Synthesis creatinine

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 synthesis of creatine. In the kidney, guanidinoace-tate is produced from arginine and glycine, then released into the blood to be taken up by the liver and methylated to form creatine (Figure 8.20(a)). The creatine is, in turn, taken up by the muscle where it is phosphorylated to produce phosphocreatine, which can maintain the ATP level, especially in explosive exercise. Creatine and phosphocreatine are converted in muscle to creatinine, which is important in clinical practice (Figure 8.20(b)) (Box 8.3). 

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 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). 

Cycloserine is an inhibitor of cell wall synthesis and is discussed in Chapter 43. Concentrations of 15-20 mcg/mL inhibit many strains of M tuberculosis. The dosage of cycloserine in tuberculosis is 0.5-1 g/d in two divided doses. Cycloserine is cleared renally, and the dose should be reduced by half if creatinine clearance is less than 50 mL/min. 

Homocysteine is formed as an intermediary amino acid in the methionine cycle (Fig. I). Methionine is metabolized to s-adenosylmethionine (SAM), the methyl donor in most methylation reactions and essential for the synthesis of creatinine, DNA, RNA, proteins, and phospholipids. SAM is converted by methyl donation to s-adenosylhomocysteine (SAH), which is then hydrolyzed to homocysteine. SAH is an inhibitor of methyl group donation from SAM. 

While low serum cholesterol levels have been observed in malnourished patients, largely as a result of decreased synthesis of lipoproteins in the liver, hypocholesterolemia occurs later in the course of malnutrition and is therefore not useful as a screening test. PEM usually results in low serum urea nitrogen (BUN), urinary urea, and total nitrogen. Estimation of 24-h urine creatinine excretion is also a valuable biochemical index of muscle mass (when there is no impairment in renal function). The urinary CHI is correlated to lean body mass and anthropometric measurements. In edematous patients, for whom the extracellular fluids contribute to body weight and spuriously high body mass index values, the decreased CHI values are especially useful in diagnosing malnutrition. 

The laboratory also measured biochemical markers of bone metabolism. The urinary excretion of deoxypyrolidone, a marker of bone resorption, was elevated (128 nmol/mmol creatinine normal is 31-110 nmol/mmol creatinine). Bone-specific alkaline phosphatase, a marker of bone synthesis, was also elevated at 400 U/L (normal is 70-139 U/L for girls between 3 and 8 years of age) (Tsai et al., 1999). The concentration of another marker of bone resorption, NTx (N-teleopeptide), in the patient s serum was elevated (110 nmol BCE/L normal is 20-68 nmol BCE/L [bone collagen equivalents]). 

Urea and creatinine elevations in plasma are in general not sensitive enough to detect low-level alterations (less than 75 % loss) in functional nephron mass, due to the contribution of renal secretion and/or reabsorption to their overall excretion, (which can compensate for their decreased filtration), to wide variations in baseline levels of some analytes, and to inherent imprecision in the assays used (Finn and Porter 1998 Price 2002 Starr et al. 2002 Shemesh et al. 1985). In particular, urea will underestimate GFR (due to extensive tubular reabsorption with decreased GFR) (Baum et al. 1975 Kaplan and Kohn 1992 Newman and Price 1999). Creatinine tends to overestimate GFR because it is secreted by the tubule in many species and secretion increases with reduced GFR (Shemesh et al. 1985 Andreev et al. 1999 Newman and Price 1999 Starr et al. 2002). In addition, creatinine synthesis is regulated by feedback inhibition which limits the degree of elevation than can occur in plasma with renal injury (Watson et al. 2002). 

Baseline levels of urea and creatinine can be highly variable. Plasma urea reflects hepatic synthesis rate and will be elevated with increased protein catabolism (increased dietary protein intake, gastrointestinal hemorrhage, fever, severe bums, corticosteroid administration, sustained exercise or muscle wasting),... 

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]. 

As a result of this resorption and the protein binding of plasma biotin, which reduces filtration at the glomerulus, renal clearance of biotin is only 40% of that of creatinine. This efficient conservation of biotin, together with the recycling of biocytin released from the catabolism of biotin-containing enzymes, may be as important as intestinal bacterial synthesis of the vitamin in explaining the rarity of deficiency. 

Here I is the rate of synthesis of creatinine in the body and CLcr P is the rate of creatinine elimination. At steady state these rates are equal and there is no change in the total body content of creatinine (dX/dt = 0)/ so ... 

This equation explains why it is hazardous to estimate the status of renal function solely from serum creatinine results in patients who have a reduced muscle mass and a decline in creatinine synthesis rate. For example creatinine synthesis rate maybe substantially reduced in elderly patients so it is not unusual for serum creatinine concentrations to remain within normal limits even though renal function is markedly impaired. 

The simultaneous administration technique was used to study a 64-year-old man with a creatinine clearance of 79 mL/ min who was started on N-acetyl-procainamide (NAPA) therapy for ventricular arrhythmias (see Figure 4.4). The oral NAPA dose was 66% absorbed in this patient, compared to 91.6 9.2% when this method was used to assess NAPA absorption in normal subjects. Although this approach is ideally suited for studies of drug absorption in various patient populations, the required additional chemical synthesis of stable isotope-labeled drug and mass spec-trometric analysis of patient samples have precluded its widespread adoption. 

Spontaneously reversible increases in serum creatinine concentrations occurred in 8-18% of muromonab-treated patients, and were thought to have resulted from inhibition of renal prostaglandin synthesis and release of cytokines (32,33). There were no adverse consequences on short-term graft survival or graft function (32). 

The use of potentially nephrotoxic drugs requires close monitoring of renal function. The serum creatinine concentration is the most common method utilized to assess renal function but suffers from its lack of sensitivity. In patients with normal baseline renal function substantial renal injury can occur before there is a demonstrable rise in the serum creatinine concentration. A rise in the serum creatinine concentration that just exceeds the normal range may reflect as much as a 50% dechne in the GFR. The failure of the serum creatinine to accurately reflect the degree of renal injury is particularly evident in patients with decreased muscle mass or those with chronic liver failure. Creatinine is produced from the metabolism of creatine in skeletal muscle. In turn, creatine is derived from the liver. In the setting of chronic liver disease or malnourished patients with decreased muscle mass creatinine synthesis becomes impaired. As a result... 

However, creatinine and purine derivatives are very important in the field of animal nutrition because measurements of urinary excretion of these compounds have been proposed as an internal marker for microbial protein synthesis. 

Figure 7-18. The synthesis of creatine phosphate and its spontaneous (nonenzymatic) conversion to creatinine. SAM= S-adenosylmethionine SAH= S-adenosylhomocysteine.

A. The amount of creatine in liver cells determines its rate of synthesis from glycine, arginine, and SAM. In muscle, creatine is converted to creatine phosphate, which is nonenzymati-cally cyclized to form creatinine. The amount of creatinine excreted by the kidneys each day depends on body muscle mass. In kidney failure, the excretion of creatinine into the urine will be low. 

Intraperitoneal administration of coptisine at dosages of 0.5, 1, and 5 mg/kg/day to original-type anti-GBM-induced nephritic rats was shown to be effective in the inhibition of urinary protein excretion, elevation of serum cholesterol, and creatinine contents, as well glomerular histopathological changes. The alkaloid inhibited platelet aggregation in both in vitro and in vivo assays. These results suggest that the antinephritic effect of coptisine may be due partly to antiplatelet action and improved renal hemodynamics, via the alteration of prostanoid synthesis [223]. 

Demethylation. The last step in a synthesis of N-methyl-3,4-dihydroxyphenyl-alanine from vanillin and creatinine is demethylation of the phenolic monomethyl ether formulated." A mixture of the ether, red phosphorus, 60 ml. of constantboiling hydriodic acid, and 60 ml. of acetic anhydride is refluxed for 3 hrs. 

In a synthesis of N-methyl-3,4-dihydroxyphenylalanine (6) from vanillin (1) and creatinine (2), one step is a sodium amalgam reduction of (3)— (4), earned out by adding 3% amalgam in portions to a stirred suspension of (3) in water. The solid dissolves, and the initial orange-red color of the solution slowly fades as the reduction proceeds. With good agitation, decolorization is complete in 45-60 min. 

Glycogenolysis and a negative nitrogen balance occur with the onset of fever. These are prompted by the typically decreased food intake and wasting of skeletal muscle that accompany fever. Although there is usually an increase in the blood volume with fever, the serum concentrations of creatinine and urate are usually increased. Aldosterone secretion is increased with retention of sodium and chloride. Secretion of antidiuretic hormone also contributes to the retention of water by the kidneys. Increased synthesis of protein... 

Meanwhile Rapport and his colleagues had been investigating the vasoconstrictor substance in serum which they named serotonin, and isolated in 1948 (693, 694). The isolated material was shown (692) to be a complex of creatinine with what was thought to be 5-hydroxytryptamine (structure diagram 23) and identification of the latter was confirmed by synthesis (19, 341, 363, 821). It then became clear that enteramine and serotonin were identical (e.g., 238, 239), and an enormous amount of work on the physiology and pharmacology of 5-hydroxytryptamine has subsequently appeared (reviews 235a, 237, 660, 958). 

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