Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 16 Kidney Function and Damage
action of 1α-hydroxylase on 25-hydroxyvitamin D 3 produced
by liver hydroxylation of vitamin D 3 . Calcitriol is a
major antihypocalcemic hormone acting at the transcriptional
level to induce active intestinal absorption of calcium. It acts
in synergy with PTH to activate calcium release from bone.
PTH increases the expression and activity of 1α-hydroxylase
activity during calcium and vitamin D 3 deficiency. The
direct modulating effects of calcium and phosphates are
weaker. 1 α -Hydroxylase activity was recently shown to be
down-regulated by phosphaturic peptides called phosphatonins.
See the reviews in Ebert et al. (2006) , Jones et al.
(1998) , and Kumar (1984) . Calcitriol synthesis is decreased
in CRF, and its administration is recommended for
the treatment of animals with CRF and concomitant hyperparathyroidism.
See the review in Nagode et al. (1996) .
Cr-P Cr
Crn
Cr
Cr
GAA
GAA + Orn
Arg + Gly
III . TESTS OF KIDNEY FUNCTION
Kidney function can be evaluated from the concentrations
of plasma or urine analytes, which are mainly dependent
on their elimination (e.g., P-Creatinine). These indirect
markers can be easily and rapidly measured, but their
sensitivity is poor and generally remains unaltered until
75% of renal function has been lost and their concentrations
may be modified by extrarenal factors. Direct tests
of kidney function are based on the elimination kinetics of
markers of glomerular filtration, blood flow, or tubule reabsorption/secretion
and are based on the clearance concept.
These tests are more difficult and take longer to perform
but allow earlier detection of reduced function.
A . Indirect Tests of Glomerular Function
P-Creatinine is the test most often used to diagnose and
monitor kidney disease in human and animal clinical
pathology. P-Urea is also used frequently but is subject to
more numerous extrarenal factors of variation. These molecules
are almost totally eliminated by glomerular filtration,
so that in the case of kidney failure their plasma concentration
increases. However, neither test is sensitive in the
early diagnosis of kidney disease because of the large
functional reserve of the kidneys. Moreover, variations of
P-Urea and P-Creatinine are not proportional to the number
of functional nephrons (e.g., a mean increase of 85% in
P-Creatinine and of 140% in P-Urea was observed after a
two-fold reduction of GFR, with values close to the upper
limit of the reference interval) ( Lefebvre et al. , 1999 ).
1 . Creatinine
a . Creatinine Metabolism
Creatinine is a small molecule (MW 113) produced by degradation
of creatine and creatine-phosphate, an energy-storing
Crn
FIGURE 16-5 Schematic representation of creatinine metabolism. The
first step is the transamidination of arginine and glycine yielding guanidinoacetic
acid (GAA) by the kidney enzyme arginine:glycine amidinotransferase.
In the liver, N-methylation of guanidinoacetate into creatine
is catalyzed by guanidinoacetate methyltransferase, using methyl groups
donated by S-adenosylmethionine. Creatine is distributed to muscle cells
where it is reversibly phosphorylated to creatine phosphate by creatine
kinase. Creatinine is the product of the spontaneous, irreversible, nonenzymatic,
internal dehydration of creatine, and dephosphorylation of
creatine phosphate.
molecule mainly present in skeletal muscles. See the
reviews in Braun et al. (2003) , Perrone et al. (1992) , and
Wyss and Kaddurah-Daouk (2000) . Creatine is synthesized
from the amino acids glycine, arginine, and methionine,
the final step occurring in the liver ( Fig. 16-5 ). It is then
taken up by the muscles where it is reversibly phosphorylated
by creatine-kinase into creatine-phosphate. Skeletal
muscles contain about 95% of the total body creatine and
creatine-phosphate pool. The estimated turnover of creatine-phosphate
(about 2%) is fairly constant in a given
individual. The resulting estimated daily input of endogenous
creatinine into plasma was 380 45 μ mol/kg BW
in healthy beagles and 10% to 20% lower in animals with
reduced kidney mass ( Watson et al. , 2002a ). In carnivores
and omnivores, creatinine can also originate from the creatine
and creatinine in food ( Harris and Lowe, 1995 ; Harris
et al. , 1997 ).
Creatinine mainly circulates in a free form in the
plasma and is distributed into the whole body water compartment
( Schloerb, 1960 ; Watson et al. , 2002a ). It was
reported that, in dog plasma, 6% were bound to plasma
proteins ( Kennedy et al. , 1952 ). Creatinine is freely filtered
by the glomerulus and is not reabsorbed or secreted
in cats ( Finco and Barsanti, 1982 ) and ponies ( Finco and
Groves, 1985 ), but it may be strongly secreted in horses