Creatine and Creatinine Metabolism - Physiological Reviews
Creatine and Creatinine Metabolism - Physiological Reviews
Creatine and Creatinine Metabolism - Physiological Reviews
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July 2000 CREATINE AND CREATININE METABOLISM 1173<br />
H. Creatin(in)e <strong>Metabolism</strong> <strong>and</strong> Renal Disease<br />
The kidney plays a crucial role in Cr metabolism (see<br />
Fig. 4). On one h<strong>and</strong>, it is a major organ contributing to<br />
guanidinoacetate synthesis. On the other h<strong>and</strong>, it accomplishes<br />
urinary excretion of Crn, the purported end product<br />
of Cr metabolism in mammals.<br />
In chronic renal failure (CRF) rats, the renal AGAT<br />
activity <strong>and</strong> rate of guanidinoacetate synthesis are depressed<br />
(520, 554). Accordingly, the urinary excretion of<br />
guanidinoacetate is decreased in a variety of renal diseases<br />
(10, 77, 412, 598, 969). Although the serum concentration<br />
of guanidinoacetate was also shown to be decreased<br />
in both uremic patients <strong>and</strong> renal failure rats (39,<br />
412, 520, 598, 747), it was found, in a few other studies, to<br />
be unchanged (10, 165, 168, 638) or even slightly increased<br />
(163, 757). These conflicting results may be due to<br />
compensatory upregulation of guanidinoacetate synthesis<br />
in the pancreas, to different degrees of depression of<br />
urinary guanidinoacetate excretion, to unknown effects<br />
of peritoneal or hemodialysis, <strong>and</strong>/or to different stages of<br />
disease progression.<br />
Similarly conflicting results were obtained for the<br />
serum concentration of Cr in uremic patients. It was<br />
found to be increased (163, 165, 412, 598, 757, 877), unchanged<br />
(165, 598), or even depressed relative to control<br />
subjects (168). The latter finding may be due to dialysis of<br />
these patients, which was shown to decrease the serum<br />
concentration of Cr (169, 877). Both the erythrocyte concentration<br />
of Cr (even after hemodialysis) <strong>and</strong> the urinary<br />
excretion of Cr may be increased in uremia (77, 412, 877),<br />
although in one study decreased urinary Cr clearance was<br />
observed (598). In striated muscle of uremic patients, the<br />
concentrations of PCr <strong>and</strong> ATP are decreased (716),<br />
whereas those of Cr <strong>and</strong> P i are increased (99), thus suggesting<br />
that intracellular generation of high-energy phosphates<br />
is impaired.<br />
The most consistent, <strong>and</strong> clinically most relevant,<br />
findings are an increase in the serum concentration <strong>and</strong> a<br />
decrease in the renal clearance of Crn with the progression<br />
of renal disease. Crn clearance (C Crn; in ml/min) is<br />
defined as<br />
C Crn � U Crn � V<br />
P Crn<br />
where U Crn <strong>and</strong> P Crn are the urine <strong>and</strong> serum concentrations<br />
of Crn, respectively, <strong>and</strong> V is the urine flow rate (in<br />
ml/min). Both the serum concentration of Crn <strong>and</strong> Crn<br />
clearance have been, <strong>and</strong> still are, widely used markers of<br />
renal function, in particular of the glomerular filtration<br />
rate (GFR). The validity of this approach critically depends<br />
on the assumptions that Crn is produced at a steady<br />
rate, that it is physiologically inert, <strong>and</strong> that it is excreted<br />
solely by glomerular filtration in the kidney. In recent<br />
years, these assumptions were shown to be invalid under<br />
uremic conditions, <strong>and</strong> several factors have been identified<br />
that may result in gross overestimation of the GFR<br />
(see, e.g., Refs. 108, 358, 536, 758, 791). For example, an<br />
increasing proportion of Crn in CRF is excreted by tubular<br />
secretion rather than glomerular filtration.<br />
Another factor contributing to the overestimation of<br />
the GFR seems to be degradation of Crn in the human <strong>and</strong><br />
animal body. Jones <strong>and</strong> Burnett (438) <strong>and</strong> Walser <strong>and</strong><br />
co-workers (652, 1085) in fact showed, by calculating Crn<br />
balances, that 16–66% of the Crn formed in patients with<br />
CRF cannot be accounted for by accumulation in the body<br />
or by excretion in urine or feces. The most likely explanation<br />
for this apparent “Crn deficit” or “extrarenal Crn<br />
clearance” is Crn degradation. Whereas the normal renal<br />
Crn clearance is �120 ml/min, the renal <strong>and</strong> extrarenal<br />
Crn clearances in CRF patients were calculated to be<br />
�3–5 <strong>and</strong> 1.7–2.0 ml/min, respectively. Therefore, Crn<br />
degradation may be negligible in healthy individuals,<br />
which led to the postulate that Crn is physiologically<br />
inert, but it may become highly relevant under conditions<br />
of impaired renal function.<br />
Several pathways for Crn degradation have to be<br />
considered. 1) Up to 68% of the metabolized Crn may be<br />
reconverted to Cr (652). To this end, Crn is most likely<br />
excreted into the gut where it is converted by bacterial<br />
creatininase to Cr which, in turn, is retaken up into the<br />
blood (“enteric cycling”) (439). This pathway may be a<br />
powerful means for limiting Crn toxicity (see below) <strong>and</strong><br />
may also explain in part why the serum concentration of<br />
Cr is increased in many patients with CRF.<br />
2) Bacterial degradation of Crn in the gut may not be<br />
limited to the conversion to Cr but may proceed further.<br />
1-Methylhydantoin, Cr, sarcosine, methylamine, <strong>and</strong> glycolate<br />
were identified as degradation products when rat<br />
<strong>and</strong> human colon extracts or feces were incubated with<br />
Crn (439, 745). Upon incubation of colon extracts with<br />
radioactively labeled 1-methylhydantoin, however, no decomposition<br />
products were observed. These findings suggest<br />
at least two independent Crn degradation pathways:<br />
a) Crn 3 1-methylhydantoin, catalyzed most likely by<br />
bacterial Crn deaminase; <strong>and</strong> b) Crn 3 Cr 3 urea � sarcosine<br />
3 methylamine � glyoxylate 3 glycolate, with the<br />
first two steps probably being catalyzed by bacterial creatininase<br />
<strong>and</strong> creatinase (see also Fig. 7). Last but not<br />
least, Pseudomonas stutzeri, which may be present in<br />
human gut, produces MG when incubated with Crn, both<br />
under aerobic <strong>and</strong> anaerobic conditions (1049). Accordingly,<br />
rat colon extracts proved to convert Crn to MG<br />
(437).<br />
In support of these Crn degradation pathways, creatininase<br />
activity was recently shown to be increased<br />
considerably in the feces of patients with CRF (204). Crn<br />
degradation was lower in stool isolates of CRF patients