Accumulation of uremic solutes in the cerebrospinal fluid in experimental acute renal failure.

The accumulation of uremic solutes in kidney failure may impair mental function. The present study profiled the accumulation of uremic solutes in the cerebrospinal fluid (CSF) in acute renal failure. CSF and plasma ultrafiltrate were obtained from rats at 48 h after sham operation (control; n = 10) or bilateral nephrectomy (n = 10) and analyzed using an established metabolomic platform. Two hundred forty-eight solutes were identified as uremic based on their accumulation in the plasma ultrafiltrate of nephrectomized compared with control rats. CSF levels of 124 of these solutes were sufficient to allow calculation of CSF-to-plasma ultrafiltrate concentration ratios. Levels of many of the uremic solutes were normally lower in the CSF than in the plasma ultrafiltrate, indicating exclusion of these solutes from the brain. CSF levels of the great majority of the uremic solutes increased in renal failure. The increase in the CSF was, however, relatively less than in the plasma ultrafiltrate for most solutes. In particular, for the 31 uremic solutes with CSF-to-plasma ultrafiltrate ratios of <0.25 in control rats, the average CSF-to-plasma ultrafiltrate ratio decreased from 0.13 ± 0.07 in control rats to 0.09 ± 0.06 in nephrectomized rats, revealing sustained ability to exclude these solutes from the brain. In summary, levels of many uremic solutes are normally kept lower in the CSF than in the plasma ultrafiltrate by the action of the blood-brain and blood-CSF barriers. These barriers remain functional but cannot prevent accumulation of uremic solutes in the CSF when the kidneys fail.

Treatment of two cases on the same day of intrathecal methotrexate overdose using cerebrospinal fluid exchange and intrathecal instillation of carboxypeptidase-G2.

BACKGROUND: Two 14-year old boys with acute lymphocytic leukemia were treated according to the NOPHO-ALL-08 protocol with intrathecal methotrexate (MTX) on the same day. Due to a preparation error in the hospital pharmacy, they were both given 240 mg of MTX instead of the prescribed 12 mg. Treatment (or methods): Both patients developed acute neurotoxicity with confusion, pain and seizures. Intravenous dexamethasone and folinic acid (leucovorin) was given. Exchange of cerebrospinal fluid was performed. Intrathecal glucarpidase (carboxypeptidase-G2) was administered after 11 h. RESULTS: One patient developed a toxic arachnoiditis. Three years after the incident, one patient has no neurological or neuropsychological sequelae after the overdose, while the other reports some loss of short-term memory. CONCLUSION: Fast recognition and treatment of intrathecal MTX overdose is critical to survival and outcome. Efforts to prevent such overdoses are of vital importance.

Bath salt intoxication causing acute kidney injury requiring hemodialysis.

Traditional bath salts contain a combination of inorganic salts like Epsom salts, table salt, baking soda, sodium metaphosphate, and borax that have cleansing properties. Since 2010, there have been rising concerns about a new type of substance abuse in the name of "bath salts." They are beta-ketone amphetamine analogs and are derivates of cathinone, a naturally occurring amphetamine analog found in the "khat" plant (Catha edulis). Effects reported with intake included increased energy, empathy, openness, and increased libido. Serious adverse effects reported with intoxication included cardiac, psychiatric, and neurological signs and symptoms. Not much is known about the toxicology and metabolism of these compounds. They inhibit monoamine reuptake (dopamine, nor epinephrine, etc.) and act as central nervous system stimulants with high additive and abuse potential because of their clinical and biochemical similarities to effects from use of cocaine, amphetamine, and 3,4-methylenedioxy-N-methylamphetamine. Deaths associated with use of these compounds have also been reported. We report a case of acute kidney injury associated with the use of "bath salt" pills that improved with hemodialysis.

Decreased lithium disposition to cerebrospinal fluid in rats with glycerol-induced acute renal failure.

PURPOSE: The lithium disposition to cerebrospinal fluid (CSF) was evaluated in rats with acute renal failure (ARF) to examine whether electrolyte homeostasis of the CSF is perturbed by kidney dysfunction. In addition, the effects of renal failure on choroid plexial expressions of the Na+-K+-2Cl- co-transporter (NKCC1) and Na+/H+ exchanger (NHE1) were also studied. METHODS: After lithium was intravenously administered at a dose of 4 mmol/kg, its concentration profile in plasma was evaluated by collecting plasma specimens, while that in CSF was monitored with a microdialysis probe in the lateral ventricles. NKCC1 and NHE1 expressions were measured via the Western immunoblot method using membrane specimens prepared from the choroid plexus in normal and ARF rats. RESULTS: The lithium concentration in CSF of ARF rats was 30% lower than that of normal rats, while their plasma lithium profiles were almost the same, indicating that the lithium disposition to CSF was decreased in ARF rats. It was revealed that the choroid plexial expression of NKCC1 was increased by 40% in ARF rats, but that of NHE1 was unchanged. CONCLUSION: ARF decreases the lithium disposition to CSF, possibly by promoting lithium efflux from CSF due to increased NKCC1 expression in the choroid plexus.

Effect of acute renal failure on the distribution of iomeprol, a nonionic contrast agent, to cerebrospinal fluid in rats.

The effect of acute renal failure on the pharmacokinetics concerning the cerebrospinal fluid (CSF) distribution of iomeprol, a nonionic contrast agent, was studied. The concentrations of iomeprol in the plasma and CSF were measured after intravenous (i.v.) administration at the dose of 50 or 500 mg/kg body weight. The time courses of plasma and CSF concentration were linear within the dose studied. Influx and efflux clearances estimated by simultaneous fitting were 4.6 x 10(-5) ml/min and 8.8 x 10(-4) ml/min, respectively, which suggested that the distribution of iomeprol to CSF low and linear. The distribution volume at steady state was 300-500 ml/kg, suggesting that iomeprol was readily distributed to the extracellular space but hardly distributed to the intercellular space. Total body clearance (9-13 ml/min/kg) indicated that iomeprol was mainly excreted by glomerular filtration. In the rat with acute renal failure induced by ligating the binary ureters, the concentration of iomeprol in CSF after i.v. administration of 500 mg/kg dose was much higher than that in the intact rat according to the delay of elimination from plasma (CLtot = 0.07 ml/min/kg). However, the time course of iomeprol concentration in CSF was predictable using the values of the influx clearance to CSF and the efflux clearance from CSF determined by intact rats. In conclusion, renal failure is one risk factor for central nervous system toxicity because of decreased total body clearance, while acute renal failure may not affect the transport of iomeprol to CSF.

Kinetics of drug action in disease states. II. Effect of experimental renal dysfunction on phenobarbital concentrations in rats at onset of loss of righting reflect.

The purpose of this investigation was to determine if renal dysfunction is associated with an alteration in the concentration-pharmacologic activity relationship of phenobarbital (PB). Adult female rats (congruent to 200 g) were pretreated with uranyl nitate or subjected to bilateral ureteral ligation to produce renal dysfunction. Saline-injected and sham-operated rats, respectively, served as controls. PB (0.824 mg/min) was infused i.v. until the animals lost their righting reflex (LRR). Renal dysfunction reduced the total dose of PB required to produce LRR, the concentrations of total and free (unbound) PB in serum and the concentrations of PB in brain and cerebrospinal fluid at onset of LRR. Results were quantitatively similar in both experimental models of impaired renal function. Concomitant infusion of p-hydroxyphenobarbital (the major metabolite of PB) and PB in rats with uranyl nitrate-induced renal dysfunction had no effect on the PB concentrations at onset of LRR. When PB was infused at different rates (either 0.412, 0.824, 2.04 or 4.12 mg/min), rats with renal dysfunction had increasing concentrations of PB at onset of LRR with increasing infusion rate, not only in serum and brain but also (unlike normal rats) in cerebrospinal fluid. Thus, renal dysfunction is associated with increased sensitivity to PB and with a change in the kinetic relationship between PB in cerebrospinal fluid and in the biophase.

Changes in the electroencephalogram in acute uremia. Effects of parathyroid hormone and brain electrolytes.

Studies were carried out in order to evaluate the effects of changes in brain calcium and the influence of parathyroidectomy and administration of parathyroid extract on the electroencephalogram (EEG) of normal and uremic dogs. Manual analysis of frequency and power distribution of the EEG in uremic dogs revealed a significant increase in both the percentage distribution and the area or power occupied by frequencies below 5 Hz. In addition, high amplitude bursts of delta activity were apparent in the uremic dog. These changes were largely prevented by parathyroidectomy before the induction of uremia, but the administration of parathyroid extract to either normal dogs, or to previously parathyroidectomized uremic dogs, induced EEG changes similar to those noted in uremic animals with intact parathyroid glands. In all groups of animals which showed EEG changes, brain content of calcium was significantly higher than in either normal dogs or previously parathyroidectomized uremic dogs. Changes in arterial pH and bicarbonate, or in the concentrations of Na+, K+, urea, or creatinine in plasma or cerebrospinal fluid were similar in uremic animals with intact parthyroid glands and in previously parathyroidectomized uremia dogs. The results indicate that the EEG changes found in dogs with acute renal failure require the presence of excess parathyroid hormone in blood, and they may be related to the observed changes in brain content of calcium.

Calcium metabolism of brain in acute renal failure. Effects of uremia, hemodialysis, and parathyroid hormone.

Studies were carried out to evaluate the changes in content of calcium and magnesium in brain during acute uremia in dogs. Ca content in gray and white matter of brain increased significantly after 3 days of acute uremia and this increment was prevented by thyroparathyroidectomy (TPTX). The administration of parathyroid extract (PTE) to normal dogs and TPTX uremic animals produced a significant rise in brain Ca. These changes were not related to alteration in the concentration of Ca in plasma or cerebrospinal fluid, to changes in calcium-phosphorus product, or to changes in blood pH. Furthermore, the infusion of large amounts of phosphate to vitamin D2-treated animals with suppressed parathyroid gland activity produced marked elevation in calcium-phosphorus product but no significant change in brain Ca. Also, uremia in vitamin D2-treated TPTX dogs failed to increase calcium content in brain despite marked elevation in calcium-phosphorus product. Hemodialysis significantly reduced Ca content of brain but the values were still significantly higher than normal. Mg content increased modestly only in the white matter of uremic dogs with intact parathyroid glands and in normal dogs and TPTX uremic dogs receiving PTE. The results indicate that (a) acute uremia of 3 days is associated with a marked rise of Ca content of brain and modest increment of Mg in certain parts of the brain, and (b) these alterations are not related to uremia, per se, but are dependent on the presence of excess parathyroid hormone. It is suggested that the neurological abnormalities noted in acute uremia may be related in part to the rise in the Ca content of brain.