Metabolic and Hemodynamic Advantages of an Acetate-Free Citrate Dialysate in a Uremic Case of Congenital Methylmalonic Acidemia

Clinical History and Initial Laboratory Data 

A 26-year-old woman was admitted to the emergency department of Jichi Medical University Hospital, Shimotuke, Tochigi, Japan, on October 10, 2007, with fever, cough, and vomiting that had persisted for several days. She was the second child born to nonconsanguineous parents after a full-term normal pregnancy, and her elder sister did not have medical problems. At age 1 month, her growth had been slightly delayed because of weak breastfeeding, and at 3 months, she was vomiting 1 to 2 times daily. MMA was diagnosed at 6 months of age, but genetic analysis was not performed. During infancy, she received vitamin B12 therapy, but her symptoms did not improve. At 2 years of age, she had a severe acidosis episode that resulted in spastic leg paralysis. Subsequently, she had intermittent acidosis episodes. At 12 years of age, serum urea nitrogen (SUN) and serum creatinine levels were 7 mg/dL (2.5 mmol/L) and 1.0 mg/dL (88 μmol/L), respectively. Her kidney function then gradually deteriorated. At a regular medical checkup in August 2007, SUN and serum creatinine levels were 56 mg/dL (20.0 mmol/L) and 4.7 mg/dL (415 μmol/L), respectively. Estimated glomerular filtration rate was 10.5 mL/min/1.73 m2 (0.18 mL/s/1.73 m2).

At hospitalization, SUN and serum creatinine levels were 64 mg/dL (22.8 mmol/L) and 6.04 mg/dL (534 μmol/L), respectively. Acute-on-chronic renal failure was diagnosed that probably was precipitated by acute bronchitis and dehydration. After admission, the patient was treated with intravenous infusion and injection of furosemide in addition to antibiotics. On October 15, SUN and serum creatinine levels were increased to 74 mg/dL (26.4 mmol/L) and 7.26 mg/dL (642 μmol/L), respectively.

HD was initiated for 3 hours 3 times each week, and nausea and vomiting disappeared gradually. HD first was performed using an acetate-containing bicarbonate dialysate (AK Solita DP; Ajinomoto Corp), but the patient's blood pressure (BP) was unstable during these sessions and she sometimes reported systemic flushing when she had acute hypotension. In patients with MMA, there is a tendency for methylmalonic, methylcitric, propionic, and acetic acids to accumulate in serum because of enzymatic deficiencies, and we were concerned about an overload of acetic acid with use of the acetate-containing dialysate. Therefore, she was switched to HD with a citrate dialysate (Carbostar). This led to a dramatic decrease in acute hypotension, and she became asymptomatic during HD. Based on this observation, we studied the changes in hemodynamic and laboratory data associated with the switch from acetate to citrate dialysate.

Additional Investigations 

HD using an acetate or citrate dialysate was performed 6 times sequentially. The composition of the 2 dialysates is listed in Table 1. The patient gave informed consent to undergo HD using each dialysate. Both treatments were performed under the same conditions using an APS-13S polysulfone membrane (Asahi Medical, Tokyo, Japan) with the same dry weight and ultrafiltration rate. Dialysate flow and blood flow were 500 and 150 mL/min, respectively. Each treatment lasted 180 minutes, with use of 500 U/h of heparin. BP and heart rate were measured every 30 minutes. A Crit-Line III TOA (JMS Corp, Tokyo, Japan) was used to monitor the change in blood volume, and a Physio Flow Lab-1 impedance cardiograph (Manatec Biomedical, Macheren, France) was used to evaluate hemodynamic status by noninvasive measurement of cardiac output and systemic vascular resistance.16 Blood samples were collected before (from systemic arterial circulation), at the midpoint, and after (from the arterial dialysis tubing) HD to determine pH and bicarbonate, ionized calcium, acetoacetic acid, 3-hydroxybutyric acid, and acetate levels. Acetoacetic acid and 3-hydroxybutyric acid were assayed enzymatically by using 3-HB (for 3-hydroxybutyric acid) and Total Ketone Body kits (Kainos Laboratories, Tokyo, Japan), and acetate was assayed by using an F-kit (R-Biopharm AG, Darmstadt, Germany).

Table 1. Composition of Acetate and Citrate Dialysates

		Acetate	Citrate
	Sodium (mEq/L)	140	140
	Chloride (mEq/L)	111	111
	Calcium ion (mEq/L)	3	3
	Magnesium (mEq/L)	1.0	1.0
	Potassium (mEq/L)	2.0	2.0
	Glucose (mg/dL)	100	150
	Bicarbonate (mEq/L)	25	35
	Acetate (mg/dL)	60	0
	Citrate (mg/dL)	0	12.8
	Final pH	7.0-7.8	7.5-8.0
	Osmolality (mOsm/kg)	296	298

Note: Conversion factors for units: calcium ion and magnesium in mEq/L to mmol/L, ×0.5; glucose in mg/dL to mmol/L, ×0.05551; citrate in mg/dL to μmol/L, ×52.05. No conversion is necessary for sodium, chloride, potassium, and bicarbonate levels expressed in mmol/L and mEq/L and osmolality expressed in mmol/kg and mOsm/kg.

Data are presented as mean ± SD. Statistical significance was evaluated by using a paired t test with P < 0.05 considered to indicate a significant difference. Estimated glomerular filtration rate was calculated by using the formula 194 × Creatinine−1.094 × Age−0.287 × 0.739.17

Diagnosis 

Comparison of clinical data during HD with the 2 dialysates (Table 2) showed that minimal systolic BP, minimal diastolic BP, and post-HD diastolic BP were significantly lower when the acetate dialysate was used. Minimal heart rate was also lower in HD with the acetate dialysate, and the decrease in BP during acetate dialysis often led to discontinuation of dialysis before the dry weight could be reached. Consequently, the decrease in circulating blood volume and final weight loss were significantly lower with the acetate dialysate.

Table 2. Clinical Data for HD With Acetate or Citrate Dialysate

		Acetate	Citrate	P
	Set dry weight (kg)	32.2±0.2	32.2±0.2	0.5
	Set ultrafiltration rate (L/h)	0.71±0.08	0.75±0.03	0.3
	Systolic blood pressure (mm Hg)
	Pre-HD	153.7±4.9	158.7±11.6	0.4
	Minimum during HD	85.3±2.7	117.7±6.7	<0.001
	Post-HD	129.7±18.5	137.7±2.2	0.3
	Diastolic blood pressure (mm Hg)
	Pre-HD	110.0±6.2	110.0±3.2	0.9
	Minimum during HD	42.7±5.9	76.0±3.5	<0.001
	Post-HD	84.0±14.7	109.3±9.2	0.03
	No. of interventions for hypotension	8	0
	Heart rate (beats/min)
	Pre-HD	75.7±3.6	76.0±3.5	0.9
	Minimum during HD	50.7±2.1	66.0±9.5	0.003
	Post-HD	66.0±4.7	69.0±3.2	0.2
	Pre-HD weight (kg)	34.3±0.2	34.4±0.2	0.7
	Post-HD weight (kg)	32.4±0.2	32.0±0.1	0.04
	Final weight loss (kg)	1.9±0.1	2.4±0.2	0.02
	Change in blood volume (%)⁎	−19.5±0.5	−21.6±1.3	0.02

Abbreviation: HD, hemodialysis.

⁎ Measured on a Crit-Line instrument.

Representative hemodynamic parameters monitored by using Physio Flow Lab-1 are shown in Fig 1 for both dialysates. With the acetate dialysate, BP decreased suddenly at 2 hours into the dialysis session with no increase in heart rate or systemic vascular resistance; that is, vascular tone failed to increase and BP decreased. In contrast, BP and systemic vascular resistance remained constant during HD with the citrate dialysate.

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Figure 1. Changes in hemodynamic parameters during hemodialysis (HD) with acetate-containing bicarbonate dialysate or acetate-free citrate dialysate. With acetate dialysate, blood pressure (BP) decreased suddenly at 2 hours into the dialysis session (arrow), and heart rate failed to increase to compensate for hypotension. The volume of cardiac output did not change and systemic vascular resistance was not increased at this time. With citrate dialysate, BP was maintained and systemic vascular resistance was stable throughout the HD session. Parameters were measured using Physio Flow Lab-1.

Biochemical parameters before, during, and after HD with the 2 dialysates are listed in Table 3. Pre-HD acetate levels did not differ significantly between the 2 dialysates. However, as expected, the mid- and post-HD levels of acetate were greater with the acetate dialysate. The pH and bicarbonate levels at the midpoint of HD with the citrate dialysate were significantly greater than with the acetate dialysate. However, there were no significant differences in pH and bicarbonate levels after HD with the 2 dialysates and no significant difference in ionized calcium levels at any time. Acetoacetic acid and 3-hydroxybutyric acid levels with the citrate dialysate were lower than those with the acetate dialysate. We then compared levels of ketone bodies at the post-HD time with pre-HD amounts and expressed these as ratios. With acetate dialysate, the relative levels of post-HD acetoacetic acid (2.06) and 3-hydroxybutyric acid (2.79) were significantly different from the initial levels (P = 0.001 and P < 0.001, respectively), whereas with citrate dialysate, the relative post-HD levels of acetoacetic acid (1.23) and 3-hydroxybutyric acid (1.35) were not significantly different from the initial levels (P = 0.2 and P = 0.1, respectively).

Table 3. Comparison of Pre-, Mid-, and Postdialysis Biochemical Parameters

		Acetate Dialysate	Citrate Dialysate	P
	Acetate (mg/dL)
	Pre-HD	1.14±0.23	1.19±0.28	0.3
	Mid-HD	18.33±9.38	0.98±0.47	0.008
	Post-HD	15.05±8.93	0.72±0.18	0.01
	pH
	Pre-HD	7.34±0.04	7.36±0.02	0.4
	Mid-HD	7.41±0.02	7.45±0.02	0.02
	Post-HD	7.46±0.02	7.45±0.02	0.8
	Bicarbonate (mEq/L)
	Pre-HD	13.9±2.8	16.6±0.9	0.07
	Mid-HD	18.2±1.8	22.8±2.0	0.01
	Post-HD	19.6±2.1	22.7±2.2	0.07
	Calcium ion (mEq/L)
	Pre-HD	2.31±0.21	2.26±0.23	0.8
	Mid-HD	2.47±0.23	2.26±0.28	0.3
	Post-HD	2.50±0.16	2.34±0.16	0.2
	Acetoacetic acid (mg/dL)
	Pre-HD	3.05±2.67	0.74±0.18	0.06
	Mid-HD	3.29±2.66	0.49±0.07	0.03
	Post-HD	5.54±3.35	0.98±0.54	0.01
	3-Hydroxybutyric acid (mg/dL)
	Pre-HD	4.52±4.16	1.21±0.35	0.08
	Mid-HD	4.01±3.74	0.61±0.29	0.05
	Post-HD	9.75±3.98	1.84±1.07	0.001
	Ratio of acetoacetic acid levels
	Mid-HD v pre-HD	1.11	0.67	<0.001
	Post-HD v pre-HD	2.06	1.23	0.01
	Ratio of 3-hydroxybutyric acid levels
	Mid-HD v pre-HD	0.90	0.48	<0.001
	Post-HD v pre-HD	2.79	1.35	0.02

Note: Values expressed as mean ± SD based on 6 dialysis sessions per buffer. For ratios of acetoacetic acid and 3-hydroxybutyric acid, raw values were log transformed before calculating the mean and performing t tests. Normal ranges of serum acetoacetic acid and 3-hydroxybutyric acid in HD patients are 0.14 to 0.69 and 0 to 0.77 mg/dL, respectively, similar to those in patients with normal kidney function. Conversion factors for units: calcium ion in mEq/L to mmol/L, ×0.5; acetoacetic acid in mg/dL to mmol/L, ×0.09795; 3-hydroxybutyric acid in mg/dL to μmol/L, ×96.05; acetate in mg/dL to mmol/L, ×0.167. Bicarbonate levels expressed in mEq/L and mmol/L are equivalent. Abbreviation: HD, hemodialysis.

Clinical Follow-up 

The patient was discharged from our hospital after 1 month and has continued HD therapy with citrate dialysate as an outpatient. She and her family have expressed a desire for future kidney transplantation.