Creatine and Creatinine Metabolism - Physiological Reviews

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