Creatine excretion

The output of creatinine remains relatively constant, because muscle creatine phosphate concentration is relatively constant and a given portion is converted to creatinine, which is then excreted. Thus, the amount of creatine excreted over a 24-hour period is fairly constant this is of clinical advantage when studying single collections of urine. In clinical laboratories, clinicians measure the amount of material being examined in urine per gram of creatinine in the urine. This partially corrects for dilution of the urine when there is a large fluid intake, or concentration of the urine sample if fluid intake is markedly decreased. Since most of the creatinine is excreted in the urine, a marked increase in blood creatinine is usually indicative of kidney disorder. 

During the past eight years the analyses for urinary creatine excretion has been performed almost every month. Many of the depleted individuals... 

The basis of this relationship is that urinary creatinine is the only degradation product of creatine phosphate [338] that cardiac and skeletal muscle contribute more than 90% of body creatine [346] and that creatine phosphate to creatinine degradation occurs at a fixed rate (non-enzymatically) [347]. Thus normally, the rates of formation and excretion of urinary creatinine would depend on the size and turnover rate of the creatine pool, and the relationship between muscle mass and creatine excretion would depend primarily on muscle creatine content. 

A test for the investigation of myopathies in which creatine is given orally and its output in the urine is measured. Increased urine creatine excretion (i.e. reduced tolerance) is found when the muscle mass is reduced or the muscle is unable to take up creatine (e.g. hyperthyroidism and muscular dystrophy). Decreased urinary creatine excretion (i.e. increased tolerance) is. found in hypothyroidism. 

Burke, D.G., T. Smith-Palmer, L.E. Holt, B. Head, and ED. Chilibeck, The effect of 7 days of creatine supplementation on 24-hour urinary creatine excretion. J Strength CondRes, 15 59-62, 2001. 

Description of Method. Creatine is an organic acid found in muscle tissue that supplies energy for muscle contractions. One of its metabolic products is creatinine, which is excreted in urine. Because the concentration of creatinine in urine and serum is an important indication of renal function, rapid methods for its analysis are clinically important. In this method the rate of reaction between creatinine and picrate in an alkaline medium is used to determine the concentration of creatinine in urine. Under the conditions of the analysis, the reaction is first-order in picrate, creatinine, and hydroxide. 

Creatinine is formed in muscle from creatine phosphate by irreversible, nonenzymatic dehydration and loss of phosphate (Figure 31-6). The 24-hour urinary excretion of creatinine is proportionate to muscle mass. Glycine, arginine, and methionine all participate in creatine biosynthesis. Synthesis of creatine is completed by methylation of guanidoacetate by S-adenosylmethio-nine (Figure 31-6). 

The underlying biochemical defect is a failure of mitochondrial uptake of ornithine. This results in a failure of citrulline synthesis and a consequent hyperammonemia. Urinary orotic acid is high, presumably because of underutilization of carbamyl phosphate. In contrast, excretion of creatine is low, reflecting the inhibition of glycine trans-amidinase by excessive levels of ornithine. 

Urinary excretion patterns of six individuals. Gu = glucose C = creatine ... 

With respect to amino acid excretion Woodson and co-workersl3 and othersl4,15 have found by microbiological methods large variations. Stein 16 obtained evidence of wide variations in the amino acid excretion of cystinurics. Further data are also available with respect to creatine and creatinine excretion which bear out our conclusion regarding individuality of excretion patterns. 17,18,19... 

A number of clinical tests are available to detect kidney damage. The clinician examining a patient or the toxicologist monitoring an animal toxicity stndy collects urine and blood samples. Indications of kidney damage (which, of course, for the human patient could be related to many factors other then chemical toxicity) include urinary excretion of excessive amonnts of proteins and glucose, and excessive levels in the blood of unexcreted waste products such as urea and creatine. A number of additional kidney function tests are available to help pin down the location of kidney dysfunction. 

Figure 8.20 (a) The synthesis of phosphocreatine. The compound guanidinoacetate is formed from arginine and glycine in the kidney and is then transported to the liver where it is methylated addition of CHj (see Chapter 15) to form creatine (see Appendix 8.4 for details). Creatine is taken up by tissues/ organs/cells and phosphorylated to form phosphocreatine, particularly in muscle, (b) Conversion of phosphocreatine and creatine to creatinine in muscle. Creatinine is gradually formed and then released into blood and excreted in urine. 

In the muscle, phosphocreatine and creatine undergo cyclisation to form creatinine (Figure 8.20(b)). Since creatinine cannot be metabohsed, it is released from muscle and is then excreted in the urine. This biochemical process is useful in clinical practice, since creatinine production is spontaneous and is remarkably constant 1.7% of the phosphocreatine and creatine in muscle cyclises each day, so that its concentration in blood provides an indication of the glomerular filtration rate, and hence provides an indication of the function (i.e. the health) of the kidney. 

Daily intake (mg/kg/day) = urinary concentration (mg/g creatine) x creatinine excretion (g/kg/day) x (monoester in urine (mol)/diester ingested (mol)) x (molecular weight of diester (g/mol)/molecular weight of monoester (g/mol)). 

Uric acid is the end product of the purine metabolism. When uric acid excretion via the kidneys is disturbed, gout can develop (see p. 190). Creatinine is derived from the muscle metabolism, where it arises spontaneously and irreversibly by cyclization of creatine and creatine phosphate (see p. 336). Since the amount of creatinine an individual excretes per day is constant (it is directly proportional to muscle mass), creatinine as an endogenous substance can be used to measure the glomerular filtration rate. The amount of amino acids excreted in free form is strongly dependent on the diet and on the ef ciency of liver function. Amino acid derivatives are also found in the urine (e.g., hippu-rate, a detoxification product of benzoic acid). 

In resting muscle, creatine phosphate forms due to the high level of ATP. If there is a risk of a severe drop in the ATP level during contraction, the level can be maintained for a short time by synthesis of ATP from creatine phosphate and ADP. In a nonenzymatic reaction [6], small amounts of creatine and creatine phosphate cyclize constantly to form creatinine, which can no longer be phosphorylated and is therefore excreted with the urine (see p. 324). 

The stress of cold produced increased urinary excretion of norepinephrine but not of epinephrine or vasopressin (K8). Cold in the form of accidental hypothermia also resulted in increased serum creatine phos-phokinase (M2). Mental stress (problem solving) resulted in increases of urinary vasopressin from 33 to 47.6 units, epinephrine from 5.5 to 11.3 mg, and norepinephrine from 17 to 21 mg (K8). 

Degradation Creatine and creatine phosphate spontaneously cyclize at a slow, but constant, rate to form creatinine, which is excreted in the urine. The amount of creatinine excreted is proportional to the total creatine phosphate content of the body, and thus can be used to estimate muscle mass. When muscle mass decreases for any reason (for example, from paralysis or muscular dystrophy), the creatinine content of the urine falls. In addition, any rise in blood creatinine is a sensitive indicator of kidney malfunction, because creatinine is normally rapidly removed from the blood and excreted. A typical adult male excretes about 15 mmol of creatinine per day. The constancy of this excretion is sometimes used to test the reliability of collected 24-hour urine samples—too little creatinine in the submitted sample may indicate an incomplete sample. 

In addition, muscle can only absorb up to 160 mmol/kg of creatine. All excess dietary and supplemental creatine must be excreted out of the body, which can increase urinary output and put undue stress on the kidneys. 

On June 6, this patient developed severe loin pain after he participated in two 150-m sprints at a town athletics meeting. After 5 days, he was referred to the outpatient clinic of our department. His serum creatinine and uric acid levels and FEUA, were 2.9mg/dl, 2.1 mg/dl, and 49.7%, respectively. His creatine phosphokinase (CPK) level was normal. When his serum creatinine level decreased to 1.58 mg/dl, a contrast medium was administered. A delayed computed tomography (CT) scan after 24 and 48 h confirmed patchy wedge-shaped contrast enhancement (Fig. 58). Under a diagnosis of ALPE, his body water balance (hydration) was controlled. In this patient, recovery was achieved 4 weeks after onset, and his serum creatinine and uric acid levels were then 1.0 mg/dl and 0.6 mg/dl, respectively. Furthermore, load tests with a uric acid reabsorption inhibitor (benzbromarone) and a uric acid excretion inhibitor (pyrazinamide) suggested presecretory reabsorption defect-related renal hypouricemia. A kidney biopsy 16 days after onset confirmed the recovery from acute tubular necrosis. 

Most doctors use the plasma concentrations of creatinine, urea and electrolytes to determine renal function. These measures are adequate to determine whether a patient is suffering from kidney disease. Protein and amino acid catabolism results in the production of ammonia, which in turn is converted via the urea cycle into urea, which is then excreted via the kidneys. Creatinine is a breakdown product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body (depending on muscle mass). Creatinine is mainly filtered by the kidney, though a small amount is actively secreted. There is little to no tubular reabsorption of creatinine. If the filtering of the kidney is deficient, blood levels rise. 

After sulfide is oxidized to sulfate (the major metabolic pathway), sulfate is excreted in the urine (Beauchamp et al. 1984). A human volunteer exposed at a concentration of 18 ppm hydrogen sulfide for 30 min was found to have urinary thiosulfate concentrations of approximately 2, 4, 7, 30, and 5 /nnol/mM creatine 1, 2, 5, 15, and 17 h after exposure, respectively (Kangas and Savolainen 1987). Blood thiosulfate concentrations decreased in rabbits exposed to hydrogen sulfide at a concentration 100-200 ppm for 60 min from 0.061 /tmol/mL immediately after exposure to an undetectable amount after 4 h (Kage et al. 1992). Urine... 

It is difficult to obtain an accurate measure of renal function in patients with cirrhosis. A number of studies have shown that they tend to have low serum creatinine levels. This has been explained by a reduced muscle mass in cirrhotic patients and a reduced conversion of creatine to creatinine [10]. The calculation of creatinine clearance using the Cockcroft and Gault formula is also inaccurate in predicting GFR in these patients because it uses the serum creatinine level (which may be falsely low) and body weight in the calculation, which is likely to be inflated due to the presence of ascites [12]. The measured creatinine clearance, based on urinary excretion of creatinine, should theoretically be more accurate, even in patients with reduced muscle mass or impaired creatinine synthesis. However, it has been shown that this also overestimates the GFR because of an increased fractional tubular secretion of creatinine in cirrhotic patients, particularly those with reduced GFR [10]. 

Both creatine and creatine phosphate undergo a nonenzymic reaction to yield creatinine, which is metaboUcaUy useless and is excreted in the urine. Because the formation of creatinine is a nonenzymic reaction, the rate at which it is formed, and the amount excreted each day, depends mainly on muscle mass, and is therefore relatively constant from day to day in any one individual. This is commonly exploited in clinical chemistry urinary metabolites are commonly expressedper mole of creatinine, and the excretion of creatinine is measured to assess the completeness of a 24-hour urine collection. There is normally Utffe or no excretion of creatine in urine significant amounts are only excreted when there is breakdown of muscle tissue. 

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