Creatine and Creatinine Metabolism - Physiological Reviews

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1172 MARKUS WYSS AND RIMA KADDURAH-DAOUK Volume 80 nal injection into rabbits (433). Crn also had convulsive activity after intracerebroventricular administration in mice (164). The relevance of these findings is questionable since intracisternal or intracerebroventricular injection cannot be compared directly with oral or intravenous administration of these compounds. In mouse spinal cord neurons in primary dissociated cell culture, Crn, MG, guanidine, GSA, and some other guanidino compounds depressed GABA and Gly responses in a concentration-dependent manner, possibly by blocking the chloride channel (164, 167). The accompanying reduction in GABA- and Gly-dependent inhibition may lead to epilepsy. GSA, in contrast to Crn, MG, and guanidine, displayed significant effects at concentrations similar to those in cerebrospinal fluid and brain of uremic patients. The relative potencies with which the studied guanidino compounds depressed inhibitory amino acid responses corresponded with the relative potencies of the same compounds to induce epileptic symptomatology in behavioral experiments. MG, which is increased in uremia, may contribute to the neurological symptoms also by inhibiting acetylcholinesterase and/or Na � -K � -ATPase (609, 610). Some evidence suggests that guanidino compounds may exert their effects by influencing membrane fluidity. The lipid composition, including cholesterol concentration, is abnormal in epileptogenic whole brain tissue from cobalt lesions in animals, and dietary cholesterol appears to be inversely related to seizure susceptibility in animal models (see Ref. 696). Cholesterol administration normally is associated with a decrease in membrane fluidity (552, 705). Membranes from epileptogenic freeze-lesioned cat brain cortex displayed a lower order parameter (i.e., slightly higher fluidity) than control membranes (696). In contradiction to these results, guanidino compounds including MG, GSA, guanidine, and GPA decrease synaptosomal membrane fluidity of rat cerebral cortex, whereas anticonvulsant drugs, including diazepam, valproic acid, and phenobarbital, increase the fluidity of synaptosomal membranes in hippocampus and whole brain (see Ref. 361). Guanidino compounds may not only be a trigger of epileptic seizures, but may also change in concentration during and after convulsions. Already in 1940, Murray and Hoffmann (680) noted that “in the instances of essential epilepsy studied, the basal content of ‘guanidine’ in the blood was found significantly high. All who presented convulsions of the grand mal variety showed a blood guanidine rise during the aura reaching a high point during convulsion.” The levels of guanidinoacetate and Crn in cerebrospinal fluid increased at the onset of pentylenetetrazol-induced convulsion in the rabbit, while Arg started to decrease 2 h after the convulsion (360). Similarly, MG and guanidinoacetate levels in the rat brain were elevated for up to 3 mo after amygdala or hippocampal kindling, whereas Cr and Arg showed no significant change (362, 885). In rodent, piglet, or dog brain, upon single and repeated seizures induced by either electroshock, flurothyl, or pentylenetetrazol, or in bicuculline-induced status epilepticus, PCr concentration in the brain decreased with seizure activity (see Refs. 198, 373–375, 849). The change in PCr was associated with a corresponding increase in Cr content so that total Cr concentration remained constant. Although it is widely accepted that the Cr-to-N-acetylaspartate ratio is significantly elevated in patients with temporal lobe epilepsy (e.g., Refs. 136, 146, 385, 761), it is not yet clear whether total Cr concentration in the brain is also increased (146) or unchanged (2, 761, 1034). In conclusion, the evidence for relationships between alterations in Cr metabolism and neurological symptoms in uremia is indirect and incomplete at present and, thus, needs further substantiation in the future. Although guanidino compounds may have adverse effects on the nervous system in uremia, oral Cr (or cCr) supplementation is very unlikely to induce neurological complications in normal individuals, since only slight alterations in cerebrospinal fluid and brain concentrations of guanidino compounds may be expected. Cr and its analogs have been given to animals in high amounts and over several weeks and months with no neurological side effects. Likewise, oral Cr supplementation in humans with up to 30 g/day for several days as well as cCr administration in a phase I/II clinical study in gram amounts per day over an extended period of time also had no adverse neurological effects. Finally, disturbances in Cr or guanidino compound metabolism were also seen in AIDS dementia (86); in patients with affective disorders, where, for example, Crn concentration in the cerebrospinal fluid was suggested to be negatively correlated with suicidal ideation and appetite (467, 704, 880); in hyperargininemic patients (595, 596); in the human brain after acute stroke (284); in brain tumors such as gliomas, astrocytomas, and meningiomas (488, 594); in the brain of dystrophin-deficient mdx mice (1014); in audiogenic sensitive rats (1103); or in rats intoxicated with the neurotoxins ethylene oxide or acrylamide (612). In summary, brain function seems to be linked in a number of different ways with the CK system and with Cr metabolism, although the causal relationships in many cases are not yet known. Preliminary data suggest that both Cr and Cr analogs may have a therapeutic potential in brain disease. Cr supplementation, despite relatively slow uptake of Cr into the brain, may be indicated in diseases characterized by decreased brain concentrations of Cr or slowed PCr recovery. Cr and its analogs may also turn out to have therapeutic effects in neurodegenerative diseases associated with oxidative stress, such as Alzheimer’s disease, Parkinson’s disease, or amyotrophic lateral sclerosis.
July 2000 CREATINE AND CREATININE METABOLISM 1173 H. Creatin(in)e Metabolism and Renal Disease The kidney plays a crucial role in Cr metabolism (see Fig. 4). On one hand, it is a major organ contributing to guanidinoacetate synthesis. On the other hand, it accomplishes urinary excretion of Crn, the purported end product of Cr metabolism in mammals. In chronic renal failure (CRF) rats, the renal AGAT activity and rate of guanidinoacetate synthesis are depressed (520, 554). Accordingly, the urinary excretion of guanidinoacetate is decreased in a variety of renal diseases (10, 77, 412, 598, 969). Although the serum concentration of guanidinoacetate was also shown to be decreased in both uremic patients and renal failure rats (39, 412, 520, 598, 747), it was found, in a few other studies, to be unchanged (10, 165, 168, 638) or even slightly increased (163, 757). These conflicting results may be due to compensatory upregulation of guanidinoacetate synthesis in the pancreas, to different degrees of depression of urinary guanidinoacetate excretion, to unknown effects of peritoneal or hemodialysis, and/or to different stages of disease progression. Similarly conflicting results were obtained for the serum concentration of Cr in uremic patients. It was found to be increased (163, 165, 412, 598, 757, 877), unchanged (165, 598), or even depressed relative to control subjects (168). The latter finding may be due to dialysis of these patients, which was shown to decrease the serum concentration of Cr (169, 877). Both the erythrocyte concentration of Cr (even after hemodialysis) and the urinary excretion of Cr may be increased in uremia (77, 412, 877), although in one study decreased urinary Cr clearance was observed (598). In striated muscle of uremic patients, the concentrations of PCr and ATP are decreased (716), whereas those of Cr and P i are increased (99), thus suggesting that intracellular generation of high-energy phosphates is impaired. The most consistent, and clinically most relevant, findings are an increase in the serum concentration and a decrease in the renal clearance of Crn with the progression of renal disease. Crn clearance (C Crn; in ml/min) is defined as C Crn � U Crn � V P Crn where U Crn and P Crn are the urine and serum concentrations of Crn, respectively, and V is the urine flow rate (in ml/min). Both the serum concentration of Crn and Crn clearance have been, and still are, widely used markers of renal function, in particular of the glomerular filtration rate (GFR). The validity of this approach critically depends on the assumptions that Crn is produced at a steady rate, that it is physiologically inert, and that it is excreted solely by glomerular filtration in the kidney. In recent years, these assumptions were shown to be invalid under uremic conditions, and several factors have been identified that may result in gross overestimation of the GFR (see, e.g., Refs. 108, 358, 536, 758, 791). For example, an increasing proportion of Crn in CRF is excreted by tubular secretion rather than glomerular filtration. Another factor contributing to the overestimation of the GFR seems to be degradation of Crn in the human and animal body. Jones and Burnett (438) and Walser and co-workers (652, 1085) in fact showed, by calculating Crn balances, that 16–66% of the Crn formed in patients with CRF cannot be accounted for by accumulation in the body or by excretion in urine or feces. The most likely explanation for this apparent “Crn deficit” or “extrarenal Crn clearance” is Crn degradation. Whereas the normal renal Crn clearance is �120 ml/min, the renal and extrarenal Crn clearances in CRF patients were calculated to be �3–5 and 1.7–2.0 ml/min, respectively. Therefore, Crn degradation may be negligible in healthy individuals, which led to the postulate that Crn is physiologically inert, but it may become highly relevant under conditions of impaired renal function. Several pathways for Crn degradation have to be considered. 1) Up to 68% of the metabolized Crn may be reconverted to Cr (652). To this end, Crn is most likely excreted into the gut where it is converted by bacterial creatininase to Cr which, in turn, is retaken up into the blood (“enteric cycling”) (439). This pathway may be a powerful means for limiting Crn toxicity (see below) and may also explain in part why the serum concentration of Cr is increased in many patients with CRF. 2) Bacterial degradation of Crn in the gut may not be limited to the conversion to Cr but may proceed further. 1-Methylhydantoin, Cr, sarcosine, methylamine, and glycolate were identified as degradation products when rat and human colon extracts or feces were incubated with Crn (439, 745). Upon incubation of colon extracts with radioactively labeled 1-methylhydantoin, however, no decomposition products were observed. These findings suggest at least two independent Crn degradation pathways: a) Crn 3 1-methylhydantoin, catalyzed most likely by bacterial Crn deaminase; and b) Crn 3 Cr 3 urea � sarcosine 3 methylamine � glyoxylate 3 glycolate, with the first two steps probably being catalyzed by bacterial creatininase and creatinase (see also Fig. 7). Last but not least, Pseudomonas stutzeri, which may be present in human gut, produces MG when incubated with Crn, both under aerobic and anaerobic conditions (1049). Accordingly, rat colon extracts proved to convert Crn to MG (437). In support of these Crn degradation pathways, creatininase activity was recently shown to be increased considerably in the feces of patients with CRF (204). Crn degradation was lower in stool isolates of CRF patients
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