagonist which possesses vasodilating properties and lowers systemic vascular resistance in dogs and humans, presumably by a nitric oxide-related mechanism. In the present study, clearance techniques were applied to anaesthetized male Sprague Dawley rats, and the effects of nebivolol on renal hemodynamics (glomerular filtration rate and renal plasma flow), on urinary excretion of sodium, chloride and potassium, on renal NO-excretion, and on plasma renin activity were studied. Nebivolol doses ranging from 0.1 to 2 mg/kg i.v. were tested. The results revealed that nebivolol dose-dependently increased glomerular filtration rate, urine flow and urinary excretion of sodium and chloride. Potassium excretion was only inconsistently increased and showed no dose dependency. At a dose of 1 mg/kg, the drug also significantly increased renal plasma flow measured as 3H-PAH (p-aminohippurate) clearance. The effect of nebivolol on the glomerular filtration rate could be abolished by L-NMMA (N6-monomethyl-L-arginine) (1 mg/kg), a non-selective inhibitor of NO-synthase and by iminoethyllysine (1 mg/kg), a relatively selective inhibitor of the inducible NO-synthase, but not by 7-nitroindazole (1 mg/kg), a relatively selective inhibitor of the neuronal NO-synthase isoform. The saluretic effect of nebivolol was diminished by all of the three NO-synthase inhibitors, but could not be completely reversed. At a dose of 2 mg/kg, nebivolol increased renal NO-excretion by 70.7%. This effect could be completely abolished by L-NMMA (1 mg/kg). Plasma renin activity was lowered by nebivolol (2 mg/kg) from 14.6 +/- 1.49 to 6.5 +/- 1.66 ng angiotensin I/ml/h (p < 0.01). The results demonstrate that, in anaesthetized rats, nebivolol exerts significant renal vasodilating effects and increases urinary excretion of fluid and solutes. The actions of nebivolol on renal hemodynamics are assumed to be mediated by a stimulation of the NO-synthase, probably the inducible isoform. Since none of the NO-synthase inhibitors could completely abolish the saluretic effect of nebivolol, an additional mechanism, not related to NO, may be involved in the tubular action of this drug.

The Evolution of Urogenital Tissue Engineering

In Boston in 1954, Hartwell Harrison, the chief of urology at Harvard University, harvested a kidney and performed the first ever human organ transplantation [1]. The concept of cell transplantation developed after kidney transplantation and led to the first human bone marrow cell transplantation in the 1970s. At that time, researchers combined the scientific fields of device and material sciences with cell biology and in effect pioneered a new field called [2]. The first use of the term can be traced in the literature to a reference dealing with corneal tissue in 1985 [3]. The discovery of mouse embryonic stem (ES) cells in the early 1980s gave a huge boost to the stem cell field and led to the description of human ES (hES) in 1998 [4]. The creation of the first cloned mammal, a sheep named Dolly, was announced in 1997 [5]. Two years later, the term was coined to describe the unifying goal of cell transplantation, tissue engineering, and nuclear transfer, i.e., the regeneration of living tissues and organs [6]. Over the past decade, the number of patients waiting for transplantation has doubled, while the actual number of transplantations has remained practically unchanged. This disparity is a consequence of our aging population. As time passes, we get older and older, and medicine does a better job of keeping us alive. However, as we age, our organs tend to fail more often. This, then, is our new challenge. Although advanced medicines and treatments have saved many lives, we now face a major shortage of organs. The human body has many organs, each of which has a cell population that is ready to take over at the time of injury. It happens every day of our lives. Thus, our body is constantly regenerating. When challenges occur through an injury or a disease, the human body's first reaction is to seal off the area. Whether it is the organs inside the body or the skin, the development of scar tissue is the immediate response to solve the problem. How can we harness that power? One way is through the use of smart biomaterials. In 1996, the first use of natural biomaterials in humans for tissue regeneration demonstrated that smart biomaterials could be used as a bridge in the treatment of an injured urethra [7]. First, the injured area was closed off from the outside environment. Then, cells that were regenerated in the body crossed the bridge and followed the pathway or channel that connected to the bladder or to outside the body. Tissue engineering for urethral reconstruction may involve matrices alone, wherein the body's natural ability to regenerate is used to orientate or direct new tissue growth, or the use of matrices with cells. Acellular collagen matrices that are derived from donor bladder submucosa have been used both experimentally and clinically for urethral replacement. Urethra successfully regenerates, but only over a limited distance. What if the injury is in a larger organ? What can we do to repair injuries in structures that are much larger than the limited distance of regeneration? Researchers have turned to cells to solve these problems. The strategy is to take a very small piece of tissue from the injured or diseased organ and to tease that tissue apart into its basic components. Then, the patient's own cells are taken and grown outside the body in large quantities. Next, scaffold materials are used. The scaffold acts as a cell delivery vehicle, bringing the cells into the body and allowing them to regenerate into new tissue. Scaffold materials are designed to disintegrate in the body a few months later. Currently, gastrointestinal (GI) segments are commonly being used as tissue for bladder and urethral replacement or repair. However, GI tissue is designed to absorb specific solutes, whereas bladder and urethral tissue are designed for the excretion of solutes. When GI tissue comes in contact with the urinary tract, multiple complications may occur, such as infection, metabolic disturbances, urolithiasis, perforation, increased mucus production, and malignancy [8]. James J. Yoo, the Associate Director of the Wake Forest Institute for Regenerative Medicine, focuses his work on growing and regenerating tissues and organs. His team engineered the first lab-grown organ to be implanted into a human - a bladder. His article 'in this issue of the Journal' [9] will introduce the novel tissue engineering-based regenerative strategies that are being applied to bladder reconstruction and will discuss how these strategies can be used to treat the neurogenic bladder.

Diagnostic Value of Urinary Sodium, Chloride, Urea, and Flow

Up to 30% of hospitalized critically ill patients may have a rise in serum creatinine concentration. In addition to history and physical examination, there is diagnostic value in assessing urinary electrolytes, solute excretion, and urine flow in these patients. The correct interpretation of these urinary parameters can avoid unnecessary volume overload and mechanical ventilation, risk factors for increased mortality in patients with rising serum creatinine. The present article also discusses the role of arterial underfilling in causing prerenal azotemia in the presence of an increase in total body sodium and extracellular fluid expansion. As with extracellular fluid volume depletion, arterial underfilling secondary to impaired cardiac function or primary arterial vasodilation can delay or prevent recovery from ischemic or toxic acute tubular necrosis. The present brief review discusses the various aspects of the correct interpretation of urinary electrolytes, solute excretion, and urine flow in the setting of a rising serum creatinine concentration.

Quantitating nocturia: a study into the recording of solute and water excretion to determine causation

Nocturia is common but the clinical assessment of its severity and cause rarely involves any biochemical analysis. Investigating the cause of nocturia needs to be informed by the overall 24 h fluid and solute excretion patterns. The aim of this study was to establish a practical method of monitoring the renal excretion of water and solutes over a complete 24 h cycle. The excretion patterns of sodium, volume and osmoles were assessed in 89 healthy control subjects over a 24 h period by sampling each voiding from the 24 h collection and then using the total urine creatinine as the denominator. A group of 21 patients under investigation for sleep-disordered breathing (SDB: a group of disorders known to increase the risk of nocturia) were also studied to determine comparative excretion patterns. Reference excretion patterns of sodium, volume and osmoles were described. Patients under investigation for SDB had overall a significant (P < 0.001) increase in urine sodium excretion at night (nocturnal natriuresis) matched by an increased osmotic excretion and accompanied by a significantly increased nocturnal urine volume (P < 0.001). Breaking down a 24 h urine collection into voided aliquots provides practical information on the pattern of water and solute excretion. Such patterns may assist in identifying the underlying mechanism of significant nocturia in individual patients presenting with this symptom, and could be used as a method of monitoring treatment.

The influence of prostaglandin E2 and indomethacin on the renal corticomedullary solute gradient in the rat.

The renal corticomedullary solute gradient and the urinary excretion of fluid and solute were determined during a saline infusion in anaesthetized and conscious rats. In the anaesthetized group the influence of PGE2 (100 ng min-1) given by a local renal infusion was investigated. In the conscious group (where prostaglandin synthesis does not contribute to renal blood flow) the effect of indomethacin (i.v. 10 mg kg-1) was determined. Following PGE2 infusion the corticomedullary gradient for sodium was depressed, equalizing the sodium concentration between the papilla tip and the final urine. Sodium output and urine flow were elevated, but both urinary and gradient changes could be dissociated from any increase in renal blood flow, assessed by PAH clearance. Following treatment with the prostaglandin synthetase inhibitor indomethacin in the conscious rat, the corticomedullary osmotic gradient was elevated while the urine flow was reduced. This increase in the gradient produced by indomethacin was, however, found to be independent of the decrease in urine flow. The results of the present experiments are consistent with the hypothesis that prostaglandin synthesis helps to determine the renal corticomedullary osmotic gradient, and does so by a mechanism unlikely to involve changes in renal blood flow or tubular flow rate: a permeability hypothesis is proposed.

Update on nephrolithiasis: beyond symptomatic urinary tract obstruction

Nephrolithiasis research and care have been focused on biochemical changes in urinary solute excretion leading to stone formation, but abnormalities in urine chemistry alone do not explain many aspects of the condition of patients with kidney stone disease. Evidence exists of an association with metabolic syndrome, obesity, diabetes and hypertension, and of enhanced risk of chronic kidney disease and metabolic bone disease. Very recently also a higher risk of cardiovascular events and damage has been reported in kidney stone formers when compared with non-stone formers. It is time to view nephrolithiasis as a condition predictive of chronic kidney disease and cardiovascular damage, which deserves full metabolic evaluation together with an early prevention care strategy, mainly consisting of dietary and lifestyle changes, in a multidisciplinary approach. Kidney stone disease should be considered as a systemic disorder with clinical relevance beyond symptomatic urinary tract obstruction.

Urinary pH and stone formation.

The formation of various types of kidney stones is strongly influenced by urinary pH. An alkaline pH favors the crystallization of calcium- and phosphate-containing stones, whereas and acidic urine pH promotes uric acid or cystine stones. The activity of many transport processes involved in calcium, citrate and phosphate handling are sensitive to changes in systemic or local pH as shown for several phosphate transporters, the citrate transporter NaDC1 and the TRPV5 calcium channel. Defects in urinary acidification (excretion of inappropriately alkaline or acidic urines, respectively) contribute to kidney stone disease. The low excretion of ammonium in patients with metabolic syndrome has been linked to more acidic urine and a higher incidence of uric acid stones. In this state, insulin resistance may reduce ammonium excretion by the proximal tubule. On the other hand, defensive mechanisms may protect from kidney stone formation in conditions such as hypercalciuria where high luminal calcium concentrations stimulate urinary acidification and reduce urinary concentration via a calcium-sensing receptor, resulting in the excretion of acidic and diluted urine. This review will discuss a few aspects that relate to the capacity of the kidney to regulate pH and its impact on the excretion of solutes that participate in the formation or prevention of stones.

Accidental Use of Sodium Hypochlorite Instead of Haemodialysis Solution: A Case Report

Haemodialysis that involves diffusion of solutes across a semi-permeable membrane allows excretion of harmful solutes and excess fluids. All dialysis machines are disinfected by chemical agents (e.g. sodium hypochlorite, formaldehyde, glutaraldehyde, peroxyacetic acid). Sodium hypochlorite (NaOCl), which is known as household bleach, is a whitening agent and used in medical treatment and disinfection of tap water. Herein, we present a 66-year-old female patient who was inadvertently connected to NaOCl solution infusion in a routine haemodialysis session. By the time the accident was noticed, approximately 200 ml of undiluted NaOCl cleaning solution (concentration 1.21-1.23 g/ml) had been added to the dialysis bath, soaking the membrane fibres. The patient was admitted to the hospital about 30 minutes after the exposure, and her Glasgow Coma Scale score was recorded as 5/15 (E1, V1, M3). In conclusion, more stringent standards should be enforced in the sterilization of haemodialysis machines and related equipments. Accidental contacts with disinfectants should be prevented in dialysis units.

Toward the optimal clinical use of the fraction excretion of solutes in oliguric azotemia

While the fractional excretion of solutes have long been considered excellent research tools to investigate tubular physiology, their clinical use has become common over the last 40 years in the diagnoses of many disorders; however, none have reached the clinical utility of the fractional excretion of sodium in the ability to distinguish pre-renal azotemia from acute tubular necrosis. Nevertheless, there are many drugs and medical conditions that interfere with that utility and recently other solutes, including urea, uric acid and lithium, have been recently investigated to improve the diagnostic ability in clinical situations where the fractional excretion of sodium is known to be unreliable. We review the tubular physiology of these solutes and show how the differences in tubular physiology might be exploited to develop a strategy for their optimal clinical use.

Carnitine Deficiency and Oxidative Stress Provoke Cardiotoxicity in an Ifosfamide‐Induced Fanconi Syndrome Rat Model

In addition to hemorrhagic cystitis, Fanconi Syndrome is a serious clinical side effect during ifosfamide (IFO) therapy. Fanconi syndrome is a generalized dysfunction of the proximal tubule which is characterized by excessive urinary excretion of glucose, phosphate, bicarbonate, amino acids and other solutes excreted by this segment of the nephron including L-carnitine. Carnitine is essential cofactor for β-oxidation of long-chain fatty acids in the myocardium. IFO therapy is associated with increased urinary carnitine excretion with subsequent secondary deficiency of the molecule. Cardiac abnormalities in IFO-treated cancer patients were reported as isolated clinical cases. This study examined whether carnitine deficiency and oxidative stress, secondary to Fanconi Syndrome, provoke IFO-induced cardiomyopathy as well as exploring if carnitine supplementation using Propionyl-L-carnitine (PLC) could offer protection against this toxicity. In the current study, an animal model of carnitine deficiency was developed in rats by D-carnitine-mildronate treatment Adult male Wistar albino rats were assigned to one of six treatment groups: the first three groups were injected intraperitoneally with normal saline, D-carnitine (DC, 250 mg/kg/day) combined with mildronate (MD, 200 mg/kg/day) and PLC (250 mg/kg/day), respectively, for 10 successive days. The 4th, 5th and 6th groups were injected with the same doses of normal saline, DC-MD and PLC, respectively for 5 successive days before and 5 days concomitant with IFO (50 mg/kg/day). IFO significantly increased serum creatinine, blood urea nitrogen (BUN), urinary carnitine excretion and clearance, creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), intramitochondrial acetyl-CoA/CoA-SH and thiobarbituric acid reactive substances (TBARS) in cardiac tissues and significantly decreased adenosine triphosphate (ATP) and total carnitine and reduced glutathione (GSH) content in cardiac tissues. In carnitine-depleted rats, IFO induced dramatic increase in serum creatinine, BUN, CK-MB, LDH, carnitine clearance and intramitochondrial acetyl-CoA/CoA-SH, as well as progressive reduction in total carnitine and ATP in cardiac tissues. Interestingly, PLC supplementation completely reversed the biochemical changes-induced by IFO to the control values. In conclusion, data from the present study suggest that: Carnitine deficiency and oxidative stress, secondary to Fanconi Syndrome, constitute risk factors and should be viewed as mechanisms during development of IFO-induced cardiotoxicity. Carnitine supplementation, using PLC, prevents the development of IFO-induced cardiotoxicity through antioxidant signalling and improving mitochondrial function.

Spot Urine Osmolality/Creatinine Ratio in Healthy Humans

Background: Spot urine albumin/creatinine ratio is a reliable estimate of 24-hour urine albumin excretion. In a pilot study, we observed that the spot urine osmolality/creatinine ratio (U_osm/U_cr) in healthy adults is reproducible. Therefore, we postulated that U_osm/U_cr of a spot urine sample may give an overall estimate of urinary excretion of solutes, renal concentrating ability and body hydration status. Method: Early morning spot urine samples were collected from healthy humans, frozen and analyzed in batches to establish spot U_osm/U_cr and its variation in relation to sex, age, body weight and height. Results: Two hundred and twenty-nine healthy volunteers participated. They were stratified into seven age groups: (a) 1.5–5, (b) >5–10, (c) >10–20, (d) >20–30, (e) >30–45, (f) >45–60, and (g) >60 years. Fifteen males and 15 females were allocated to each age category. A spot urine sample was collected from all subjects in the morning after the first void and was analyzed for osmolality and creatinine. The influence of age, sex, body weight and height on spot U_osm/U_cr was investigated using multiple linear regression. Only height showed a significant correlation (R² = 0.02). Further analysis after excluding the 1.5–5 years age group revealed no significant correlation between age, sex, body weight and height and the U_osm/U_cr ratio. Conclusion: Spot U_osm/ U_cr of healthy humans is a consistent index in steady state and needs no correction for sex, age and body weight above the age of 5 years.

Effects of fresh and seawater ingestion on osmoregulation in Atlantic bottlenose dolphins (Tursiops truncatus)

Bottlenose dolphins (Tursiops truncatus) are marine mammals with body water needs challenged by little access to fresh water and constant exposure to salt water. Osmoregulation has been studied in marine mammals for a century. Research assessing the effects of ingested fresh water or seawater in dolphins, however, has been limited to few animals and sampling times. Nine 16- to 25-h studies were conducted on eight adult dolphins to assess the hourly impact of fresh water, seawater, and seawater with protein ingestion on plasma and urine osmolality, urine flow rate (ufr), urinary and plasma solute concentrations, and solute clearance rates. Fresh water ingestion increased ufr. Fresh water ingestion also decreased plasma and urine osmolality, sodium and chloride urine concentrations, and solute excretion rates. Seawater ingestion resulted in increased ufr, sodium, chloride, and potassium urine concentrations, sodium excretion rates, and urine osmolality. Seawater with protein ingestion was associated with increased ufr, plasma osmolality, sodium excretion, and sodium, chloride, potassium, and urea urine concentrations. In conclusion, bottlenose dolphins appear to maintain water and plasma solute balance after ingesting fresh water or seawater by altering urine osmolality and solute clearance. Ingestion of protein with seawater appears to further push osmoregulation limits and urine solute concentrations in dolphins.

Twenty-four Hour and Spot Urine Metabolic Evaluations: Correlations Versus Agreements

To investigate the correlations and agreements between the solute/creatinine ratios from the 24-hour and early morning spot urine samples for metabolic evaluation in stone-formers given the various pitfalls with the 24-hour urinary metabolic evaluation in stone-formers. 30 urinary stone-formers out of an initial 62 recruited provided a complete 24-hour urine and early morning spot urine samples for metabolic evaluation. Pearson correlation and Bland and Altman Test were used to assess the correlations and agreements. Significant correlations were established between the 24-hour urinary solute excretions and the corresponding early morning spot urine solute/creatinine ratios for calcium, magnesium, urate, potassium, oxalate, citrate, and the Differential Gibb's free energy value of calcium oxalate DG(CaOx) values. However, all these solute/creatinine measurements between the 24-hour and early morning spot urine samples were judged to be not within the acceptable limits based on the estimated "limit of agreement" by the Bland and Altman Test of Agreement. Diurnal circadian rhythm and postprandial excretion surge are thought to be responsible for the disagreements. Thus, the early morning spot urine is not suitable to be used interchangeably to replace the 24-hour urine collection in the evaluation of urinary metabolic abnormalities in stone-formers. A good correlation does not translate to an agreement between the 2 measurements.