Creatine and Creatinine Metabolism - Physiological Reviews
Creatine and Creatinine Metabolism - Physiological Reviews
Creatine and Creatinine Metabolism - Physiological Reviews
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1176 MARKUS WYSS AND RIMA KADDURAH-DAOUK Volume 80<br />
catabolism, anemia, a decrease in the circulating platelet<br />
count, central <strong>and</strong> peripheral neuropathy, pruritus, arrhythmias<br />
<strong>and</strong> myocardial degeneration, congestion, <strong>and</strong>,<br />
in later stages of intoxication, anorexia, vomiting, increased<br />
salivation, <strong>and</strong> diarrhea (see Ref. 53). In vitro<br />
studies have shown that MG has a variety of potentially<br />
toxic effects by inhibiting, for example, mitochondrial<br />
oxidative phosphorylation, growth of cultured cells, or<br />
Na � -K � -ATPase in the brain (for references, see Refs. 168,<br />
735, 1147) or by affecting membrane fluidity (1138). Furthermore,<br />
MG, which is also present in various foods (for<br />
references, see Refs. 223, 294, 685), may be nitrosated<br />
intragastrically <strong>and</strong> may thereby become a potent mutagen<br />
(223) (see also sect. IXF).<br />
Recently, MG was identified as a nonselective reversible<br />
inhibitor of NOS isoenzymes (see Refs. 341, 581, 930,<br />
931, 1004, 1114). The three major isoenzymes of NOS,<br />
neuronal NOS (nNOS), endothelial NOS (eNOS), <strong>and</strong> inducible<br />
NOS (iNOS), were inhibited with IC 50 values of<br />
90–370 �M (931, 1114). By inhibiting eNOS, intravenously<br />
administered MG increased mean arterial blood pressure<br />
in rats, thus raising the hypothesis that MG may contribute<br />
to the hypertension seen in patients with CRF (929,<br />
930). Similarly, by inhibiting NOS in kidney <strong>and</strong> brain, MG<br />
may have an impact on the regulation of glomerular capillary<br />
pressure <strong>and</strong> on neurological functions, respectively.<br />
Guanidino compounds including Cr, Crn, guanidine,<br />
MG, GAA, GPA, GBA, <strong>and</strong> GSA were also shown to have<br />
a series of other, potentially harmful, side effects (see also<br />
sect. VIIIB). Insulin resistance is a common finding in CRF.<br />
Accordingly, insulin binding to erythrocyte receptors was<br />
shown to be decreased in uremic patients, but increased<br />
rapidly upon hemodialysis (814). Binding of insulin to<br />
erythrocytes is also depressed by 1 mM concentrations of<br />
Crn, Cr, <strong>and</strong> guanidinoacetate. Plasma of uremic patients<br />
as well as �- <strong>and</strong> �-GPA inhibit the hexose monophosphate<br />
shunt in red blood cells (453). GPA, GBA, GAA, <strong>and</strong><br />
GSA inhibit the phytohemagglutinin-induced stimulation<br />
of proliferation of normal human lymphocytes (878). This<br />
inhibitory action may possibly explain the depression in<br />
total lymphocyte count <strong>and</strong> function as well as the greatly<br />
depressed cell-mediated response to protein antigens in<br />
uremia. Finally, guanidine, MG, Crn, Cr, GSA, <strong>and</strong> GBA<br />
have convulsive effects in animals <strong>and</strong> may thus contribute<br />
to the neurological symptomatology in uremia (see<br />
sect. IXG).<br />
In conclusion, Crn degradation seems to be virtually<br />
irrelevant under normal conditions when Crn might even<br />
have a beneficial effect by acting as a hydroxyl radical<br />
scavenger. At greatly reduced GFR, on the other h<strong>and</strong>,<br />
when the serum concentration of Crn as well as oxidative<br />
stress are considerably increased, the formation of toxic<br />
Crn degradation products is favored <strong>and</strong> may contribute<br />
significantly to further disease progression. Because Crn<br />
degradation is stimulated by ROS <strong>and</strong> in particular by the<br />
hydroxyl radical, the serum concentrations of creatol <strong>and</strong><br />
MG as well as the creatol/Crn <strong>and</strong> MG/Crn ratios may not<br />
only serve as diagnostic indexes for the degree of CRF,<br />
but may also be used as measures of oxidative stress in<br />
uremic patients (25, 683, 687, 747, 1146).<br />
XI. ANALYTICAL METHODS AND THEIR<br />
IMPLICATIONS FOR CLINICAL DIAGNOSIS<br />
Ever since the suggestion of Popper <strong>and</strong> M<strong>and</strong>el in<br />
1937 (779) that the clearance of endogenous Crn approximates<br />
the GFR, investigation of serum <strong>and</strong> urinary [Crn]<br />
has been popular in clinical medicine. Even though the<br />
parallelism between Crn clearance <strong>and</strong> GFR turned out to<br />
be less strict than previously presumed (see sect. IXH),<br />
there is still a broad interest in improving analytical methods<br />
for measuring [Crn] <strong>and</strong> [Cr] in biological samples.<br />
For many decades, chemical methods prevailed (551,<br />
758, 932, 1071). Crn has been, <strong>and</strong> still is, measured<br />
mostly by the Jaffé reaction (422) in which Crn <strong>and</strong> picric<br />
acid under alkaline conditions form an orange-red-colored<br />
complex. Despite considerable effort, the detailed<br />
mechanism of color formation could not yet be resolved<br />
(see Refs. 551, 932, 958). The major disadvantage of the<br />
Jaffé reaction is its lack of specificity due to interference<br />
by a variety of metabolites, e.g., ketones <strong>and</strong> ketoacids,<br />
protein, bilirubin, <strong>and</strong> cephalosporins (e.g., Refs. 71, 443,<br />
635, 926, 932, 958, 1071, 1110). Although a large number of<br />
modifications <strong>and</strong> improvements of the Jaffé reaction<br />
were proposed, none has eliminated all interferences.<br />
This disadvantage was outscored in the past by the usefulness<br />
of the Jaffé reaction in the clinical environment,<br />
by the lack of valid alternatives, <strong>and</strong>, in particular, by the<br />
low price of the required chemicals. Cr was frequently<br />
determined chemically by the �-naphthol-diacetyl reaction<br />
(1117), but this method is rather cumbersome <strong>and</strong><br />
nonspecific as well.<br />
Already in 1937, using crude bacterial extracts, Miller<br />
<strong>and</strong> Dubos managed to estimate enzymatically the Crn<br />
content of plasma <strong>and</strong> urine (see Ref. 55). But it is only in<br />
recent years that significant progress has been made toward<br />
developing <strong>and</strong> improving enzymatic Cr <strong>and</strong> Crn<br />
determination methods (see Refs. 758, 862, 926, 932). In<br />
keeping with the diversity of Crn degradation pathways<br />
(see Fig. 7), a series of alternative reaction sequences was<br />
proposed to be specific <strong>and</strong> accurate. 1) A first method is<br />
based on creatininase, creatinase, sarcosine oxidase, <strong>and</strong><br />
a peroxidase. The hydrogen peroxide liberated in the<br />
sarcosine oxidase reaction is used by the peroxidase to<br />
produce a colored substance that can be measured spectrophotometrically<br />
or fluorimetrically (for references, see<br />
Refs. 432, 443, 926, 958, 1110). 2) In the reaction sequence<br />
of creatininase, CK, pyruvate kinase, <strong>and</strong> lactate dehydro-