Correlation of Coronary Artery Calcification WithPre-Hemodialysis Bicarbonate Levels in Patients on
Machiko Oka, Takayasu Ohtake, Yasuhiro Mochida, Kunihiro Ishioka, Kyoko Maesato,Hidekazu Moriya, Sumi Hidaka, and Shuzo Kobayashi
Department of Nephrology, Immunology and Vascular Medicine, Shonan Kamakura General Hospital,Kamakura, Kanagawa, Japan
Abstract: Coronary artery calcification (CAC) leads to asignificant increase in cardiovascular morbidity and mor-tality in hemodialysis (HD) patients. Metabolic acidosis,which is common in HD patients, promotes bone resorp-tion in human and animals as a result of buffer function ofbone, and calcium and phosphate elute from bone intoblood stream. However, the effect of acidosis on CAC inHD patients has never been precisely investigated.This is across-sectional observational study performed in a singlecenter. One hundred and seven prevalent HD patients (35women and 72 men) underwent electron-beam computedtomography (EBCT) to evaluate CAC score (CACS), andthen we evaluated associated factors of CACS with clinicaland laboratory parameters including pre-HD pH andbicarbonate levels. Pre-HD pH and bicarbonate levelswere 7.35 0.04, and 17.6 1.8mmol/L, respectively.The pre-HD pH had no significant correlation to CACS(r = -0.025, P = 0.81). CACS was significantly negatively
correlated with pre-HD bicarbonate levels (r = -0.329,P = 0.0009) and serum albumin levels (r = -0.298,P = 0.0467), while it was positively correlated with age(r = 0.319, P = 0.0008) and HD duration (r = 0.385,P = 0.0004). Serum levels of calcium, phosphorus, intactparathyroid hormone, and use of phosphorus binders werenot related to CACS. Multivariate analysis indicated thatplasma pre-HD bicarbonate level was independently asso-ciated with CACS. The present study showed that bloodlevels of pre-HD bicarbonate were significantly associatedwith CAC in HD patients. Further studies are needed toconfirm these results and to determine whether correctionof metabolic acidosis prevents the development of CAC,one of the features of accelerated atherosclerosis in HDpatients. KeyWords: Acidosis, Coronary artery calcifica-tion, Hemodialysis, Bicarbonate levels, Correlation, Car-diovascular disease.
Coronary artery calcification (CAC) has a signifi-cant effect on cardiovascular morbidity and mortalityin patients on hemodialysis (HD) (13). We haverecently reported that CAC was significantly associ-ated with cardiovascular events, cardiovasculardeaths, and all-cause deaths in HD patients (3). Theetiology of CAC in HD patients is thought to bemulti-factorial, and has been reported to show anassociationwith several uremia-related factors such asmineral abnormalities, fetuin-A, microinflammation,and vitamin D deficiency (39).
Metabolic acidosis promotes bone resorption inhuman and animals (1012) as a result of the bufferfunction of bone, and calcium and phosphate elutefrom bone into the blood stream.At the same decre-ment in pH (acidemia), calcium efflux from bone isfar more prominent in metabolic acidosis than in res-piratory acidosis (13). If these eluted bone-formingminerals deposit in the vascular wall, metabolic aci-dosis may promote vascular calcification, which ischaracteristically seen in HD patients.Hemodialysis patients usually exhibit pre-HD aci-
dosis and post-HD neutralization of acid-base status.Thus, Acid-base status fluctuates three times everyweek in HD patients. We hypothesized that boneresorption and elution of bone-forming miner-als during the metabolic acidic state and calcium
Received August 2011; revised October 2011.Address correspondence and reprint requests to Dr Machiko
Oka,Department of Nephrology, Immunology, andVascular Medi-cine, Shonan Kamakura General Hospital, 1370-1 Okamoto,Kamakura, 247-8533, Japan. Email: firstname.lastname@example.org
Therapeutic Apheresis and Dialysis 2012; ():doi: 10.1111/j.1744-9987.2011.01054.x 2012 The AuthorsTherapeutic Apheresis and Dialysis 2012 International Society for Apheresis
deposition in vascular walls in corrected acid-basebalance after HD (namely acid-base cycling) may beone of the key factors for remarkable and accelerat-ing vascular calcification in HD patients. However,the effect of acidosis on coronary artery calcificationin HD patients has never been precisely investigated.Therefore, the primary goal in this study was to assessthe relationship between the pre-HD acid-base statusand quantitatively measured coronary artery calcifi-cation by electron-beam computed tomography(EBCT) in HD patients.
PATIENTS AND METHODS
Patients and study protocolThe potential subjects comprised all 141 HD
patients on maintenance HD at the dialysis center inShonan Kamakura General Hospital (Kamakura,Japan). Patients with arrhythmia or inability to holdtheir breath were excluded because it was impossibleto obtain good CT scans.The other exclusion criteriawere acute infection or inflammatory diseases withinat least 4 weeks before study entry, as well as malig-nancy, severe liver disease, and pregnancy.As a result,107 patients were eligible for the study. All of thesepatients gave informed consent and underwentEBCT for the evaluation of CAC.
EBCTAccording to the method described by Agatston
et al. (14), we calculated theAgatston score after per-forming EBCT with a C-100 scanner (Imatron; SouthSan Francisco, CA,USA), and this was used to deter-mine the coronary artery calcification score (CACS).The total CACS was calculated as the sum of thescores for the four major epicardial coronary arteriesand was used for analysis.
Clinical and laboratory parametersThe clinical parameters assessed at study entry
included age, sex, duration of HD, Kt/V (dialysisdose), systolic and diastolic blood pressure at thestart of first HD session of a week, use of calciumbicarbonate and/or sevelamer hydrochloride (asphosphorus binders), use of vitamin D analogue, andcomorbidities including hypertension or diabetesmellitus.Arterial blood samples were collected from arte-
riovenous fistula at the start of the first HD session ofthe week to measure the levels of serum albumin, uricacid, calcium (Ca), phosphorus (Pi), CaPi product,intact parathyroid hormone (i-PTH), total choles-terol, high density lipoprotein (HDL) cholesterol,low density lipoprotein (LDL) cholesterol, high
sensitivity C-reactive protein (hsCRP), and beta 2microglobulin (b2MG) within one week of the firstEBCT study. Both serum Ca and the CaPi productwere corrected according to the following formulae.Corrected Ca = (4 - serum albumin) + serum Ca, andCaPi product = corrected Ca Pi. Blood gas analy-sis was also done using pre-HD arterial bloodsamples at the start of first HD session of the week.
HD treatmentHemodialysis was performed for 4 h three times
per week. Blood flow rate (Qb) was 4.55.0 mL/minper kg body weight and dialysate flow rate (Qd) wasset at 500 mL/min. Composition of dialysate(Kindary AF 3, Fuso Pharmaceutical Industries. Ltd.Osaka, Japan) was Na+ 140 mEq/L, K+ 2.0 mEq/L, Cl-
114.5 mEq/L, Ca2+ 2.5 mEq/L, Mg2+ 1.0 mEq/L,HCO3- 25.0 mmol/L, glucose 150 mg/dL, andCH3COO- 8 mEq/L. The target levels of Ca and Picontrol were 8.410.0 mg/dL and 3.56.0 mg/dL,respectively. The dose of phosphorus binders werechanged if necessary to achieve these control levels.Dialysis dose (Kt/V) was calculated according to thefollowing formula: Kt/V = -ln(Post BUN/Pre BUN-0.008t) + (43.5Post BUN/Pre BUN)UltrafiltrateVolume/Weight (15)
Statistical analysisData are expressed as the mean SD. Data that
did not show a normal distribution, such as CACSand hsCRP, underwent log transformation before sta-tistical analysis. For comparisons between twogroups, the paired or unpaired t-test or the MannWhitney U-test was used. Univariate analysis wasperformed to assess the relation between CACS andseveral parameters by calculating Spearmans rankcorrelation coefficients. Multivariate analysis wasperformed with CACS as the dependent variable andthe parameters found to be significant by univariateanalysis as the independent variables to determinethe factors with an independent influence on CACS.Statview 5.0 software (SAS Institute,Cary,NC,USA)was used for these analyses, and P < 0.05 was consid-ered to indicate statistical significance.
Patient profileThe basic characteristics of the subjects are shown
in Table 1. The mean age and duration of HD were66.2 11.5 years and 87.5 68.1 months, respec-tively. Twenty-three patients (21.5%) had diabetesmellitus. The serum Ca, Pi, CaPi product, andiPTH levels were 9.2 1.0 mg/dL, 6.0 1.2 mg/dL,
M Oka et al.2
2012 The AuthorsTherapeutic Apheresis and Dialysis 2012 International Society for ApheresisTher Apher Dial, Vol. , No. , 2012
53.8 12.4 mg2/dL2, and 209.1 140.5 pg/mL, resp-ectively.Vitamin D was administered to 66 out of 107patients (61.7%). Calcium bicarbonate and/or seve-lamer hydrochloride was administered to 81.3%(87/107) and 28.0% (30/107) of patients, respec-tively. The EBCT study yielded a mean CACS of1745.2 3144.7 (022103). The plasma bicarbonatelevels before HD were 17.6 1.8 (12.522.4)mmol/L.
Association between CACS and other parametersAs shown in Table 2, the CACS displayed a signifi-
cant positive correlation with the age (r = 0.319,P = 0.0008), and duration of HD (r = 0.385, P =0.0004), while there was a negative correlationwith the pre-HD bicarbonate level (r = -0.329,P = 0.0009) and serum albumin (r = -0.198, P =0.0467). Pre-HD pH levels, corrected Ca, IP, i-PTH,hsCRP, b2MG, diabetes mellitus, use of phos-phorus binders or vitamin D, had no significantassociation with CACS. The correlation between thepre-HD bicarbonate levels and the CACS wasshown in Figure 1. The corrected serum Ca levelsshowed marginal correlation with CACS (r = 0.171,P = 0.0874) (Table 2).As shown in Table 3, multivari-ate regression analysis showed the duration of HD
and pre-HD bicarbonate level were independentcontributing factors for CAC.
The present study clearly demonstrated that thequantitatively evaluated CACS of HD patients wassignificantly correlated with their pre-HD bicarbon-
TABLE 1. Basic characteristics of the subjects
(n = 107)
Age (years) 66.2 11.5Sex (M/F) 72/35HD duration (months) 87.5 68.1Kt/V urea 1.38 0.22Diabetes mellitus (Yes/No) 23/84Systolic blood pressure (mm Hg) 139.3 18.6Diastolic blood pressure (mm Hg) 80.5 9.6Albumin (g/dL) 3.6 0.3Uric acid (mg/dL) 7.5 1.4Corrected calcium (mg/dL) 9.2 1.0Phosphorus (mg/dL) 6.0 1.2Calcium phosphorus (mg2/dL2) 53.8 12.4iPTH (pg/dL) 216.5 136.5Total cholesterol (mg/dL) 157.3 39.3High density lipoprotein cholesterol(mg/dL)
Low density lipoprotein cholesterol(mg/dL)
High-sensitivity CRP (mg/dL) 0.41 0.71Fibrinogen (mg/dL) 313.3 67.72 microglobulin (mg/dL) 29.6 5.8Calcium bicarbonate (Yes/No) 87/20Vitamin D analogue (Yes/No) 66/41Sevelamer (Yes/No) 30/77Pre-HD bicarbonate (mmol/L) 17.6 1.8 (12.522.4)Pre-HD pH 7.35 0.04 (7.257.44)CACS 1745.2 3144.7 (022103)log(1 + CACS) 2.52 1.09
CACS, coronary artery calcification score; i-PTH, intact para-phyroid hormone.
TABLE 2. Correlation coefficients between coronaryartery calcification score (CACS) and continuous
Age 0.319 0.0008*HD duration (months) 0.385 0.0004*Kt/V -0.030 0.7629Diabetes mellitus 0.049 0.6628Systolic blood pressure (mm Hg) -0.072 0.5885Diastolic blood pressure (mm Hg) 0.084 0.5656Albumin (g/dL) -0.198 0.0467*Uric acid (mg/dL) -0.122 0.2239Corrected calcium (mg/dL) 0.171 0.0874Phosphorus (mg/dL) -0.071 0.4784Calcium phosphorus (mg2/dL2) 0.016 0.8712iPTH (pg/dL) 0.103 0.3116Total cholesterol (mg/dL) 0.086 0.3920High density lipoprotein cholesterol (mg/dL) -0.046 0.6464Low density lipoprotein cholesterol (mg/dL) 0.016 0.2956High-sensitivity C-reactive protein (mg/dL) 0.089 0.3739Fibrinogen (mg/dL) 0.120 0.23062 microglobulin (mg/dL) 0.076 0.4937Calcium bicarbonate -0.037 0.7106Vitamin D analogue -0.018 0.8633Sevelamer -0.044 0.6586Pre-HD bicarbonate (mmol/L) -0.329 0.0009*Pre-HD pH -0.025 0.8081
*P < 0.05; i-PTH, intact paraphyroid hormone.
FIG. 1. Significant correlation between pre-HD bicarbonatelevel and coronary artery calcification score (CACS). CACS wasnegatively correlated with pre-HD bicarbonate levels.
Acidosis and Coronary Artery Calcification 3
2012 The AuthorsTherapeutic Apheresis and Dialysis 2012 International Society for Apheresis Ther Apher Dial, Vol. , No. , 2012
ate levels. Multivariate analysis indicated pre-HDbicarbonate level as an independent associatingfactor for CAC in HD patients.This is the first report,to our knowledge, to assess the relationship of meta-bolic acidosis with quantitatively evaluated CAC inHD patients.In general, calcium solubility is enhanced in acidic
conditions. However, at the same decrement in pH(acidemia), calcium efflux from bone is far moreprominent in metabolic acidosis than in respiratoryacidosis (13). Metabolic, but not respiratory acidosisinduces production of bone prostaglandin 2, whichmediates bone resorption (16).Thus, the bicarbonatelevel, which reflects metabolic acidosis, is importantwhen we consider bone resorption and arterial calci-fication. The significant correlation between CACSand pre-HD bicarbonate levels, not pre-HD pH, wasa compatible result.Metabolic acidosis in patients on HD promotes
bone resorption, and bone-forming Ca and Pi elutefrom bone into the blood (17). Under continuousacidic conditions, however, vascular calcification hasbeen reported to be rather decreased because of thehigh solubility of Ca and Pi in the blood (1820).Therefore, although metabolic acidosis promotesbone resorption and mobilizes Ca and Pi, the changesmight not be sufficient for accelerated vascular calci-fication in HD patients. In this respect, acid-basecycling, i.e.,metabolic acidosis before HD and correc-tion after HD, might be an important key factor foraccelerated vascular calcification in HD patients.Mobilized bone-forming minerals in the blood mayprecipitate in vascular wall in more normal acid-basestatus after HD. Although we could not clarify theimpact of acid-base cycling on coronary calcificationin this study, we could indicate, at least in part,pre-HD metabolic acidosis independently associatedwith CAC in HD patients.Key determinants of metabolic acidosis are
reported to be uremia, the dialysis dose, specificphosphorus binders, and protein breakdown (21).Metabolic acidosis is enhanced via the process ofprotein breakdown and subsequent production ofacids, while metabolic acidosis also leads to low
serum albumin levels by enhancing protein break-down. Therefore, metabolic acidosis and low serumalbumin levels may have a deleterious inter-action. In the present study, CAC was shown to bemore severe among patients with severe pre-HDacidosis, in whom the serum albumin level was sig-nificantly lower. Lower albumin levels may either bethe cause and/or result of increased protein catabo-lism related to the metabolic acidosis (22,23). Seve-lamer hydrochloride is an ion-e...