We studied the effects of varying degrees and durations of hypernatremia on the brain concentrations of organic compounds believed to be important, so-called "idiogenic" osmoles in rats by means of conventional biochemical assays, nuclear magnetic resonance spectroscopy, and high-performance liquid chromatography. There were no changes in the concentrations of these osmoles (specifically myoinositol, sorbitol, betaine, glycerophosphorylcholine [GPCI, phosphocreatine, glutamine, glutamate, and taurine) in rats with acute (2 h) hypernatremia (serum Na 194±5 meq/liter). With severe (serum Na 180±4 meq/liter) chronic (7 d) hypernatremia, the concentrations of each of these osmoles except sorbitol increased significantly: myoinositol (65%), betaine (54%), GPC (132%), phosphocreatine (73%), glutamine (143%), glutamate (84%), taurine (78%), and urea (191%). Together, these changes account for 35% of the change in total brain osmolality. With moderate (serum Na 159±3 meq/liter) hypernatremia, more modest but significant increases in the concentrations of each of these osmoles except betaine and sorbitol were noted. When rats with severe chronic hypernatremia were allowed to drink water freely, their serum sodium as well as the brain concentrations of all of these organic osmoles except myoinositol returned to normal within 2 d. It is concluded that: idiogenic osmoles play an important role in osmoregulation in the brain of rats subjected to hypernatremia; the development of these substances occur more slowly than changes in serum sodium; and the decrease in concentration of myoinositol occurs significantly more slowly than the decrease in serum sodium which occurs when animals are allowed free access to water. These observations may be relevant to the clinical management of patients with hypernatremia. (J.

As part of the Spare-the-Nephron trial, we evaluated the combination mycophenolate mofetil (MMF) and sirolimus (SRL) as a calcineurin inhibitor (CNI)-free regimen for the preservation of renal function in renal allograft recipients. This 2-year, open-label, multicenter trial randomized 299 patients of which 151 were maintained on MMF and a CNI, 148 on MMF plus SRL (n=120, tacrolimus; n=31, cyclosporine). Baseline characteristics including measured (iothalamate) glomerular filtration rate (GFR) were similar between groups. After 1 year, the mean percentage change from baseline in the primary end point of measured GFR was significantly higher in the MMF/SRL group compared with the MMF/CNI group. After 2 years, the change was indistinguishable. Calculated creatinine clearance and GFR were significantly greater with MMF/SRL at 2 years within which biopsy-proven acute rejection (BPAR) occurred in 14 MMF/SRL-treated patients (3 graft losses) and in 17 receiving the MMF/CNI (6 graft losses). Significantly, no patients receiving MMF/SRL but five treated with MMF/CNI died. Thus, compared with MMF/CNI treatment, a 2-year regimen of MMF/SRL resulted in similar measures of renal function but with fewer deaths and a trend to less BPAR and graft loss.

Osmotic injury induced by rapid correction of severe chronic hyponatremia has been implicated in the development of central pontine myelinolysis. Organic osmolytes known previously as "idiogenic osmoles" accumulate intracellularly to protect cells from osmotic injury. We investigated the changes of these organic osmolytes as well as electrolytes in the brain during the induction and correction of chronic hyponatremia. Using 'Hnuclear magnetic resonance spectroscopy and HPLC, we found that in rats with chronic hyponatremia (3 d, serum sodium = 109±3 meq/liter), brain concentrations of myoinositol (41%), glycerophosphorylcholine (45%), phosphocreatine/creatine (60%), glutamate (53%), glutamine (45%), and taurine (37%) were all significantly decreased compared with control values (percentage control value shown, all P < 0.01). The contribution of measured organic osmolytes and electrolytes to the total brain osmolality change was 23 and 72%, respectively. With rapid correction by 5% NaCI infusion, significant brain dehydration and elevation of brain Na and Cl levels above the normal range occurred at 24 h. These changes were not seen with slow correction by water deprivation. Reaccumulation of most organic osmolytes except glycerophosphorylcholine is delayed during the correction of hyponatremia and is independent ofthe correction rate of serum sodium. It is concluded that: most of the change of brain osmolality in chronic hyponatremia can be accounted by the changes in organic osmolytes and brain electrolytes; and rapid correction of hyponatremia is associated with an overshoot of brain sodium and chloride levels along with a low organic osmolyte level. The high cerebral ion concentrations in the absence ofadequate concentrations oforganic osmolytes may be relevant to the development of central pontine myelinolysis. (J. Clin. Invest. 1991. 88:303-309.)

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Thymoglobulin was found to be superior to Atgam in reversing acute rejection and preventing recurrent rejection after therapy in renal transplant recipients.