administration
Friedrich
E. Easterling,
K. Port,
M.D.,
Ronald
ABSTRACT
An
eight normal hemodialysis. infusion, term
there study,
dialysis
infusion
of
was
acetate
no
patients.
Am.
not
appear
J. C/in.
JournalofClinical
Nutrition
sodium
Nutr.
31: OCTOBER
Rex
V. Barnes,
acetate
was
of acetate had almost
cholesterol
to be
Acetate has been widely used in clinical hemodialysis as a substitute for bicarbonate. The concentration of acetate used in the dialysate bath varies from 30 to 40 mEq/liter, which is in the range of the initial recommendation by Mion et al. (1) in 1964. The buffering action of acetate requires metabolism via acetyl CoA which utilizes hydrogen ions gencrating 1 mole bicarbonate for each mole acetate mobilized. We have been interested in the metabolism of acetate since we demonstrated in some patients “acetate intolerance” which is related to a low metabolic clearance of acetate as compared to high transfer rates from large surface hemodialyzers (2, 3). The acetate transferred from the dialysis bath to the patient can be metabolized along several major pathways: 1) via the Krebs cycle to CO2 and water, generating energy, 2) to cholesterol synthesis, and 3) to fatty acid and triglyceride synthesis. Hypertriglyceridemia has been reported to occur in 35 to 68% of patients maintained by chronic intermittent hemodialysis (4, 5). This is probably less prevalent in patients with end-stage renal failure not requiring hemodialysis (6). Tsaltas (7) suggested the possibility that acetate might contribute to the hypertriglyceridemia in dialysis patients. Other factors probably play important roles such as toxicity related to uremia (6), increased synthesis as suggested by hyperinsulinemia (8), and impaired degradation of triglycerides as indicated by decreased lipoprotein lipase activity (8, 9). The purpose ofthis study was to investigate a possible contributing effect of acetate adThe American
and
the transfer concentrations
in serum
increase
does
M.D.,
180 mEq
volunteers simulating While serum acetate
on
and
a major
to nine
that occurs normalized
triglyceride
contributing
3 1: 1893-1896,
given
M.D.
dialysis
concentrations. factor
patients
and
during 30 mm of rapid 15 mm after the end of for
the
In this
short-
hyperlipidemia
of
1978.
ministration on hyperlipidemia in the setting an infusion experiment which was designed to avoid interference by factors related to dialysis itself such as heparin administration and dialyzer clearance of intermediate metabolites.
of
Methods Nine unselected patients with end-stage chronic renal failure were studied after they had been stable on chronic intermittent hemodialysis using the 2.5 M2 hollow fiber artificial kidney 4 hr thrice weekly. All studies were performed in the fasting state just before a regularly scheduled dialysis treatment. Serial blood samples were obtained from the fistula vein using an indwelling dialysis needle. A solution containing 180 mEq sodium acetate in 500 ml sterile water was infused into a vein of the nonfistulated arm at a constant rate over 28 to 30 min. One patient underwent a repeated study. As a control group, eight volunteers ofour health care group with normal serum creatinine concentrations were studied in the same fashion after an overnight fast. They received the same infusion, and blood was sampled from the contralateral arm. Urinary excretion of acetate was determined over the 45-mm period of observation. The rate of infusion was chosen according to data obtained from our in vitro (3) and in vivo clearance studies. Using the 2.5 M2 hollow fiber artificial kidney, in vitro transfer rates for acetate from the dialysis bath averaged (±SEM) 349.9 ± 16.8 and 437.2 ± 5.4 mEq/hr for blood flow rates of 200 and 300 mI/minute, respectively. Subsequent in vivo measurements during clinical dialysis with the same dialyzer gave average transfer rates to the patient of 278.4 ± 36.0 mEq/hour at a blood flow of 200 mh/minute. Thus the infusion of 180 mEq over 30 mm (rate of 360 mEq/hour) was an approximation of the rate of acetate transfer that occurs during
I From ministration 2
Grant
the
Supported
University of Michigan and Hospital, Ann Arbor, Michigan. by the Michigan Heart
Veterans
Ad-
Association,
340725.
1978, pp. 1893-1896.
Printed
in U.S.A.
1893
Downloaded from https://academic.oup.com/ajcn/article-abstract/31/10/1893/4656057 by Boston University Libraries user on 13 January 2019
Effect of acetate blood lipids1’2
1894
PORT
ET
pH of arterialized fistula blood for patients and venous blood for normal volunteers increased significantly in both groups (P < 0.01) and remained almost constant after termination o the infusion (Table 1). Serum cholesterol concentrations were similar in patients and normal subjects averaging respectively 174.4 ± 16.7 and 182.9 ± 15.5 mg/lOO ml before infusion. At the end of infusion corresponding mean values had decreased by 15.8 and 14.9 mg/ 100 ml. Fifteen minutes later mean cholesterol concentrations were still below the preinfusion levels (Fig. 2). The differences between the two groups were not significant. Mean serum triglyceride concentrations were higher in the patient group (148.0 ± 1 1.2 mg/lOO ml) than in the control group (1 10.5 ± 18.1 mg/lOO ml) as shown in Figure
Results Intravenous infusion ofsodium acetate was well tolerated by patients and normal volunteers. Subjects with normal renal function (serum creatinine concentration less than 1.3 mg/ 100 ml) had urinary losses of acetate ranging from 1.0 to 4.2 mEq in 204 ± 42 ml during the 45 mm of observation. Serum acetate concentration increased in all studies and showed significantly higher values in the patient group at 20 and 30 min (P < 0.05) and reached almost pre-infusion values at the end of observation (Fig. 1). The
2OOftlSubts 4
Dialysis Patients
(n9)
Dialysis
0.05). During acetate infusion these concentrations decreased significantly in patients and control subjects (P < 0.05). At the end of observation triglyceride concentration in the patient group had decreased by 10.3 mg/l00 ml even though three patients showed an increase by 2 to 11 mg/ 100 ml. In the control group the reduction in triglyceride level appeared more marked. Measurements of serum lactate and pyruvate concentrations revealed no significant changes during or after infusion of sodium acetate (Table 1). Discussion The infusion of sodium acetate at a rate similar to that occurring during highly efficient hemodialysis has the disadvantage that the amount that can be given safely to anuric patients is limited by the risk of volume overload. Approximately one eighth of the total amount transferred during 4 hr of dialysis was infused. This design however allowed an evaluation independent of heparinization, changes in glucose balance, and clearance of important metabolites as would necessarily occur in a study of hemodialysis. It allows furthermore a comparison with a normal control group and considers, therefore, influences of the uremic state on a possible lipogenic
BLOOD
LIPIDS
1895
effect of acetate. Urinary losses of acetate were negligible in subjects with normal renal function, accounting for 0.6 to 2.3% of the amount infused. The absence of an increase in serum cholesterol or triglyceride concentrations is particularly interesting in view of the slightly elevated serum triglyceride levels in the uremic group. Acetate was metabolized rapidly in all patients studied as indicated by the slope for serum acetate concentrations during the 15 mm after the infusion. None of the patients studied had a pattern of impaired acetate tolerance and prolonged metabolic clearance of acetate. The possible effect of impaired acetate metabolism (2) on lipogenesis remains to be studied. Recent studies in rats (13) and dogs (14) suggest that approximately 30 to 35% of ‘4Cacetate may be utilized other than in the Krebs cycle, and small but significant amounts of radioactive label were detected in triglyceride and phospholipid fractions. A very rapid incorporation of acetate into tnglycerides was shown by Hennes (15) in nonuremic patients suggesting that an increase in triglyceride concentration could have been observed during the short period of observation. The mechanism for the decrease in serum lipid concentration is unexplained but may be in part due to the dilutional effect of the acetate infusion. Our negative fmdings for acetate related lipogenesis have recently been supported by a long-term comparative study (16) on the effect of intermittent hemodialysis with acetate versus bicarbonate containing dialysate over periods of 3 to 5 weeks alternatingly in 9 patients. No changes in serum cholesterol or triglyceride concentrations were observed at the end of repeated study periods. Our data do not rule out the possibility that some acetate is incorporated into triglycendes; however, from this short-term study it appears unlikely that acetate plays a major role in lipogenesis. References 1. MION, C. M., R. M. HEGSTROM, S. T. BOEN AND B. H. SCRIBNER. Substitution of sodium acetate for sodium bicarbonate in the bath fluid for hemodialysis. Trans. Am. Soc. Artif. Internal Organs 10: 110, 1964. 2. NOVELLO, A., R. C. KELSCH AND R. E. EASTERLING.
Downloaded from https://academic.oup.com/ajcn/article-abstract/31/10/1893/4656057 by Boston University Libraries user on 13 January 2019
Dialysis
15o.
ON
1896
PORT
AL. Med.
134: 603, 1970. W. D., K. J. JARRETr, JR. AND J. B. LEVINE. An improved automated determination of serum total cholesterol with a single color reagent. Clin. Chem. 12: 681, 1966. 1 1. BLOCK, W. D., AND K. J. JARRE1-F, JR. An automated technique for the quantitative determination of serum total triglycerides. Am. J. Med. Technol. 35:1, 1969. 12. ROSE, I. A., M. GRUNBERG-MANAGO, S. R. KOREY AND S. OCHOA. Enzymatic phosphorylation of acetate. J. Biol. Chem. 21 1: 737, 1954. 13. COCKBURN, R. M., AND J. T. VAN BRUGGEN. Acetate metabolism in vivo: effect of refeeding. J. Biol. Chem. 234: 431, 1959. 14. RoRiut, S. J., W. D. DAVIDSON, R. J. MORIN AND L. 10.
BLOCK,
GU0.
Metabolic
hemodialysis. 15.
HENNES,
16.
adrenal 1962.
fate
of
acetate
in dogs
E., J. F. MAHONY AND J. Effect ofacetate on serum lipids during hemodialysis. Am. Soc. Artif. Internal
SAVDIE,
1977.
undergoing
Chin. Res. 24: 4A, 1976. A. Abnormalities in acetate metabolism insufficiency in man. Am. J. Med. 32:
in 343,
H. STEWART. maintenance Organs 6: 76,
Downloaded from https://academic.oup.com/ajcn/article-abstract/31/10/1893/4656057 by Boston University Libraries user on 13 January 2019
Acetate intolerance during hemodialysis. Chin. Nephrol. 5: 29, 1976. 3. PORT, F. K., AND R. E. EASTERLING. Evaluation of acetate tolerance during highly efficient hemodialysis. Proc. Dial. Transplant. Forum 5: 128, 1975. 4. SAMiR, R. E., 1 W. MONCRIEF, J. F. DECHERD AND R. P. POPOVICH. Lipoprotein binding and hypertriglyceridemia in chronic uremia. Trans. Am. Soc. Artif. Internal Organs 21: 455, 1975. 5. GUTMAN, R A., A. Uy, R. J. SHALHOUB, A. D. WADE, J. M. B. O’CONNELL AND L. RECANT. Hypertriglyceridemia in chronic non-nephrotic renal failure. Am. J. Chin. Nutr. 26: 165, 1973. 6. BAGDADE, J. D. Uremic lipemia, an unrecognized abnormality in triglyceride production and removal. Arch. Internal Med. 126: 875, 1970. 7. TSALTAS, T. T. Uremic lipemia, discussion. Arch. Internal Med. 126: 880, 1970. 8. BAGDADE, J. D., D. PORTE, JR. AND E. L. BIERMAN. Hypertriglyceridemia, a metabolic consequence of chronic renal failure. New Engl. J. Med. 279: 181, 1968. 9. BOYER, J. L., AND R. L. SCHEIG. Inhibition of postheparin lipolytic activity in uremia and its relationship to hypertriglycendemia. Proc. Soc. Exptl. Biol.
ET
Friedrich
E. Easterling,
K. Port,
M.D.,
Ronald
ABSTRACT
An
eight normal hemodialysis. infusion, term
there study,
dialysis
infusion
of
was
acetate
no
patients.
Am.
not
appear
J. C/in.
JournalofClinical
Nutrition
sodium
Nutr.
31: OCTOBER
Rex
V. Barnes,
acetate
was
of acetate had almost
cholesterol
to be
Acetate has been widely used in clinical hemodialysis as a substitute for bicarbonate. The concentration of acetate used in the dialysate bath varies from 30 to 40 mEq/liter, which is in the range of the initial recommendation by Mion et al. (1) in 1964. The buffering action of acetate requires metabolism via acetyl CoA which utilizes hydrogen ions gencrating 1 mole bicarbonate for each mole acetate mobilized. We have been interested in the metabolism of acetate since we demonstrated in some patients “acetate intolerance” which is related to a low metabolic clearance of acetate as compared to high transfer rates from large surface hemodialyzers (2, 3). The acetate transferred from the dialysis bath to the patient can be metabolized along several major pathways: 1) via the Krebs cycle to CO2 and water, generating energy, 2) to cholesterol synthesis, and 3) to fatty acid and triglyceride synthesis. Hypertriglyceridemia has been reported to occur in 35 to 68% of patients maintained by chronic intermittent hemodialysis (4, 5). This is probably less prevalent in patients with end-stage renal failure not requiring hemodialysis (6). Tsaltas (7) suggested the possibility that acetate might contribute to the hypertriglyceridemia in dialysis patients. Other factors probably play important roles such as toxicity related to uremia (6), increased synthesis as suggested by hyperinsulinemia (8), and impaired degradation of triglycerides as indicated by decreased lipoprotein lipase activity (8, 9). The purpose ofthis study was to investigate a possible contributing effect of acetate adThe American
and
the transfer concentrations
in serum
increase
does
M.D.,
180 mEq
volunteers simulating While serum acetate
on
and
a major
to nine
that occurs normalized
triglyceride
contributing
3 1: 1893-1896,
given
M.D.
dialysis
concentrations. factor
patients
and
during 30 mm of rapid 15 mm after the end of for
the
In this
short-
hyperlipidemia
of
1978.
ministration on hyperlipidemia in the setting an infusion experiment which was designed to avoid interference by factors related to dialysis itself such as heparin administration and dialyzer clearance of intermediate metabolites.
of
Methods Nine unselected patients with end-stage chronic renal failure were studied after they had been stable on chronic intermittent hemodialysis using the 2.5 M2 hollow fiber artificial kidney 4 hr thrice weekly. All studies were performed in the fasting state just before a regularly scheduled dialysis treatment. Serial blood samples were obtained from the fistula vein using an indwelling dialysis needle. A solution containing 180 mEq sodium acetate in 500 ml sterile water was infused into a vein of the nonfistulated arm at a constant rate over 28 to 30 min. One patient underwent a repeated study. As a control group, eight volunteers ofour health care group with normal serum creatinine concentrations were studied in the same fashion after an overnight fast. They received the same infusion, and blood was sampled from the contralateral arm. Urinary excretion of acetate was determined over the 45-mm period of observation. The rate of infusion was chosen according to data obtained from our in vitro (3) and in vivo clearance studies. Using the 2.5 M2 hollow fiber artificial kidney, in vitro transfer rates for acetate from the dialysis bath averaged (±SEM) 349.9 ± 16.8 and 437.2 ± 5.4 mEq/hr for blood flow rates of 200 and 300 mI/minute, respectively. Subsequent in vivo measurements during clinical dialysis with the same dialyzer gave average transfer rates to the patient of 278.4 ± 36.0 mEq/hour at a blood flow of 200 mh/minute. Thus the infusion of 180 mEq over 30 mm (rate of 360 mEq/hour) was an approximation of the rate of acetate transfer that occurs during
I From ministration 2
Grant
the
Supported
University of Michigan and Hospital, Ann Arbor, Michigan. by the Michigan Heart
Veterans
Ad-
Association,
340725.
1978, pp. 1893-1896.
Printed
in U.S.A.
1893
Downloaded from https://academic.oup.com/ajcn/article-abstract/31/10/1893/4656057 by Boston University Libraries user on 13 January 2019
Effect of acetate blood lipids1’2
1894
PORT
ET
pH of arterialized fistula blood for patients and venous blood for normal volunteers increased significantly in both groups (P < 0.01) and remained almost constant after termination o the infusion (Table 1). Serum cholesterol concentrations were similar in patients and normal subjects averaging respectively 174.4 ± 16.7 and 182.9 ± 15.5 mg/lOO ml before infusion. At the end of infusion corresponding mean values had decreased by 15.8 and 14.9 mg/ 100 ml. Fifteen minutes later mean cholesterol concentrations were still below the preinfusion levels (Fig. 2). The differences between the two groups were not significant. Mean serum triglyceride concentrations were higher in the patient group (148.0 ± 1 1.2 mg/lOO ml) than in the control group (1 10.5 ± 18.1 mg/lOO ml) as shown in Figure
Results Intravenous infusion ofsodium acetate was well tolerated by patients and normal volunteers. Subjects with normal renal function (serum creatinine concentration less than 1.3 mg/ 100 ml) had urinary losses of acetate ranging from 1.0 to 4.2 mEq in 204 ± 42 ml during the 45 mm of observation. Serum acetate concentration increased in all studies and showed significantly higher values in the patient group at 20 and 30 min (P < 0.05) and reached almost pre-infusion values at the end of observation (Fig. 1). The
2OOftlSubts 4
Dialysis Patients
(n9)
Dialysis
0.05). During acetate infusion these concentrations decreased significantly in patients and control subjects (P < 0.05). At the end of observation triglyceride concentration in the patient group had decreased by 10.3 mg/l00 ml even though three patients showed an increase by 2 to 11 mg/ 100 ml. In the control group the reduction in triglyceride level appeared more marked. Measurements of serum lactate and pyruvate concentrations revealed no significant changes during or after infusion of sodium acetate (Table 1). Discussion The infusion of sodium acetate at a rate similar to that occurring during highly efficient hemodialysis has the disadvantage that the amount that can be given safely to anuric patients is limited by the risk of volume overload. Approximately one eighth of the total amount transferred during 4 hr of dialysis was infused. This design however allowed an evaluation independent of heparinization, changes in glucose balance, and clearance of important metabolites as would necessarily occur in a study of hemodialysis. It allows furthermore a comparison with a normal control group and considers, therefore, influences of the uremic state on a possible lipogenic
BLOOD
LIPIDS
1895
effect of acetate. Urinary losses of acetate were negligible in subjects with normal renal function, accounting for 0.6 to 2.3% of the amount infused. The absence of an increase in serum cholesterol or triglyceride concentrations is particularly interesting in view of the slightly elevated serum triglyceride levels in the uremic group. Acetate was metabolized rapidly in all patients studied as indicated by the slope for serum acetate concentrations during the 15 mm after the infusion. None of the patients studied had a pattern of impaired acetate tolerance and prolonged metabolic clearance of acetate. The possible effect of impaired acetate metabolism (2) on lipogenesis remains to be studied. Recent studies in rats (13) and dogs (14) suggest that approximately 30 to 35% of ‘4Cacetate may be utilized other than in the Krebs cycle, and small but significant amounts of radioactive label were detected in triglyceride and phospholipid fractions. A very rapid incorporation of acetate into tnglycerides was shown by Hennes (15) in nonuremic patients suggesting that an increase in triglyceride concentration could have been observed during the short period of observation. The mechanism for the decrease in serum lipid concentration is unexplained but may be in part due to the dilutional effect of the acetate infusion. Our negative fmdings for acetate related lipogenesis have recently been supported by a long-term comparative study (16) on the effect of intermittent hemodialysis with acetate versus bicarbonate containing dialysate over periods of 3 to 5 weeks alternatingly in 9 patients. No changes in serum cholesterol or triglyceride concentrations were observed at the end of repeated study periods. Our data do not rule out the possibility that some acetate is incorporated into triglycendes; however, from this short-term study it appears unlikely that acetate plays a major role in lipogenesis. References 1. MION, C. M., R. M. HEGSTROM, S. T. BOEN AND B. H. SCRIBNER. Substitution of sodium acetate for sodium bicarbonate in the bath fluid for hemodialysis. Trans. Am. Soc. Artif. Internal Organs 10: 110, 1964. 2. NOVELLO, A., R. C. KELSCH AND R. E. EASTERLING.
Downloaded from https://academic.oup.com/ajcn/article-abstract/31/10/1893/4656057 by Boston University Libraries user on 13 January 2019
Dialysis
15o.
ON
1896
PORT
AL. Med.
134: 603, 1970. W. D., K. J. JARRETr, JR. AND J. B. LEVINE. An improved automated determination of serum total cholesterol with a single color reagent. Clin. Chem. 12: 681, 1966. 1 1. BLOCK, W. D., AND K. J. JARRE1-F, JR. An automated technique for the quantitative determination of serum total triglycerides. Am. J. Med. Technol. 35:1, 1969. 12. ROSE, I. A., M. GRUNBERG-MANAGO, S. R. KOREY AND S. OCHOA. Enzymatic phosphorylation of acetate. J. Biol. Chem. 21 1: 737, 1954. 13. COCKBURN, R. M., AND J. T. VAN BRUGGEN. Acetate metabolism in vivo: effect of refeeding. J. Biol. Chem. 234: 431, 1959. 14. RoRiut, S. J., W. D. DAVIDSON, R. J. MORIN AND L. 10.
BLOCK,
GU0.
Metabolic
hemodialysis. 15.
HENNES,
16.
adrenal 1962.
fate
of
acetate
in dogs
E., J. F. MAHONY AND J. Effect ofacetate on serum lipids during hemodialysis. Am. Soc. Artif. Internal
SAVDIE,
1977.
undergoing
Chin. Res. 24: 4A, 1976. A. Abnormalities in acetate metabolism insufficiency in man. Am. J. Med. 32:
in 343,
H. STEWART. maintenance Organs 6: 76,
Downloaded from https://academic.oup.com/ajcn/article-abstract/31/10/1893/4656057 by Boston University Libraries user on 13 January 2019
Acetate intolerance during hemodialysis. Chin. Nephrol. 5: 29, 1976. 3. PORT, F. K., AND R. E. EASTERLING. Evaluation of acetate tolerance during highly efficient hemodialysis. Proc. Dial. Transplant. Forum 5: 128, 1975. 4. SAMiR, R. E., 1 W. MONCRIEF, J. F. DECHERD AND R. P. POPOVICH. Lipoprotein binding and hypertriglyceridemia in chronic uremia. Trans. Am. Soc. Artif. Internal Organs 21: 455, 1975. 5. GUTMAN, R A., A. Uy, R. J. SHALHOUB, A. D. WADE, J. M. B. O’CONNELL AND L. RECANT. Hypertriglyceridemia in chronic non-nephrotic renal failure. Am. J. Chin. Nutr. 26: 165, 1973. 6. BAGDADE, J. D. Uremic lipemia, an unrecognized abnormality in triglyceride production and removal. Arch. Internal Med. 126: 875, 1970. 7. TSALTAS, T. T. Uremic lipemia, discussion. Arch. Internal Med. 126: 880, 1970. 8. BAGDADE, J. D., D. PORTE, JR. AND E. L. BIERMAN. Hypertriglyceridemia, a metabolic consequence of chronic renal failure. New Engl. J. Med. 279: 181, 1968. 9. BOYER, J. L., AND R. L. SCHEIG. Inhibition of postheparin lipolytic activity in uremia and its relationship to hypertriglycendemia. Proc. Soc. Exptl. Biol.
ET
