Prior to the availability of commercial intact parathyroid hormone (PTH) assays, serum total alkaline phosphatase (TAP) measurements were used as one of the surrogate markers of high bone turnover that was utilized in the management of chronic kidney disease mineral and bone disorder (CKD-MBD) [
Although the role of racial disparities in adverse clinical outcomes remains controversial and inconclusive, some studies have demonstrated survival benefits attributable to race in patients undergoing MHD [
Therefore, the aim of this study was to determine if there is a link between high serum alkaline phosphatase and mortality in African MHD patients.
This study was a retrospective review of patients undergoing MHD from two dialysis centers in Johannesburg between January 2009 and March 2016. A total of 213 patients aged ≥ 18 years with available baseline line variables of interest were included. Exclusion criteria included patients with missing important data for analysis, being on dialysis for less than three months, having active or chronic liver disease, and having malignancies. In addition, we excluded Indian and mixed races to allow for a proper comparison between black and white patients. Retrieved data included patients’ demographic characteristics, blood pressure measurements, duration on haemodialysis, comorbid disease, and medication history related to CKD-MBD. Determination of race was based on self-report by the participants.
Patients were categorized into the low TAP group (≤112 U/L) versus the high TAP group (>112 U/L) based on median TAP level of 112 U/L. Secondary analysis involved exploring the relationship between race, other markers of mineral bone disorder, and primary outcome. In line with a previous study [
The primary outcome of this study was death and events other than death were censored and this included kidney transplantation, loss to follow-up, or still undergoing haemodialysis at the end of the study.
Patients’ baseline biochemical parameters (within the first three months of initiating dialysis) were assessed. Most of the biochemical markers were measured monthly except for quarterly PTH. Plasma intact PTH was measured by an electrochemiluminescence immunoassay (ECLIA) run on a Cobas 6000 autoanalyzer (Roche Diagnostics, Mannheim, Germany; reference range 10–65 pg/mL). Serum 25-OH vitamin D was measured by a chemiluminescent microparticle immunoassay (CMIA) technique run on the ARCHITECT C8000 autoanalyzer (Abbott Laboratories, Abbott Park, IL, US). Reference ranges are as follows: <10 ng/mL as severe deficiency, 10–29 ng/mL as moderate deficiency, 30–100 ng/mL as sufficiency, and >100 ng/mL as toxic.
Serum calcium, phosphate, and alkaline phosphatase were measured using the ARCHITECT C8000 autoanalyzer (Abbot Laboratories, Abbott Park, IL, US). The corrected calcium was determined using the formula: corrected calcium (mmol/L) = calcium measured (mmol/L) + 0.02 [40-albumin (g/L)]. Total alkaline phosphatase reference range is 53–128 U/L.
Plasma albumin was measured by colorimetric (bromocresol green) method on a Cobas 6000 autoanalyzer (Roche Diagnostics, Mannheim, Germany; reference range 35–52 g/L).
Other biochemical parameters were determined using routine laboratory techniques.
Blood samples were generally collected predialysis at midweek with the exception of the postdialysis serum urea for kinetic modeling.
Calculation of normalized protein catabolic rate was based on the formula [
Pearson’s or Fisher’s exact test was utilized for proportion comparisons. Continuous variables are presented as means ± standard deviations or median and interquartile range (IQR) as appropriate. Associations between serum alkaline phosphatase and other biochemical parameters were assessed by multiple linear regression analyses. The Cox proportional model was used to determine the crude and adjusted hazard ratios of death for different categories of serum alkaline phosphatase, calcium, PTH, phosphate, 25-OH vitamin D, and white versus black patients. Patients’ demographic and baseline characteristics were compared between the low and high total alkaline phosphatase groups as well as white versus black patients, using an independent
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The study included two hundred and thirteen patients (137 men, 76 women) undergoing MHD. The mean (±SD) of age, median dialysis vintage, and mean Kt/V were
Table
Comparisons of baseline characteristics between patients in high TAP and low TAP groups.
Characteristic | All ( | TAP ≤ 112 ( | TAP > 112 ( | |
---|---|---|---|---|
Age (years) | | | | 0.008 |
Female, | 76 (35.7%) | 35 (35.7%) | 41 (35.7%) | 0.25 |
Diabetes, | 56 (26.3%) | 27 (27.6%) | 29 (25.2%) | 0.76 |
Weight (Kg) | | | | 0.53 |
BMI (Kg/m2) | | | | 0.83 |
Dialysis vintage (months) | 24 (12–48) | 36 (12–60) | 36 (12–48) | 0.55 |
Systolic Bp (mmHg) | | | | 0.38 |
Diastolic Bp (mmHg) | | | | 0.86 |
Haemoglobin (g/dL) | | | | 0.10 |
Potassium (mmol/L) | | | | 0.55 |
Calcium (mmol/L) | | | | 0.58 |
Corrected calcium (mmol/L) | | | | 0.42 |
iPTH (pg/mL) | 307 (148–656) | 246 (137–527) | 325 (152–693) | 0.09 |
Phosphate (mmol/L) | | | | 0.07 |
25-OH vitamin D (ng/mL) | | | | 0.83 |
Alkaline phosphatase (U/L) | 112 (74–163) | 74 (62–96) | 163 (130–223) | <0.001 |
Albumin (g/L) | | | | 0.98 |
Type of vascular access | ||||
Arteriovenous fistula | 129 (60.6%) | 65 (66.3%) | 64 (55.7%) | 0.23 |
Graft | 39 (18.3%) | 23 (23.5%) | 26 (22.6%) | 0.88 |
Catheter | 45 (21.1%) | 21 (21.4%) | 24 (20.9%) | 0.97 |
Alanine transaminase (U/L) | | | | 0.20 |
Kt/V | | | | 0.72 |
n PCR (g/kg/day) | | | | 0.56 |
T. cholesterol (mmol/L) | | | | 0.14 |
Medications | ||||
Calcium carbonate, | 163 (76.5%) | 77 (78.6%) | 86 (74.7%) | 0.74 |
Alfacalcidol, | 137 (64.3%) | 61 (62.2%) | 76 (66.1%) | 0.55 |
ESA | 198 (93.0%) | 94 (95.9) | 104 (90.4%) | 0.50 |
ESA dose (U/week) | | | | 0.53 |
Continuous variables are presented as means ± standard deviations or median (interquartile range) and categorical data as frequencies (percentages), BP = blood pressure, i PTH = intact parathyroid hormone, TAP = total alkaline phosphatase, ESA = erythropoietin stimulating agent, n PCR = normalized protein catabolic rate, and BMI = body mass index.
Baseline characteristics of study population by race.
Parameters | All ( | Black ( | White ( | |
---|---|---|---|---|
Age (years) | | | | <0.001 |
Haemoglobin (g/dL) | | | | 0.004 |
Systolic Bp (mmHg) | | | | 0.98 |
PTH (pg/mL) | 307 (148–656) | 327 (137–658) | 290 (149–618) | 0.97 |
Calcium (mmol/L) | | | | 0.94 |
Phosphate (mmol/L) | | | | 0.004 |
Albumin (g/L) | | | | 0.03 |
25(OH) vitamin D (ng/mL) | | | | 0.77 |
TAP (U/L) | 112 (74–163) | 110 (75–151) | 115 (71–164) | 0.33 |
T. cholesterol (mmol/L) | | | | 0.05 |
Diabetes, | 56 (26.3%) | 36 (30.0%) | 20 (21.5%) | 0.02 |
Male, | 137 (64.3%) | 72 (60.0%) | 65 (69.9%) | 0.07 |
Kt/V | | | | 0.40 |
Continuous variables are presented as means ± standard deviations or median (interquartile range) and categorical data as frequencies (percentages). BP = blood pressure, TAP = total alkaline phosphatase, and PTH = parathyroid hormone.
The characteristics of the patients across different categories of serum calcium levels are shown in Table
Patient characteristics by serum calcium categories.
Parameters | <2.10 mmol/L ( | 2.10–2.37 mmol/L ( | 2.38–2.75 mmol/L ( | >2.75 mmol/L ( | |
---|---|---|---|---|---|
Age (years) | | | | | 0.09 |
Systolic Bp (mmHg) | | | | | 0.18 |
Diastolic Bp (mmHg) | | | | | 0.38 |
Haemoglobin (g/dL) | | | | | 0.20 |
Albumin g/L | | | | | 0.26 |
T.chol (mmol/L) | | | | | 0.97 |
25-OH vitamin D (ng/mL) | | | | | 0.11 |
PTH (pg/mL) | | | | | 0.01 |
Phosphate (mmol/L) | | | | | 0.66 |
Creatinine( | | | | | 0.002 |
Kt/V | | | | | 0.33 |
Dialysis vintage (months) | | | | | 0.80 |
Dialysate calcium (mmol/L) | | | | | 0.50 |
DM, | 13 | 15 | 17 | 11 | 0.40 |
Medications | |||||
Calcium carbonate | 30 (96.8%) | 79 (85.7%) | 41 (71.9%) | 13 (39.4%) | <0.001 |
Alfacalcidol | 28 (90.3%) | 63 (68.4%) | 35 (61.4%) | 11 (33.3%) | <0.001 |
Continuous variables are presented as means ± standard deviations or median (interquartile range) and categorical data as frequencies (percentages). BP = blood pressure, PTH = parathyroid hormone,
During a follow-up period of 7 years there were 57 (26.8%) deaths. After adjusting for cofounders such as age, other markers of bone disorder (calcium, phosphate, and PTH), serum alanine transaminase, 25-OH vitamin D, and comorbidity (diabetes mellitus), patients in the high TAP group had a significantly higher risk of death compared to patients in the low TAP group (hazard ratio, 2.5; 95% CI 1.24–5.01, log rank
Patients in the highest category of corrected calcium (>2.75 mmol/L) had more than a sixfold increased risk of death compared to patients with normal calcium (HR 6.34, 95% CI 1.40–28.76;
Crude and adjusted hazard ratio (95% CI) of primary outcome by baseline characteristics.
Parameter | Crude HR | 95% CI | | Adjusted HR | 95% CI | |
---|---|---|---|---|---|---|
TAP > 112 U/L | 2.20 | 1.12–4.32 | 0.02 | 2.50 | 1.24–5.01 | 0.01 |
Calcium (mmol/L) | ||||||
<2.10 | 0.66 | 0.32–1.35 | 0.26 | 0.97 | 0.22–4.26 | 0.97 |
≥2.10–≤2.37 | 1.00 | Reference | ||||
>2.37–≤2.75 | 2.31 | 1.20–4.44 | 0.02 | 1.54 | 0.57–4.18 | 0.39 |
>2.75 | 6.82 | 1.55–30.1 | 0.01 | 6.34 | 1.40–28.76 | 0.02 |
PTH (pg/mL) | ||||||
<130 | 1.00 | Reference | ||||
≥130–≤585 | 1.26 | 0.57–2.79 | 0.56 | 2.77 | 0.61–12.58 | 0.19 |
≥585 | 1.05 | 0.44–2.49 | 0.92 | 2.22 | 0.42–11.65 | 0.35 |
Phosphate > 1.50 mmol/L | 1.09 | 0.61–1.95 | 0.77 | 1.43 | 0.47-4.40 | 0.53 |
25 OH vitamin D ≤ 30 ng/mL | 2.21 | 0.66–7.35 | 0.19 | 1.07 | 0.23–4.79 | 0.92 |
White race | 1.69 | 0.95–3.04 | 0.08 | 6.88 | 1.82–25.88 | 0.004 |
HR = hazard ratio, CI = confidence interval, TAP = total alkaline phosphate, and PTH intact parathyroid hormone. Adjusted for age, phosphate, calcium, PTH, TAP, diabetes, systolic BP, 25-OH vitamin D, alanine transaminase and albumin, and serum calcium categories based on KDOQI reference range.
Kaplan Meier curve comparing patients in the high alkaline phosphatase to low alkaline phosphatase group (
Kaplan Meier survival curve between black and white (
Kaplan Meier survival curves for different categories of calcium (
Univariate linear regression analysis revealed a significant association between TAP and age (
Several studies from Europe, America, and Asia have consistently shown a linear relationship between high serum alkaline phosphate and mortality in the haemodialysis population [
Interestingly, this association was also reported in CKD patients as well as in the general population [
The mechanisms for this association have been linked to enhanced vascular calcification by high levels of serum TAP through hydrolysis of pyrophosphate or activation of apatite crystal formation [
Despite the variations in the cut-off points for defining hypercalcaemia by various studies, hypercalcaemia has been consistently associated with increased risk for mortality in haemodialysis patients [
Hypercalcaemia is an undesirable effect associated with the use of calcium based phosphate binders and vitamin D analogues in controlling secondary hyperparathyroidism. This may likely have accounted for the lower levels of PTH seen in our category of patients with calcium levels above 2.75 mmol/L. Although cinacalcet which is one of the newer drugs that effectively lowers PTH without raising serum calcium levels recently became available in South Africa, it is quite expensive, thus limiting its use to a few of our patients. In addition, the higher mean phosphate level in this group of patients is likely due to the concomitant use of alfacalcidol that enhances intestinal absorption of calcium and phosphate.
A notable finding in the current study is that white patients have a poor survival rate compared to black patients. This finding is consistent with recent emerging data from the USA that reported better survival in black patients compared with white patients on MHD [
Another important observation we made in this study was that white patients had significantly higher levels of serum albumin. We expected this to give white patients a survival benefit. However, the reason for this reversal could likely be explained by a finding from a previous study where markers of worse nutritional status (hypoalbuminemia) or smaller muscle mass and increased body fat in African American patients correlated less strongly with mortality than in whites [
In line with previous studies [
Our findings should be considered in the context of the following limitations. Firstly, the retrospective nature of this study could not allow us to make causal associations between markers of mineral bone disease and study outcome (death). In addition, the use of a single baseline laboratory measurement precludes the performance of time dependent Cox analysis to account for variations in the biochemical markers on the impact of death over a period of time. However, few studies have shown no significant difference between the baseline and time dependent Cox analysis [
Secondly, the relatively small sample size precludes generalizability of our findings to African HD patients. Thus, there is a need for multicentre studies in Africa, to provide robust data on this important clinical entity (CKD-MBD) in African HD patients.
Thirdly, similar to several observational studies we could not account for residual confounding variables. For instance, aside from diabetes mellitus, other comorbid conditions could not be ascertained. However, part of the exclusion criteria was to avoid patients with some coexisting conditions that are known as potential confounders.
The strengths of this study lie in the heterogeneous nature of our study population (black and white patients) in an African setting which has allowed comparisons of data not only for Black Africans with Black Americans, but also between whites in Africa and USA/Europe. To our knowledge, this is the first study in Sub-Saharan Africa that has given important insights regarding the impact of serum alkaline phosphatase, calcium, and race on mortality in African MHD patients.
In summary, high TAP, hypercalcaemia, and white race are associated with increased risk of death in MHD patients, thus, reaffirming the need to pay more attention to the two modifiable risk factors (calcium and TAP) in the management of CKD-MBD.
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The research protocol was approved by the Health Research and Ethics committee (HREC) of the University of the Witwatersrand; clearance certificate number is M141016.
The authors declare that they have no conflict of interests.
This study was partly supported by grants from the AstraZeneca Research Trust and the National Kidney Foundation of South Africa (NKFSA) ADCOCK INGRAM research grant.