Abstract
Intravenous administration of branched-chain amino acid (BCAA)-enriched solution is contraindicated in patients with severe chronic kidney disease (CKD). However, there have been no reports on its risks in patients with mild-to-moderate CKD. In this study, we compared the incidence of acidosis between patients with mild-to-moderate CKD (estimated glomerular filtration rate [eGFR] ≥30 and <60 mL/min/1.73 m2) and patients without CKD (eGFR ≥60 mL/min/1.73 m2) who received intravenous BCAA-enriched solution after propensity score matching (PSM). A retrospective analysis of the medical records at Hiroshima University Hospital identified 608 patients who were treated with intravenous BCAA-enriched solutions between January 2005 and December 2010. The laboratory data for these patients were analyzed. After PSM, the incidence of acidosis was compared between 91 pairs of patients with mild-to-moderate CKD or no CKD using Fisher’s exact test. The incidence of acidosis was significantly higher in the mild-to-moderate CKD group than in the non-CKD group (36.3 vs. 18.7%, p <0.05). The odds ratio for the incidence of acidosis in patients with mild-to-moderate CKD was 2.48 (95% confidence interval 1.26–4.88). Kaplan–Meier curves showed that the cumulative incidence of acidosis increased soon after initiation of intravenous BCAA-enriched solution in both groups. In conclusion, intravenous BCAA-enriched solution can cause acidosis even in patients without CKD, with an increased risk in patients with mild-to-moderate CKD, in whom this agent is not contraindicated. Therefore, intravenous BCAA-enriched solution should be administered with caution in patients with CKD, regardless of its severity.
INTRODUCTION
Branched-chain amino acids (BCAAs), such as valine, leucine, and isoleucine, are the main sources of amino nitrogen for the synthesis of glutamate from α-ketoglutarate in skeletal muscle.1) Several studies have demonstrated that BCAAs have beneficial effects on protein malnutrition in patients with liver cirrhosis.2) However, prolonged administration of BCAA-enriched solution is associated with adverse events, including metabolic acidosis.3) Intravenous BCAA-enriched solution is contraindicated in patients with severe renal dysfunction because of its potential to worsen their symptoms as a result of accumulation of urea nitrogen and other metabolites of amino acids. We have encountered acidosis in several patients who received BCAA-enriched solution, even though they did not have severe chronic kidney disease (CKD), defined as an estimated glomerular filtration rate (eGFR) of <30 mL/min/1.73 m2. Therefore, even in mild-to-moderate CKD patients, in whom BCAA-enriched solution is not contraindicated, the risk of adverse events after intravenous administration may still be higher than in non-CKD patients. In this study, we aimed to determine whether a mild-to-moderate decline in eGFR is a risk factor for acidosis in patients treated with intravenous BCAA-enriched solution.
PATIENTS AND METHODS
Data Collection
All patients treated with intravenous BCAA-enriched solution (Aminoleban® injection, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan) at Hiroshima University Hospital between January 1, 2005 and December 31, 2010 were retrospectively enrolled. Patients who were younger than 19 years, those with severe CKD (eGFR <30 mL/min/1.73 m2), and those on dialysis were excluded. The study protocol was approved by the ethics committee of Hiroshima University (Approval Number: E721). Informed consent was obtained with an opt-out method.
Eligible patients were divided into a mild-to-moderate CKD group (30 ≤ eGFR <60 mL/min/1.73 m2) and a non-CKD group (eGFR ≥60 mL/min/1.73 m2) according to the Kidney Disease Improving Global Outcomes 2012 clinical practice guideline.4) We analyzed data for the first episode of acidosis after intravenous administration with BCAA-enriched solution in each patient. Patients who had a diagnosis of acidosis with blood pH of <7.35 and bicarbonate ions of <24 mEq/L by arterial blood gas test up to 40 d after administration with BCAA-enriched solution were defined as patients with acidosis. Biological blood tests were performed on the day before or immediately before administration of BCAA-enriched solution, and arterial blood gas tests were performed after administration.
The eGFR was calculated in mL/min/1.73 m2 using the following equation: eGFR = 194 × (creatinine)–1.094 × (age)–0.287 (× 0.739 if female) according to a previous report.5) Each laboratory parameter was categorized into normal, upper, and lower groups according to the measured value relative to the normal range.
Outcomes
The study outcome was the incidence of acidosis after administration of intravenous BCAA-enriched solution according to CKD status.
Statistical Analysis
To decrease confounding bias, we adjusted the numbers of cases in the mild-to-moderate CKD group and the non-CKD group using 1:1 propensity score matching (PSM). Briefly, the propensity score was calculated using a logistic regression model that incorporated serum sodium, potassium, chloride, aspartate aminotransferase, alanine aminotransferase, albumin, blood urea nitrogen, and C-reactive protein levels and used the frequencies of hepatitis, gastrointestinal disease, and liver transplantation as variables. Age, sex, and serum creatinine level were not included as variables to avoid multicollinearities against eGFR. The propensity scores were used to perform 1:1 nearest neighbor matching without replacement within a caliper of a 0.2-fold standard deviation of the logit of the propensity score. Categorical data are shown as the number (percentage) and were compared between groups using Fisher’s exact test before and after PMS. To compare the time to onset of acidosis between patients with mild-to-moderate CKD and those without CKD who received intravenous BCAA-enriched solution, the cumulative incidence of acidosis in acidotic patients was analyzed using the Kaplan–Meier method with log-rank test. All analyses were performed using R (R Foundation for Statistical Computing, Vienna, Austria). A p-value <0.05 was defined as statistically significant.
RESULTS
Patient Characteristics
A total of 608 patients received intravenous BCAA-enriched solutions at our institution during the study period. After the exclusion of 67 patients who were younger than 19 years, had severe CKD, or were on dialysis, 541 patients with a mean age of 64.2 ± 9.7 (standard deviation) years and a male-to-female distribution of 377/164 were included. Their clinical characteristics are summarized in Table 1. The patients were divided into a mild-to-moderate CKD group (n = 176, 32.5%) and a non-CKD group (n = 365, 67.5%). Univariate analyses showed significant between-group differences in the proportion with acidosis, patient age, and the proportions with normal serum sodium, potassium, chloride, urea nitrogen, and creatinine levels. After PSM, the sample size decreased from 541 (mild-to-moderate CKD, n = 176; no CKD, n = 365) to 182 (91 pairs). This sample size could detect acidosis in 51.8% or less of non-CKD patients (36.3%) with 70% statistical power. The standardized mean differences in serum levels of sodium, potassium, chloride, aspartate aminotransferase, alanine aminotransferase, albumin, urea nitrogen, and C-reactive protein and the frequencies of hepatitis, gastrointestinal disease, and liver transplantation were <0.1 for most baseline covariates.
Table 1. Clinical Characteristics of the Study Participants before and after Propensity Score Matching
|
Before propensity score matching |
After propensity score matching |
Mild-to-moderate
CKD (n = 176) |
Non-CKD
(n = 365) |
p-Value |
OR |
95% CI |
Mild-to-moderate
CKD (n = 91) |
Non-CKD
(n = 91) |
p-Value |
SMD |
| Acidosis |
60 (34.1) |
50 (13.7) |
<0.001 |
3.26 |
2.12–5.02 |
33 (36.3) |
17 (18.7) |
0.012 |
0.402 |
| Age < 65 (years) |
72 (40.9) |
189 (51.8) |
0.022 |
0.645 |
0.440–0.942 |
34 (37.4) |
50 (54.9) |
0.025 |
0.358 |
| Sex, male |
120 (68.2) |
257 (70.4) |
0.618 |
0.901 |
0.601–1.358 |
60 (65.9) |
62 (68.1) |
0.875 |
0.047 |
| Dose ≤ 500 (mL) |
171 (97.2) |
352 (96.4) |
0.801 |
1.26 |
0.414–4.60 |
89 (97.8) |
88 (96.7) |
1 |
0.067 |
| Na normal |
51 (29.0) |
141 (38.6) |
0.021 |
|
|
30 (33.0) |
30 (33.0) |
1 |
<0.001 |
| Lower |
122 (69.3) |
223 (61.1) |
|
|
|
61 (67.0) |
61 (67.0) |
|
|
| Upper |
3 (1.7) |
1 (0.3) |
|
|
|
0 (0) |
0 (0) |
|
|
| K normal |
115 (65.3) |
243 (66.6) |
0.007 |
|
|
65 (71.4) |
65 (71.4) |
1 |
<0.001 |
| Lower |
33 (18.8) |
94 (25.8) |
|
|
|
16 (17.6) |
16 (17.6) |
|
|
| Upper |
28 (15.9) |
28 (7.7) |
|
|
|
10 (11.0) |
10 (11.0) |
|
|
| Cl normal |
112 (63.6) |
272 (74.5) |
0.005 |
|
|
65 (71.4) |
65 (71.4) |
1 |
<0.001 |
| Lower |
59 (33.5) |
76 (20.8) |
|
|
|
25 (27.5) |
25 (27.5) |
|
|
| Upper |
5 (2.8) |
17 (4.7) |
|
|
|
1 (1.1) |
1 (1.1) |
|
|
| AST normal |
32 (18.2) |
50 (13.7) |
0.201 |
1.40 |
0.831–2.33 |
10 (11.0) |
10 (11.0) |
1 |
<0.001 |
| Upper |
144 (81.8) |
315 (86.3) |
|
|
|
81 (89.0) |
81 (89.0) |
|
|
| ALT normal |
99 (56.2) |
198 (54.2) |
0.712 |
1.08 |
0.743–1.58 |
48 (52.7) |
48 (52.7) |
1 |
<0.001 |
| Upper |
77 (43.8) |
167 (45.8) |
|
|
|
43 (47.3) |
43 (47.3) |
|
|
| Alb normal |
8 (4.5) |
17 (4.7) |
1 |
1.03 |
0.410–2.80 |
0 (0) |
0 (0) |
1 |
<0.001 |
| Lower |
168 (95.5) |
348 (95.5) |
|
|
|
91 (100) |
91 (100) |
|
|
| UN normal |
54 (30.7) |
255 (69.9) |
<0.001 |
|
|
39 (42.9) |
39 (42.9) |
1 |
<0.001 |
| Lower |
0 (0) |
19 (5.2) |
|
|
|
0 (0) |
0 (0) |
|
|
| Upper |
122 (69.3) |
91 (24.9) |
|
|
|
52 (57.1) |
52 (57.1) |
|
|
| CRE normal |
103 (58.5) |
364 (99.7) |
<0.001 |
0.004 |
0.0001–0.023 |
58 (63.7) |
90 (98.9) |
<0.001 |
1.011 |
| Upper |
73 (41.5) |
1 (0.3) |
|
|
|
33 (36.3) |
1 (1.1) |
|
|
| CRP normal |
20 (11.4) |
38 (10.4) |
0.657 |
1.13 |
0.602–2.08 |
7 (7.7) |
7 (7.7) |
1 |
<0.001 |
| Upper |
156 (88.6) |
327 (89.6) |
|
|
|
84 (92.3) |
84 (92.3) |
|
|
| Hepatitis |
141 (80.1) |
286 (78.4) |
0.736 |
1.11 |
0.712–1.74 |
78 (85.7) |
78 (85.7) |
1 |
<0.001 |
| Respiratory disease |
2 (1.1) |
3 (0.8) |
0.662 |
1.39 |
0.230–8.38 |
1 (1.1) |
0 (0) |
1 |
0.149 |
| Gastrointestinal disease |
11 (6.3) |
28 (7.7) |
0.599 |
0.802 |
0.390–1.65 |
3 (3.3) |
3 (3.3) |
1 |
<0.001 |
| Cardiovascular disease |
5 (2.8) |
4 (1.1) |
0.159 |
2.639 |
0.700–9.95 |
0 (0) |
2 (2.2) |
0.497 |
0.212 |
| Others |
14 (8.0) |
42 (11.5) |
0.230 |
0.665 |
0.353–1.25 |
7 (7.7) |
8 (8.8) |
1 |
0.04 |
| Liver transplantation |
21 (11.9) |
33 (9.0) |
0.289 |
0.734 |
0.397–1.38 |
4 (4.4) |
4 (4.4) |
1 |
<0.001 |
The laboratory data were classified into normal, upper, and lower groups based on the following normal ranges in serum: sodium (Na), 138–146 mEq/L; potassium (K), 3.6–4.9 mEq/L; chloride (Cl), 99–109 mEq/L; albumin (Alb), 4.0–5.0 g/dL; nitrogen urea (UN), 8.0–22.0 mg/dL; creatinine (CRE), 0.6–1.1 mg/dL; aspartate aminotransferase (AST), 13–33 IU/L; alanine aminotransferase (ALT), 8–42 IU/L, and C-reactive protein (CRP), <0.2 mg/dL. The data are shown as the number of patients (percentage).
CKD, chronic kidney disease; OR, odds ratio; CI, confidence interval; SMD, standardized mean difference.
The overall incidence of acidosis was 20.3% (110/541) before PSM and 27.5% (50/182) after PSM (Table 1). The incidence of acidosis was significantly higher in the mild-to-moderate CKD group than in the non-CKD group, both before PSM (34.1% [60/176] vs. 13.7% [50/365], p <0.001) and after PSM (36.3% [33/91] vs. 18.7% [17/91] p <0.05). The odds ratio (OR) for acidosis up to 40 d after administration of intravenous BCAA-enriched solution was 3.26 (95% confidence interval [CI] 2.12–5.02) before PSM and 2.48 (95% CI 1.26–4.88) after PSM (Table 2).
Table 2. Result of Univariate Analysis of the Risk of Acidosis in Patients with Mild-to-Moderate CKD before and after Propensity Score Matching
|
Before propensity score matching |
After propensity score matching |
| Crude OR |
95%CI |
p-Value |
Adjusted OR |
95%CI |
p-Value |
| Mild-to-moderate CKD |
3.26 |
2.12–5.02 |
<0.001 |
2.48 |
1.26–4.88 |
0.012 |
CI, confidence interval; CKD, chronic kidney disease; OR, odds ratio; SMD, standardized mean difference.
In acidotic patients, Kaplan–Meier curves with the log-rank test showed no significant difference in the cumulative incidence of acidosis after administration of intravenous BCAA-enriched solution between the mild-to-moderate CKD group and the non-CKD group before (p = 0.920) or after (p = 0.391) PSM (Fig. 1). The hazard ratios for acidosis before and after PSM were 1.02 (95% CI 0.729–1.33) and 0.762 (95% CI 0.410–1.42), respectively. The median interval between the initiation of intravenous BCAA-enriched solution and the onset of acidosis was 1 d (interquartile range, 4.25–1) in the mild-to-moderate CKD group and 12 d (interquartile range, 19–4) in the non-CKD group before PSM and 3 d (7–1) and 5 d (7–3), respectively, after PSM.
DISCUSSION
Intravenous BCAA-enriched solution can be used in mild-to-moderate CKD patients. However, in this study, we found that acidosis could develop within a short period after initiation of this solution in mild-to-moderate CKD patients, with an OR that was approximately 2.48-fold higher than that in non-CKD patients. This is the first study to demonstrate that mild-to-moderate CKD is a risk factor for acidosis during treatment with intravenous BCAA-enriched solution.
Several intravenous fluids can cause acidosis. For example, infusion of thiamine-free total parenteral nutrition (TPN) causes lactic acidosis by promoting the production of lactic acid. In this study, the incidence of acidosis was up to 20.3% in patients who received intravenous BCAA-enriched solution. Renal excretion of hydrogen ions is the crucial step in maintaining systemic acid–base homeostasis and is achieved by titratable acidity and excretion of ammonium ions. Therefore, decreased renal excretion of ammonium ions is a major contributor to metabolic acidosis.6) Total ammonium excretion has been reported to start decreasing in humans when eGFR decreases to below 40 mL/min/1.73 m2.7) Considering that intravenous BCAA-enriched solution is acidic (pH 5.9), it could induce metabolic acidosis in mild-to-moderate CKD patients even if their CKD was not severe. In addition, Sugiura et al. reported that TPN adjusted for pH with hydrochloric acid might cause severe hyperchloremic metabolic acidosis.8) Aminoleban® injection may also induce hyperchloremic metabolic acidosis because this solution contains amino acids as hydrochloride salts. However, our preliminary data showed that the incidence of upper serum chloride levels was not different between the acidosis group and the non-acidosis group before PSM (4.5% [5/110] vs. 3.9% [17/431], p = 0.146). Therefore, the acidosis observed in this study might not be due to hyperchloremia.
Our univariate analyses showed that the OR for acidosis in mild-to-moderate CKD patients relative to that in non-CKD patients was 3.26 before PSM and 2.48 after PSM (Table 2). This finding indicates that there were confounding factors that affected the incidence of acidosis before PSM. Respiratory disease may also be a factor in patients who develop acidosis after receiving a BCAA-enriched solution. The lungs and kidneys play an important role in maintaining systemic acid–base homeostasis. When metabolic acidosis is caused by a renal disorder, the lungs decrease the serum concentration of hydrogen ions via a compensatory mechanism by increased excretion of volatile acids as carbon dioxide into the air. There were only 5 patients with respiratory disorders in this study, so we could not assess the risk of acidosis associated with BCAA-enriched solution in these patients. Hepatorenal syndrome is also a major complication in patients with cirrhosis and has an annual incidence of approximately 8% in patients with cirrhosis and ascites.9) Therefore, hepatitis with ascites may be a risk factor for acidosis induced by BCAA-enriched solution via induction of a renal disorder.
There was no significant difference in the cumulative incidence of acidosis after administration of intravenous BCAA-enriched solution between our mild-to-moderate CKD group and our non-CKD group (Fig. 1). However, after PSM, the Kaplan–Meier curves showed that the frequency of acidosis continued to increase for up to 30 d after administration of BCAA-enriched solution in mild-to-moderate CKD patients but plateaued by 10 d in non-CKD patients (Fig. 1B). We propose that patients with mild-to-moderate CKD should be warned about the increased risk of acidosis during the month after intravenous administration with BCAA-enriched solution.
Severe liver diseases, such as cirrhosis, can cause lactic acidosis by reducing lactate metabolism. However, our analysis before PMS showed that the incidences of hepatitis or liver transplantation did not affect the incidence of acidosis (Table 1). Furthermore, none of the patients in this study had abnormally upper levels of blood lactate. The limitation of this study is that we could not use the Child–Pugh score as a variable for logistic regression to calculate the propensity score because our data did not include information on the Child–Pugh score or on hepatic encephalopathy and ascites, which are necessary to calculate the Child–Pugh score.
Another limitation of this study is that we did not evaluate the association of acidosis with medications used in combination. Antibiotics10) and antiepileptic agents11) have been reported to disturb the acid–base balance. Further research is necessary to clarify whether combined medication is a risk factor for acidosis during the administration of BCAA-enriched solution.
In conclusion, this study found that intravenous BCAA-enriched solution could cause potentially fatal acidosis even in non-CKD patients. However, the risk was greater in mild-to-moderate CKD patients, in whom this agent is not contraindicated. Therefore, intravenous BCAA-enriched solution should be administered with particular caution in CKD patients, regardless of its severity.
Conflict of Interest
The authors declare no conflict of interest.
REFERENCES
- 1) Holecek M. Evidence of a vicious cycle in glutamine synthesis and breakdown in pathogenesis of hepatic encephalopathy-therapeutic perspectives. Metab. Brain Dis., 29, 9–17 (2014).
- 2) Moriwaki H, Miwa Y, Tajika M, Kato M, Fukushima H, Shiraki M. Branched-chain amino acids as a protein- and energy-source in liver cirrhosis. Biochem. Biophys. Res. Commun., 313, 405–409 (2004).
- 3) Masuda T, Amemiya M, Otomo T, Morishita Y, Tsuruoka H, Muto S, Nagae G, Inamori H, Isoda N, Ido K, Sugano K, Asano Y, Kusano E. Successful treatment with hemodiafiltration for a chronic renal failure patient with hyperchloremic metabolic acidosis associated with hepatic coma. J. Jpn. Soc. Dial. Ther., 37, 1809–1813 (2004).
- 4) Levin A, Stevens PE, Bilous RW, Coresh J, De Francisco ALM, De Jong PE, Griffith KE, Hemmelgarn BR, Iseki K, Lamb EJ, Levey AS, Riella MC, Shlipak MG, Wang H, White CT, Winearls CG. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. Suppl., 3, 1–150 (2013).
- 5) Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A. Revised equations for estimated GFR from serum creatine in Japan. Am. J. Kidney Dis., 53, 982–992 (2009).
- 6) Pourafshar N, Pourafshar S, Soleimani M. Urine ammonium, metabolic acidosis and progression of chronic kidney disease. Nephron J., 138, 222–228 (2018).
- 7) Kraut JA, Madias NF. Metabolic acidosis: pathophysiology, diagnosis and management. Nat. Rev. Nephrol., 6, 274–285 (2010).
- 8) Sugiura S, Inagaki K, Noda Y, Nagai T, Nabeshima T. Acid load during total parenteral nutrition: comparison of hydrochloric acid and acetic acid on plasma acid-base balance. Nutrition, 16, 260–263 (2000).
- 9) Arroyo V, Guevara M, Ginès P. Hepatorenal syndrome in cirrhosis: pathogenesis and treatment. Gastroenterology, 122, 1658–1676 (2002).
- 10) Zietse R, Zoutendijk R, Hoorn EJ. Fluid, electrolyte and acid-base disorders associated with antibiotic therapy. Nat. Rev. Nephrol., 5, 193–202 (2009).
- 11) Mirza N, Marson AG, Pirmohamed M. Effect of topiramate on acid-base balance: extent, mechanism and effects. Br. J. Clin. Pharmacol., 68, 655–661 (2009).
