1 Department of Anesthesiology, Oregon Health Sciences University and Veterans Affairs Medical Center, Portland, Oregon 97201; and 2 United States Department of Agriculture/Agricultural Research Services Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030
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ABSTRACT |
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It has been
suggested that hepatic urea synthesis, which consumes
HCO3, plays an important role in
acid-base homeostasis. This study measured urea synthesis rate
(Ra urea) directly to assess its
role in determining the acid-base status in patients with end-stage
cirrhosis and after orthotopic liver transplantation (OLT). Cirrhotic
patients were studied before surgery
(n = 7) and on the second
postoperative day (n = 11), using a
5-h primed-constant infusion of
[15N2]urea.
Six healthy volunteers served as controls.
Ra urea was 5.05 ± 0.40 (SE)
and 3.11 ± 0.51 µmol · kg
1 · min
1,
respectively, in controls and patients with cirrhosis (P < 0.05). Arterial base excess was 0.6 ± 0.3 meq/l in controls and
1.1 ± 1.3 meq/l in cirrhotic patients (not
different). After OLT, Ra urea was 15.05 ± 1.73 µmol · kg
1 · min
1,
which accompanied an arterial base excess of 7.0 ± 0.3 meq/l (P < 0.001). We conclude that
impaired Ra urea in cirrhotic
patients does not produce metabolic alkalosis. Concurrent postoperative metabolic alkalosis and increased
Ra urea indicate that the
alkalosis is not caused by impaired
Ra urea. It is consistent with,
but does not prove, the concept that the graft liver responds to
metabolic alkalosis by augmenting
Ra urea, thus increasing
HCO
3 consumption and moderating the
severity of metabolic alkalosis produced elsewhere.
cirrhosis; acid-base metabolism; base excess; metabolic alkalosis; ammonia
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INTRODUCTION |
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LIVER IS THE PREDOMINANT source of urea production in
the body. Urea synthesis consumes HCO3
produced from substrate metabolism, with a stoichiometric relationship
described as
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Others, using indirect methods, have not detected a decrease in basal urea synthesis by cirrhotic patients (13). Fujii et al. (16) reported no decrease in urea synthesis from 15NH4Cl in cirrhotic patients until the disease had reached end stage. One problem with the approach used by Fujii et al., however, is that their calculation of urea synthesis depends on uncompromised urinary excretion of urea (16). Hence, the calculated urea synthesis rate can be inaccurate if renal function is compromised, a distinct possibility in cirrhotic patients (6). The results can also be affected by changes in amino acid metabolism, since almost 80% of 15N from intravenously administered ammonium is first incorporated into synthesis of nonessential amino acids (37). An association whereby alterations in urea synthesis in vivo affects acid-base balance in humans has not been reported.
Conversely, primary alterations in acid-base balance may affect urea synthesis. Intravenous NaHCO3 administration in rats increases, and HCl decreases, urinary urea excretion (4). Several investigators (2, 20, 26) reported that NaHCO3 stimulates urea synthesis by incubated liver, although this has not been uniformly observed (18). A marked metabolic alkalosis occurs early after OLT, with a peak magnitude on the second postoperative day, and persists for several days (44). Its etiology is unclear but does not appear to be related to clearance of plasma lactic acid or citrate from blood transfusion because these substrates return to baseline concentrations by the first postoperative day (10, 44). Metabolic alkalosis occurs despite evidence of good graft liver function, as assessed by plasma concentrations of coagulation factors and prealbumin, as well as hepatic substrate clearance. The present treatment is to inhibit carbonic anhydrase with acetazolamide and, rarely, by HCl infusion to maintain a stable arterial pH. This therapy, however, may not address the underlying problem and may even exacerbate it, as both acetazolamide and HCl decrease urea synthesis (4, 20, 40). If the defect in OLT patients is compromised urea synthesis, steps could instead be taken to stimulate ornithine cycle activity.
The relationship between amino acid metabolism and urea synthesis has been reviewed (31). However, there have been no reports of the relationship between urea synthesis in vivo and acid-base balance in the presence of either end-stage liver disease or a graft liver. The purpose of this study was to measure urea synthesis directly in humans to determine the relationship between urea synthesis and acid-base balance in patients with end-stage liver disease and in patients after OLT with an apparently well-functioning graft liver.
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MATERIALS AND METHODS |
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Subjects. This study was approved by
the Institutional Review Boards at Oregon Health Sciences University
(OHSU) and the Portland, Oregon, Veterans Affairs Medical Center
(VAMC). Eighteen patients with stable end-stage cirrhosis were enrolled
after written informed consent. Seven of these patients were studied
while awaiting OLT. Inclusion criteria for cirrhotic patients were
end-stage liver disease, hemodynamic stability, no history of
insulin-dependent diabetes mellitus, and adequate renal function as
determined by plasma creatinine concentration <1.4 mg/dl. No subject
had gross evidence of ascites, required recent paracentesis, or had
other gastrointestinal disturbances such as nausea, vomiting, or
bleeding. All patients were receiving lactulose and diuretic therapy
consisting of furosemide and spironolactone. None was receiving
steroids or -adrenergic agonists or antagonists. Severity of liver
disease was assessed by the Pugh-Childs scoring system (38). The
remaining 11 patients were studied on the second day after OLT. The
second postoperative day was chosen because it is the time of peak
metabolic alkalosis, and patients generally were extubated,
hemodynamically stable, required no blood product transfusion, and were
ready for transfer from the intensive care unit to the ward. Additional criteria for postoperative patients, beside those for cirrhotic preoperative patients, were evidence of good graft liver function as
indicated by decreasing plasma aspartate aminotransferase, alanine
aminotransferase, and bilirubin concentrations, and no blood product
transfusion requirement for 24 h. Six healthy individuals without
clinical or laboratory evidence of liver disease were also enrolled as
controls. Postoperative OLT subjects were studied in the VAMC Surgical
Intensive Care Unit, whereas healthy control and preoperative cirrhotic
subjects were studied in the OHSU Clinical Research Center. On the
evening before the isotope infusion protocol, food intake was 18.58 ± 2.13 (SE) cal/kg for controls and 18.33 ± 1.88 cal/kg for
cirrhotic subjects, of which the protein intake was 0.81 ± 0.09 and
0.71 ± 0.11 g/kg, respectively (not different). All subjects were
awake, alert, and postabsorptive for at least 8 h, during
which time they received no intravenous glucose or other sources of
calories. Screening arterial and venous blood samples were drawn before
the start of the stable isotope infusion protocol.
Arterial blood for gas analysis was collected in tubes containing heparin and was analyzed immediately. Blood for assessment of coagulation status, collected in tubes containing sodium citrate, was also analyzed immediately. Samples for NH3 analysis, collected in chilled tubes containing EDTA, were analyzed within 15 min of collection. Samples for determination of plasma concentrations of urea and glucose, and plasma isotopic enrichment of urea and ketoisocaproic acid (KIC), were collected in chilled tubes containing lithium heparin. Samples for analysis of electrolytes, total CO2 content, and creatinine concentrations were collected in chilled tubes without additives.
Infusion protocol. The protocol began at 0700, when one intravenous catheter was placed in an upper extremity for stable isotope tracer infusion, and a second intravenous catheter was placed in the dorsum of the contralateral hand for sampling of "arterialized" blood. The sampling hand was warmed with a heating pad. For postoperative patients, an indwelling central venous catheter was used for isotope infusion, and an indwelling radial arterial catheter was used for blood sampling.
After baseline blood sampling, a 5-h-primed constant infusion of stable
isotope tracers was begun.
[15N2]urea
(99% 15N; Cambridge Isotope
Laboratories, Woburn, MA) was infused in all subjects at 0.135 µmol · kg1 · min
1.
An 81 µmol/kg
[15N2]urea
prime was used for control and postoperative OLT subjects. Preliminary
studies in seven subjects indicated that a
[15N2]urea
prime of 81 µmol/kg was inadequate in cirrhotic patients because it
failed to obtain a plateau in plasma isotopic enrichment in any of the
seven subjects (Fig. 1). Increasing the
[15N2]urea
prime for cirrhotic subjects to 162 µmol/kg produced a steady-state
plateau for urea isotopic enrichment without altering plasma urea
concentration. Control and postoperative subjects were also infused
with [1-13C]leucine
(99% 13C; Cambridge Isotope
Laboratories) at 0.12 µmol · kg
1 · min
1
with a prime of 7.2 µmol/kg. Blood was collected at 210, 240, 270, and 300 min of tracer infusion and centrifuged immediately, and the
plasma was stored at
70°C until isotope analysis.
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Analytical procedures. Arterial blood gases were determined using an automated analyzer (model 1312 blood gas manager; Instrumentation Laboratories, Lexington, MA). Whole blood base excess was calculated using the Siggaard-Andersen alignment nomogram (Radiometer, Copenhagen, Denmark). Plasma NH3 concentration was assayed by glutamate dehydrogenase using an autoanalyzer (model 917; Boehringer Mannheim/Toshiba, Indianapolis, IN; see Ref. 8). Venous plasma concentrations of electrolytes, total CO2, glucose, urea, and creatinine were measured using autoanalyzers (model CX3 and glucose analyzer 2; Beckman Instruments, Brea, CA).
Plasma for urea isotopic enrichment was deproteinated with 1 N acetic
acid, and the urea was isolated from plasma by ion exchange chromatography (Dowex 50W-X8, 100-200 mesh; Bio-Rad Laboratories, Richmond, CA) and dried. Separated urea was esterified by reacting it
with a mixture of acetyl chloride and distilled propanol (1:5 vol/vol)
at 110°C for 20 min. The propyl ester was cooled, evaporated, and
reacted with heptafluorobutyric anhydride (Sigma Chemical, St. Louis,
MO) at 60°C for 20 min to form the
n-propyl ester heptafluorobutyramide derivative. This derivative was dried under
N2 and reconstituted with 400 µl
ethyl acetate. The isotope ratio of the
n-propyl ester heptafluorobutyramide
derivative was measured by negative chemical ionization gas
chromatography-mass spectroscopy (NCI-GC/MS, models 5890e/5989;
Hewlett-Packard, Fullerton, CA), with selective monitoring of ions at
mass-to-charge ratios
(m/z)
236, 237, and 238. "Intracellular" leucine isotope ratio was
determined by measuring the isotope ratio of plasma -KIC (the
transamination product of leucine) by NCI-GC/MS, on the
pentafluorobenzyl derivative of KIC, with selective ion monitoring at
m/z
129 and 130 (17).
Calculations. Urea production rate (Ra urea) was calculated as
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To correct for the possible confounding effect of hypoalbuminemia on acid-base balance (29), we also evaluated acid-base balance using the Stewart physicochemical approach, as modified by Fencl and Leith (14). Apparent strong ion difference (SIDapparent) was calculated as the sum of electrolyte charges (14)
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Statistical analysis. Data are
expressed as means ± SE. One-way ANOVA with Tukey's post hoc test
was used to compare Ra urea and
base excess among groups. Student's
t-test was used to compare postoperative Ra leucine values
with those of controls. Statistical tests were performed using a
specialized software program (Crunch 4; Crunch Software, Oakland, CA).
Differences were considered statistically significant at
P < 0.05. Six subjects per group for
the comparison of Ra urea values
provided statistical power (1
) of 0.8 to detect a
difference of 2.0 µmol · kg
1 · min
1
between groups, with
= 0.05, given mean and SD values of 4.7 and
1.1 µmol · kg
1 · min
1,
respectively, in healthy human volunteers (9, 19, 24).
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RESULTS |
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Baseline characteristics, electrolytes, and acid-base
balance. The control group, consisting of four men and
one woman, averaged 32 ± 3 yr, weighed 68.9 ± 4.4 kg, and had a body mass index of 22.8 ± 1.2 kg/m2. Table
1 shows demographic characteristics of the
two patient groups. The most common etiology for cirrhosis in the
preoperative patients was concomitant ethanol abuse and hepatitis C
viral infection. A broad spectrum of initial presenting liver disease
was represented in the postoperative OLT group. Compared with controls,
the two patient groups were older (P < 0.001) but had similar body weight and body mass index. Cirrhotic
patients did not differ from OLT patients in any demographic
characteristic, including the severity of liver disease immediately
before OLT.
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Table 2 lists screening laboratory and
arterial blood gas values. Compared with controls, cirrhotic patients
were hyponatremic, hypoalbuminemic, hyperbilirubinemic, and
coagulopathic (as evidenced by prolonged prothrombin time). There was
no indication of an acid-base disturbance in cirrhotic patients, as
indexed by either arterial blood base excess or total venous
CO2 content. Postoperative OLT
patients also exhibited hypoalbuminemia, hyperbilirubinemia, and
coagulopathy compared with controls. OLT patients exhibited a marked
metabolic alkalosis, as indexed by both arterial blood base excess and
total venous CO2 content
(P < 0.01). When OLT patients were
compared with preoperative cirrhotics, they exhibited a similar
coagulopathy and hyperbilirubinemia, but arterial base excess was
markedly higher in the OLT patients. Immediate preoperative values for
OLT patients (plasma albumin 3.1 ± 0.1 g/dl, arterial pH 7.43 ± 0.01, arterial PCO2 34.9 ± 1.4 mmHg, arterial HCO3 22.8 ± 0.8 mmol/l, and arterial base excess
0.6 ± 0.7 meq/l) were
comparable to those for cirrhotic subjects. Thus metabolic alkalosis in
postoperative OLT subjects was not present preoperatively.
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Strong ion difference in cirrhotic and postoperative OLT patients. To determine whether arterial acid-base balance was artificially affected by hypoalbuminemia in both cirrhotic and OLT patients, the SID was compared with that in controls (Table 2). Compared with controls, the apparent SID was decreased in cirrhotic patients and increased in OLT patients (P < 0.02). Effective SID, composed of the buffers HCO3, albumin, and phosphate, was decreased in cirrhotic patients (P < 0.001) but not different from controls in the OLT group. Compared with preoperative cirrhotics, OLT patients showed a marked increase in apparent SID and an increased effective SID (P < 0.001). There was no difference in unidentified anion concentration among the three subject groups. No physicochemical evidence was found for an acid-base disturbance in cirrhotic patients vs. controls. In contrast, the metabolic alkalosis in postoperative OLT patients exceeded that which can be accounted for on the basis of hypoalbuminemia.
Effect of cirrhosis and liver transplantation on urea
synthesis and plasma concentration. Plasma urea
isotopic enrichment reached a steady-state plateau in all three groups.
Ra urea and plasma urea
concentrations in controls and cirrhotic and OLT patients are shown in
Fig. 2.
Ra urea in cirrhotic patients was
38% lower than that of controls (P < 0.05, Fig. 2A). Simultaneously,
plasma urea concentration in cirrhotic patients, a proxy for urea pool size, did not differ from the control value (5.71 ± 1.07 vs. 4.64 ± 0.36 mmol/l, Fig. 2B). OLT
patients exhibited an almost threefold greater
Ra urea and plasma urea
concentration (12.14 ± 1.43 mmol/l) than respective control values
(P < 0.001, Fig. 2). When OLT
patients were compared with the cirrhotic group, the OLT
Ra urea was sixfold greater
whereas the plasma urea concentration was only doubled (P < 0.01, Fig. 2). Plasma urea
concentration of the OLT subjects taken immediately before surgery (5.7 ± 0.7 mmol/l) did not differ from that of the cirrhotic group.
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Effect of cirrhosis and liver transplantation on
NH3 concentration and leucine flux.
We measured plasma NH3
concentration, using it as a proxy for
NH3 supply, to evaluate its
possible role in the regulation of
Ra urea. Plasma
NH3 concentration in cirrhotic
patients was twofold higher than the control value
(P < 0.02, Fig.
3). Plasma NH3 concentration in the
postoperative group did not differ from that of controls and was 42%
lower than that in preoperative cirrhotics (P < 0.02). Plasma
NH3 concentration in OLT patients
taken immediately before surgery (38.7 ± 3.5 mmol/l) did not differ
from that in the cirrhotic group.
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DISCUSSION |
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Our study showed that urea synthesis is markedly lower in the presence of end-stage cirrhosis and is stimulated early after OLT. In cirrhosis, the degree of urea synthetic impairment is not reflected by the plasma urea concentration. Compared with the control value, the almost 40% slower Ra urea was not associated with a decreased plasma urea concentration. Furthermore, the marked impairment of urea synthesis, which was accompanied by a doubling of plasma NH3 concentration, did not lead to any appreciable disturbance of acid-base balance. It thus appears that Ra urea does not play a major role in regulation of acid-base balance in cirrhotic patients. On the other hand, the higher Ra urea and concomitant metabolic alkalosis of the OLT group indicate that metabolic alkalosis after OLT is not caused by inhibited urea production.
Fencl and others (14, 29) have argued that an accurate description of
acid-base balance must account for the plasma concentration of strong
electrolytes and weak acids other than
HCO3, i.e., albumin and phosphate. We
therefore evaluated acid-base balance using the physicochemical SID, as
well as the conventional approach of calculated base excess, to assess
acid-base balance. McAuliffe and associates (29) showed that
hypoalbuminemia produces an apparent metabolic alkalosis even in the
setting of normal HCO
3 concentration,
due to loss of the buffering capacity of albumin, such that a decrease
of 1 g of plasma albumin/dl produces a calculated base excess
equivalent to +3.7 meq/l (29). Applying the physicochemical correction
to our cirrhotic patient data yields a hypoalbuminemia-induced
difference in base excess of 3.7 meq/l × 1.2 g/dl = 4.4 meq (see Table 2). Adding this to our calculated base excess of
1.1 meq yields an effective metabolic acidosis, with a base
deficit of 5.5 meq/l, concomitant with a marked decrease in urea
synthesis. Because our cirrhotic patients did not exhibit metabolic
alkalosis regardless of the acid-base approach utilized despite direct
evidence of decreased urea synthesis, our data refute the concept that
impaired urea synthesis precipitates metabolic alkalosis in cirrhosis.
Metabolic alkalosis consistently occurred in our postoperative OLT
patients. When the calculated arterial base excess, 7.0 meq/l, was
corrected for hypoalbuminemia using the physicochemical correction
factor (29), the result is 7.0 4.8 (= 3.7 meq/l × 1.3 g/dl), or + 2.2 meq/l. The hypoalbuminemic correction actually overcorrects for the observed change in base excess in our OLT patients
because they increased the effective SID to a normal value by increased
plasma phosphate and HCO
3 concentrations (see Table 2). Our OLT patients nevertheless exhibited metabolic alkalosis regardless of the method used to assess acid-base balance. Urea synthesis was markedly increased at this time to a rate
consistent with maximal stimulation, such as seen after extensive burn
injury (23). Metabolic alkalosis in our OLT subjects was not caused by
an occult decrease in urea synthesis.
Metabolic alkalosis could be due to increased production or decreased
elimination of HCO3. Increased
HCO
3 production could occur secondary
to increased metabolism of citrate or lactate. Plasma concentrations of
both citrate and lactate are increased during OLT, largely due to their
high concentrations in transfused blood products and decreased
utilization during the preanhepatic and anhepatic stages
of the operation (10, 44). Plasma citrate concentration increases
10-fold during the anhepatic period of OLT but decreases to within
normal limits by 24 h postoperatively (10). Plasma lactate
concentration increases sevenfold during OLT but is also within normal
limits by 24 h postoperatively (44). Thus the potential effect of
citrate and lactate on postoperative day
2, when the present study was conducted, is minimal.
Furthermore, a dichloroacetate-induced 50% decrease in peak
intraoperative plasma lactate concentration fails to alter the
magnitude of metabolic alkalosis after OLT (44).
Decreased HCO3 elimination, secondary
to furosemide therapy and consequent hypovolemia, could increase
HCO
3 (and total
CO2) concentration.
Postoperative OLT patients at our institution are all routinely infused
with furosemide and dopamine (2-3
µg · kg
1 · min
1). Furosemide
increases urinary chloride loss in excess of
Na+ loss, with
HCO
3 retained for electroneutrality. Dopamine combined with furosemide induces a functional hypovolemia that
perpetuates metabolic alkalosis by preventing adequate urinary HCO
3 excretion (3). It is likely that
the furosemide/dopamine diuretic regimen plays a major role in the metabolic alkalosis exhibited by our OLT patients.
Normal HCO3 flux in unstressed humans
is 128-164
µmol · kg
1 · min
1
(22), which is 30-fold greater than the control urea flux of 4-5
µmol · kg
1 · min
1
observed in the present and in previous studies (19, 24). Because each
mole of urea synthesized consumes a net equivalent of two moles of
HCO
3, a threefold increase in urea
synthesis would only increase HCO
3
consumption by ~10%. In subjects recovering from abdominal surgery,
in whom HCO
3 flux may be increased by
another 5-10% (5, 12), the impact of increased urea synthesis on
acid-base balance would be even smaller. Stimulated urea synthesis,
while not a major factor maintaining acid-base balance, may still play a minor role to ameliorate the metabolic alkalosis produced elsewhere.
The mechanism stimulating urea synthesis in our postoperative OLT
patients is uncertain. Two factors that stimulate urea synthesis are
NH3 and
HCO3 (2, 18, 35, 40). Our data provide
indirect evidence that both may be involved to different degrees.
Compared with that in healthy controls, leucine flux, an indicator of
whole body proteolysis, was increased 50% in the OLT group. This
indicates a mild protein catabolic response on postoperative
day 2, which would increase
amino-nitrogen supply for conversion to
NH3 and subsequent urea synthesis.
We previously demonstrated that, in both severely burned and septic
patients, the stress-induced percentage increase in leucine flux above
the healthy control value is paralleled by an almost identical percent increase in Ra urea (23). If the
same relationship between leucine flux and
Ra urea exists in OLT patients,
the 50% increase in leucine flux would be matched by a 50% increase
in Ra urea. Instead,
Ra urea in our OLT patients was
increased 400% compared with controls, suggesting that
proteolysis-induced NH3 supply
accounts for one-eighth of the increase in
Ra urea by our OLT subjects.
Plasma NH3 concentration was not
increased above the control value in our postoperative patients. On the
other hand, plasma HCO
3 concentration in OLT patients is persistently increased, and
HCO
3 stimulates urea synthesis both in
vivo (4) and in vitro (2, 20, 26). We speculate that most (>80%) of
the increase in Ra urea by OLT
patients was due to an increased HCO
3 supply.
Our finding of decreased urea synthesis in patients with end-stage liver disease differs from the results of Fabbri et al. (13), who detected no decrease in urea synthesis by cirrhotics using an indirect method. Their cirrhotic patients, however, had milder disease as a group, only half of whom had end-stage disease (13). Moreover, their indirect method measured the increase in urea concentration in a defined "urea space" that is sensitive to errors in determination of the urea space. This method also assumes that renal urea excretion is unchanged by cirrhosis. Fabbri et al. (13) did find that urea synthesis in cirrhotic patients is refractory to stimulation by alanine or glucagon infusion. On the other hand, our data are consistent with the results of Fujii et al. (16) and Rypins et al. (42). Fujii et al. (16) demonstrated a 60% decrease in urea synthesis from 15NH4Cl in patients with end-stage liver disease. However, assessment of urea synthesis by measuring incorporation of 15NH4Cl into urea is inaccurate for reasons already stated in the introduction. Rypins et al. (42) measured urea synthesis by an unprimed constant infusion of [14C]urea and reported a 30% decrease in Ra urea by cirrhotics, of whom only 4 of 10 had end-stage disease. [14C]urea, like [15N2]urea, is an appropriate tracer for urea synthesis (24). It is noteworthy that Rypins et al. (42) required twice as long for cirrhotic patients to obtain a steady-state isotopic plateau compared with healthy volunteers, which is consistent with the larger priming dose requirement in our cirrhotic patients (Fig. 1).
Urea pool size is determined by the difference between the rate of urea
synthesis and its rate of disposal via renal excretion plus colonic
hydrolysis and salvage of urea (30). A plasma urea concentration in our
cirrhotics that did not differ from that of healthy controls, despite a
slower synthetic rate, could be explained by either a decreased volume
of distribution or impaired disposal of urea. Our failure to adequately
label the body urea pool in cirrhotics using a standard priming dose
indicates that the volume of distribution for urea in cirrhotics is
expanded rather than contracted. This suggests a marked decrease in
urea disposal by cirrhotics, coincident with decreased synthesis.
Meakins and Jackson (30) evaluated the relationship between
diet-related changes in urea synthesis and urea disposal. When they
decreased dietary protein intake from adequate, 0.90 g · kg1 · day
1,
to inadequate, 0.39 g · kg
1 · day
1, the consequent
~50% decrease in urea production (from 5.2 to 2.9 µmol · kg
1 · min
1)
in turn decreased plasma urea concentration and urea pool size by only
~10% (30). Urea pool size and plasma concentration were conserved
secondary to a 33% decrease in renal urea excretion during the
protein-deficient diet (30). Urea production rates and corresponding
plasma urea concentrations reported by Meakins and Jackson (30) for the
healthy subjects on the adequate and inadequate protein intakes are
almost identical to those of the controls and cirrhotic patients in the
present study (see Fig. 2). Together these findings suggest that a
physiological decrease in renal urea excretion in response to a marked
decrease in urea production occurs to maintain urea pool size. That is,
renal urea clearance may be decreased despite adequate renal function
in the cirrhotic patients.
It is tempting to speculate that the adaptation to maintain urea pool size may be necessary to facilitate movement of urea into the colon for hydrolysis and salvage. However, such a notion was ruled out by Meakins and Jackson (30), who showed that the rate of urea hydrolysis decreased by 60% on the inadequate protein diet, despite maintenance of urea pool and plasma concentration near control values. There is also the possibility that renal urea elimination is pathologically compromised in cirrhotic subjects despite their normal plasma creatinine concentration. Caregaro et al. (6) found a markedly decreased creatinine clearance in cirrhotics despite a normal plasma creatinine concentration. Even creatinine clearance greatly underestimates true renal dysfunction, compared with inulin clearance, in cirrhotic patients (6). Subclinical renal dysfunction may mask the loss of urea production by limiting renal elimination and maintaining an unchanged plasma urea concentration. A limitation of the present study is that we did not undertake a more precise measure of renal function.
Slower urea synthesis could result from either a reduction in dietary
protein intake or a defect in hepatic synthetic capacity. It is
unlikely that the slower urea synthetic rate in our cirrhotic patients
was due to a lower intake of protein as the intake of the cirrhotic
patients on the evening before the study, 0.71 g/kg, did not differ
from the 0.81 g/kg of healthy controls. Langran et al. (27) showed
that, in healthy adults on a similar protein intake, 1 g · kg1 · day
1,
the rate of urea production, 4.81 µmol · kg
1 · min
1,
was almost identical to the 5.0 µmol · kg
1 · min
1
of our controls. Furthermore, there was only a modest decrease (~10%) in urea production when dietary protein intake was decreased from 1 to 0.5 g · kg
1 · day
1
(27). In a similar study, Meakins and Jackson (30) showed that urea
production decreased significantly only when dietary protein intake
fell to 0.39 g · kg
1 · day
1.
Hence it is unlikely that the 40% lower urea production rate by
cirrhotic patients was due to less dietary protein intake. Protein
catabolism, as indexed by leucine flux, is either unchanged (32, 43) or
modestly increased (45) in cirrhotic subjects. On the other hand, the
concomitant elevation in plasma
NH3 concentration indicates that
urea synthesis was likely compromised due to an ornithine cycle defect.
Our finding of a twofold increased plasma NH3 concentration in cirrhosis is
comparable to that previously reported in patients with stable
end-stage liver disease (32, 36).
Increased leucine flux in our postoperative OLT patients is comparable to that exhibited by patients with sepsis or after severe burn injury (23). However, our OLT patients showed no concomitant increase in plasma NH3 concentration. Plasma NH3 concentration is reported to normalize within 24 h after OLT, possibly even before the patient leaves the operating room, in the setting of good graft liver function (11, 36, 39). It is important to distinguish the meaning of increased leucine flux (or proteolysis) in the postoperative patient, because there are other routes for liberated amino acids besides oxidation and release of the NH3 group to aspartate or glutamine and, ultimately, urea. One important pathway for the extra amino acids released by stress-induced proteolysis is reincorporation into newly synthesized protein, e.g., the acute-phase proteins, a pathway not quantitated in the present study.
To summarize, first, there is a marked impairment of urea synthesis in
patients with cirrhosis that is not reflected by a parallel decrease in
plasma urea nitrogen concentration. This defect does not appear to
affect acid-base balance. Second, urea synthesis by the
well-functioning graft liver is not inhibited. Instead, stimulated urea
production early after OLT appears to be a physiological response to
increased HCO3 supply, possibly
attenuating the severity of the alkalosis.
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ACKNOWLEDGEMENTS |
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This work was supported in part by a Clinical Scientist Research Award from the International Anesthesia Research Society, Division of Research Resources Grant M01 RR-00334, and federal funds from the United States Dept. of Agriculture, Agricultural Research Service (Cooperative Agreement no. 58-6250-1-003).
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: R. E. Shangraw, Dept. of Anesthesiology, UHS-2, Oregon Health Sciences Univ., 3181 SW Sam Jackson Park Rd., Portland, OR 97201-3098 (E-mail: shangraw{at}ohsu.edu).
Received 28 August 1998; accepted in final form 1 January 1999.
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