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Spot determinations of the urine creatinine concentration are widely used as a substitute for 24-h urine collections. Expressed as the amount excreted per gram of creatinine, urine concentrations in a single-voided sample are often used to estimate 24-h excretion rates of protein, sodium, potassium, calcium, magnesium, urea and uric acid. These estimates are predicated on the assumption that daily creatinine excretion equals 1 g (and that a urine creatinine concentration of 100 mg/dL reflects a 1 L 24-h urine volume). Such estimates are invalid if the serum creatinine concentration is rising or falling. In addition, because creatinine excretion is determined by muscle mass, the assumption that 24-h urine creatinine excretion equals 1 g yields a misleading estimate at the extremes of age and body size. In this review, we evaluate seven equations for the accuracy of their estimates of urine volume based on urine creatinine concentrations in actual and idealized patients. None of the equations works well in patients who are morbidly obese or in patients with markedly decreased muscle mass. In other patients, estimates based on a reformulation of the Cockroft–Gault equation are reasonably accurate. A recent study based on this relationship found a high strength of correlation between estimated and measured urine output with chronic kidney disease (CKD) studied in the African American Study of Kidney Disease (AASK) trial and for the patients studied in the CKD Optimal Management with Binders and NictomidE (COMBINE) trial. However, the equation systematically underestimated urine output in the AASK trial. Hence, an intercept was added to account for the bias in the estimated output. A more rigorous equation derived from an ambulatory Swiss population, which includes body mass index and models the non-linear accelerated decline in creatinine excretion with age, could potentially be more accurate in overweight and elderly patients. In addition to extremes of body weight and muscle mass, decreased dietary intake or reduced hepatic synthesis of creatine, a precursor of creatinine or ingestion of creatine supplements will also result in inaccurate estimates. These limitations must be appreciated to rationally use predictive equations to estimate urine volume. If the baseline urine creatinine concentration is determined in a sample of known volume, subsequent urine creatinine concentrations will reveal actual urine output as well as the change in urine output. Given the constraints of the various estimating equations, a single baseline timed collection may be a more useful strategy for monitoring urine volume than entering anthropomorphic data into a calculator.

Once the standard of care for cerebral edema, urea can also be used to treat hyponatremia. The 2014 European Clinical Practice Guidelines recommend urea for the treatment of the syndrome of inappropriate antidiuretic hormone, while discouraging use of vasopressin antagonists. Although there is evidence that urea can diminish hypertonic injury to brain cells caused by rapid correction of hyponatremia, clinical trials are needed that include patients at high risk to develop complications from overcorrection.

Hyponatremia exerts most of its clinical effects on the brain. An acute onset (usually in24 hours) of hyponatremia causes severe, and sometimes fatal, cerebral edema. Given time, the brain adapts to hyponatremia, permitting survival despite extraordinarily low serum sodium concentrations. Adaptation to severe hyponatremia is critically dependent on the loss of organic osmolytes from brain cells. These intracellular, osmotically active solutes contribute substantially to the osmolality of cell water and do not adversely affect cell functions when their concentration changes. The adaptation that permits survival in patients with severe, chronic (48 hours' duration) hyponatremia also makes the brain vulnerable to injury (osmotic demyelination) if the electrolyte disturbance is corrected too rapidly. The reuptake of organic osmolytes after correction of hyponatremia is slower than the loss of organic osmolytes during the adaptation to hyponatremia. Areas of the brain that remain most depleted of organic osmolytes are the most severely injured by rapid correction. The brain's reuptake of myoinositol, one of the most abundant osmolytes, occurs much more rapidly in a uremic environment, and patients with uremia are less susceptible to osmotic demyelination. In an experimental model of chronic hyponatremia, exogenous administration of myoinositol speeds the brain's reuptake of the osmolyte and reduces osmotic demyelination and mortality caused by rapid correction.

When chronic hyponatremia is rapidly corrected, reaccumulation of brain organic osmolytes is delayed and brain cell shrinkage occurs, leading to the osmotic demyelination syndrome (ODS). We hypothesized that treatment with myoinositol, a major organic osmolyte, could prevent ODS. Severe hyponatremia was induced in adult male rats by administration of arginine vasopressin and intravenous infusion of dextrose and water. Sixty-four hours after induction of hyponatremia, all animals underwent rapid correction of hyponatremia with infusion of hypertonic saline over 4 hours, increasing the serum sodium from 105 to 135 mM; half of the animals were also given myoinositol intravenously beginning 20 minutes before correction and continuing for 28 hours. Serum sodium concentrations were equivalent in both groups at all time points. At 7 days, 7 of 8 animals that received myoinositol survived compared with one of the 9 control animals (p < 0.01). In a second study, sodium was reduced to 106 mM over 64 hours in 24 animals and then corrected by 20 mM over 4 hours with concomitant loading and infusion of either mannitol (control) or myoinositol. Animals were killed 96 hours after correction of hyponatremia was begun. Myoinositol-treated animals had significantly fewer demyelinating lesions than mannitol (2.25 +/- 1.1 versus 6.42 +/- 1.4 lesions/brain, p < 0.03). We conclude that myoinositol administration improves survival and reduces myelinolysis after rapid correction of chronic hyponatremia in rats.

Pathogenesis of cerebral edema after treatment of diabetic ketoacidosis. We studied the roles of acidosis, plasma osmolality, and organic osmolytes in the pathogenesis of cerebral edema in an animal model of diabetes mellitus. Normonatremic rats with streptozotocin-induced nonketotic (NKD) and ketotic (DKA) diabetes were sacrificed before or after treatment with hypotonic saline and insulin. Brains were analyzed for water, electrolyte, and organic osmolyte content. Brain water decreased by 2% in untreated DKA and NKD despite a 12% increase in plasma osmolality due to hyperglycemia. After treatment of both NKD and DKA, brain water increased equivalently by 8%. The cerebral edema that occurred after treatment was associated with decreased brain sodium content and no change in total major brain organic osmolytes in both NKD and DKA. However, brain content of the individual osmolytes glutamine and taurine increased after treatment of DKA. In a separate study, brain water and solute content of rats with DKA were compared after treatment with either hypotonic or isotonic fluid. Animals treated with isotonic fluid had significantly less cerebral edema and higher brain sodium content than those treated with hypotonic fluid. In our studies, brain swelling after treatment of DKA and NKD was primarily due to a rapid reduction of plasma glucose and osmolality, and was not caused by sodium movement into the brain. Acidosis did not appear to play a major role in the pathogenesis of cerebral edema after treatment of DKA.

The pathogenesis of brain swelling and neurological deterioration after rapid hemodialysis (dialysis disequilibrium syndrome) is controversial. The "reverse urea hypothesis" suggests that hemodialysis removes urea more slowly from the brain than from the plasma, creating an osmotic gradient that results in cerebral edema. The "idiogenic osmole hypothesis" proposes that an osmotic gradient between brain and plasma develops during rapid dialysis because of newly formed brain osmoles. In this review, the experimental basis for the two hypotheses are critically examined. Based on what is known about the physiology of urea and water diffusion across the blood-brain barrier, and empiric observations of brain solute composition after experimental hemodialysis, we conclude that the "reverse urea hypothesis" remains a viable explanation for dialysis disequilibrium and that rapid reduction of a high urea level in and of itself predisposes to this condition.

Dialysis disequilibrium syndrome (DDS) is characterized by the neurologic deterioration and cerebral edema that occurs after hemodialysis. To investigate the pathogenesis of DDS, the effects of rapid hemodialysis on brain electrolytes, urea, and several organic osmolytes were studied in the rat. Forty-two h after bilateral ureteral ligation, 11 uremic rats were hemodialyzed for 90 min, yielding a decrease in plasma urea from 96 +/- 4 to 44 +/- 5 mM (p < 0.01). This group was compared with 10 uremic and 11 nonuremic animals that were not dialyzed. In dialyzed animals, compared with nondialyzed uremic controls, there was an increase in brain water (3.98 +/- 0.02 versus 3.77 +/- 0.02 L/kg dry wt; P < 0.01) and the brain to plasma (urea) ratio (1.32 versus 0.65). There was no significant difference in the brain content of sodium and potassium between groups. The retention of brain urea, despite the large decrease in plasma urea concentration, was able to account for the increase in brain water observed in rapidly dialyzed animals. Major organic osmolytes in the brain, including glutamine, glutamate, taurine and myoinositol, did not increase significantly after rapid dialysis. Cerebral edema in this model of DDS was primarily due to a large brain-to-plasma urea gradient, not to the formation of organic osmolytes.

Background Prompt correction of severe hyponatremia is important, but correction also must be limited to avoid iatrogenic osmotic demyelination. Expert opinion recommends that serum sodium level not be increased by more than 10-12 mEq/L in any 24-hour period and/or 18 mEq/L in any 48-hour period. However, inadvertent overcorrection is common, usually caused by the unexpected emergence of a water diuresis. Study Design Quality improvement report. Setting & Participants All 25 patients admitted to a community teaching hospital between October 1, 2008, and September 30, 2011, who were treated for serum sodium level Quality Improvement Plan Concurrently administered desmopressin (1-2 µg parenterally every 6-8 hours) and hypertonic saline with weight-based doses adjusted to increase the serum sodium concentration by 6 mEq/L, avoiding inadvertent overcorrection of severe hyponatremia. Outcomes Rate of correction of hyponatremia, predictability of response to the combination, adverse events related to therapy. Measurements Rate of correction of hyponatremia at 4, 24, and 48 hours; administered dose of 3% saline solution, salt tablets, and potassium; predicted increase in serum sodium level. Results Mean changes in serum sodium levels during the first and second 24 hours of therapy were 5.8 ± 2.8 (SD) and 4.5 ± 2.2 mEq/L, respectively, without correction by >12 mEq/L in 24 hours or >18 mEq/L in 48 hours and without a decrease during therapy. There was no significant difference between actual and predicted increases during the first 24 hours. There was no adverse effect associated with therapy. Limitations Without concurrent controls, we cannot be certain that outcomes are improved. Balance studies were not performed. Conclusions Combined 3% saline solution and desmopressin appears to be a valid strategy for correcting severe hyponatremia, but studies comparing the regimen with other therapeutic strategies are needed.

We review literature from the past 18 months on the treatment of hyponatremia. Therapy must address both the consequences of the untreated electrolyte disturbance (including fatal cerebral edema due to acute water intoxication) and the complications of excessive therapy (the osmotic demyelination syndrome).Correction of hyponatremia by 4-6 mEq/l within 6 h, with bolus infusions of 3% saline if necessary, is sufficient to manage the most severe manifestations of hyponatremia. Planning therapy to achieve a 6 mEq/l daily increase in the serum sodium concentration can avoid iatrogenic brain damage by staying well clear of correction rates that are harmful. Conservative correction goals are wise because inadvertent overcorrection is common. Administration of desmopressin to halt a water diuresis can help prevent overcorrection; if overcorrection occurs, therapeutic relowering of the serum sodium concentration is supported by data in experimental animals and was found to be safe in a small observational clinical trial. Even mild and apparently asymptomatic hyponatremia may lead to falls because of impaired gait, and an increased likelihood of fracture because of hyponatremia-induced osteoporosis, a newly described entity. Recently approved vasopressin antagonists now make it possible to normalize the serum sodium concentration on a chronic basis, but practical considerations have limited their use.

It was recently demonstrated that renal failure and exogenous urea prevent myelinolysis induced by rapid correction of experimental hyponatremia. To determine why elevated blood urea levels favorably affect brain tolerance to osmotic stress, the changes in brain solute composition that occur when chronic hyponatremia is rapidly corrected were studied in rats with or without mercuric chloride-induced renal failure. After 48 h of hyponatremia, the brains of azotemic and nonazotemic animals became depleted of sodium, potassium, and organic osmolytes. Twenty-four hours after rapid correction of hyponatremia, the brains of animals without azotemia remained depleted of organic osmolytes, with little increase in myo-inositol or taurine contents above those observed in animals with uncorrected hyponatremia; brain electrolytes were rapidly reaccumulated, increasing the brain sodium content to a level 17% higher than values for normonatremic control animals. In contrast, within 2 h after correction of hyponatremia, brain myo-inositol contents in azotemic rats returned to control levels and brain taurine levels were significantly higher than those in azotemic animals with uncorrected hyponatremia (16.5 versus 9 micromol/g dry weight). There was no "overshooting" of brain sodium and water contents after rapid correction in the azotemic animals. Rapid reaccumulation of brain organic osmolytes after correction of hyponatremia could explain why azotemia protects against myelinolysis.

An acute increase in plasma tonicity results in an adaptive increase in brain organic osmolyte content, but this process requires several days to occur. Slow reaccumulation of brain organic osmolytes may contribute to osmotic demyelination. It was investigated whether administration of intravenous myoinositol in rats could speed entry of the osmolyte into the brain. Two groups of animals were studied: normonatremic animals and animals with hyponatremia (105 mmol/L) of 3-d duration. Animals were intravenously administered either 1 M NaCl to induce a 25 to 28 mM increase in serum sodium concentration over 200 min or an infusate that maintained serum sodium concentration. In some animals, myoinositol was administered intravenously over the same time period to raise plasma myoinositol levels by 5 to 10 mM. Brain myoinositol, electrolyte, and water contents were determined at the end of the infusions. In both normonatremic and hyponatremic rats, infusion of hypertonic saline without myoinositol or infusion of myoinositol without hypertonic saline did not increase brain myoinositol levels above control levels. In normonatremic animals, concurrent infusion of hypertonic saline and myoinositol increased brain myoinositol levels by about 50% above control levels. Brain myoinositol content in animals with uncorrected hyponatremia was about 50% of that found in normonatremic controls; concurrent infusion of hypertonic saline and myoinositol increased brain myoinositol to levels similar to those found in normonatremic controls. Intravenous infusion of myoinositol did not alter brain water content compared with animals not infused with myoinositol. In conclusion, systemic infusion of myoinositol can rapidly increase brain myoinositol content, but only when plasma tonicity is concomitantly increased.

Brain swelling after acute hyponatremia in prepubescent rats, in contrast to adults, has recently been associated with an increase in brain sodium and a high mortality that could be prevented by preadministration of testosterone. To reexamine the effect of acute hyponatremia in young brain, we measured brain water and solute content in prepubescent rats after induction of hyponatremia over 4 h with water and arginine vasopressin. An 18% decrease in plasma sodium was associated with a 13% increase in brain water and a decrease in brain sodium and glutamate contents. No animals died. To assess the effect of sex hormones on brain adaptation, prepubescent rats were pretreated with estrogen or testosterone before acute hyponatremia. Brain sodium and potassium contents were significantly reduced in comparison to normonatremia in testosterone-pretreated but not estrogen-pretreated animals. However, there was no difference between estrogen-pretreated and testosterone-pretreated groups in mortality or in brain contents of water, electrolytes, or major organic osmolytes. In conclusion, we found that brain adaptation to acute hyponatremia in prepubescent rats is similar to that observed in adults.

Glycine-induced hyponatremia in the rat: A model of post-prostatectomy syndrome. Post-prostatectomy syndrome (PPS) is characterized by hyponatremia after absorption of glycine irrigant. To study the pathogenesis of this syndrome, adult male rats with ligated ureters were infused over 15 minutes with 7.5 ml/100 g body weight of isosmotic glycine (N = 9) or mannitol (N = 9) and were compared to non-infused, ureter-ligated controls (N = 9). Immediately post-infusion, plasma sodium had decreased similarly in glycine- and mannitol-infused animals (111 ± 2 vs. 106 ± 1 mmol/liter), but plasma osmolality remained at control levels in both groups (285 ± 1 vs. 288 ± 1 mOsm/kg). Two hours post-infusion, hyponatremia was stable in the mannitol group (108 ± 1 mmol/iter), but in the glycine group plasma sodium increased significantly (to 120 ± 1 mmol/liter). Plasma osmolality two hours post-infusion was maintained in both the glycine (287 ± 2) and mannitol (292 ± 2) groups. Brain water in glycine-infused animals (3.90 ± 0.01 liter/kg dry wt) was not significantly different from the mannitol-infused group (3.85 ± 0.01) and only 1.8% higher than non-infused controls (3.83 ± 0.02). Brain tissue glycine did not differ between the three groups. In contrast, muscle water two hours post-infusion in the glycine group was 6% higher than mannitol-infused and 13% higher than non-infused animals. Muscle glycine content in the glycine group (67 ± 4 mM/kg dry tissue) was increased when compared to both mannitol-infused (25 ± 1) and non-infused (20 ± 1) groups. Plasma ammonia and brain glutamine were significantly increased in glycine-infused animals. In a second set of studies, infusion of 7.5 ml/100 g body weight of 1.5% (200 mmol/liter) glycine caused only a non-significant increase in brain water. In conclusion, in a model of PPS in rats, acute hyponatremia induced by intravenous isosmotic glycine did not decrease plasma osmolality. Hyponatremia induced by isosmotic or hypoosmotic glycine caused minimal brain edema.

Dialysis disequilibrium syndrome (DDS) in the rat: Role of the reverse urea effect. DDS is characterized by neurologic deterioration and cerebral edema which occurs after hemodialysis. To investigate the pathogenesis of DDS, we studied the effects of rapid hemodialysis on plasma and brain electrolytes, urea, and osmolality in the rat. Forty-two hours after bilateral nephrectomy, nine uremic rats were hemodialyzed for 90 minutes against dialysate without urea (model of DDS), yielding a decrease in plasma urea from 72 ± 2mM to 34 ± 2mM (P < 0.01) and an 8% (29mOsm/kg) decrease in plasma osmolality. This group was compared to three control groups: 11 uremic animals dialyzed against a bath with urea added so that no fall in plasma urea occurred, and 15 uremic and 12 nonuremic animals that were not dialyzed. In animals dialyzed without urea, compared to uremic non-dialyzed animals, there was a 6% increase in brain water (3.89 ± 0.04 liter/kg dry wt vs. 3.67 ± 0.03, P < 0.01) and an increase in the brain to plasma (urea) ratio (1.30 ± 0.06 vs. 0.79 ± 0.05, P < 0.01). Comparison of these parameters in animals dialyzed without urea versus other control groups yielded similar results. In animals dialyzed without urea, the 53% decrease in plasma urea was associated with only a 13% decrease in brain urea content. Brain content of sodium and potassium was not significantly different among groups. Retention of brain urea despite the large decrease in plasma urea was able to account for the increased brain water observed in animals dialyzed without urea. The brain to plasma osmolality ratio in animals dialyzed without urea (1.00 ± 0.04) was not significantly different from the three control groups. We conclude that the cerebral edema in our model of DDS appears primarily due to a large brain to plasma urea gradient.