The aim of this study was to compare mineral metabolism between anuric and nonanuric chronic hemodialysis patients, and determine the differences in phosphate control between the two groups.
A total of 77 chronic hemodialysis patients were enrolled in this cross-sectional study from January 2012 to February 2012. Patient demographics, laboratory findings, medication histories, and vascular calcification scores were collected. We divided the patients into anuric and nonanuric groups according to the residual renal function and then compared their clinical features. Multivariate binary regression analysis was used in each group to determine the independent factors related to phosphate control.
The mean patient age was 59.27±13.95 years, and 57.1% of patients were anuric. In anuric patients, dialysis vintage was significantly longer, but the mean Kt/V was not different between groups. Serum phosphate, fibroblast growth factor (FGF)-23, and Ca/P products were significantly higher, and 1,25(OH)2D3 levels were significantly lower in the anuric patients, although the intact parathyroid hormone and 25(OH)D levels were not different. In anuric patients, LnFGF-23 [hazard ratio (HR) 2.894, 95% confidence interval (CI) 1.294–6.474,
In chronic hemodialysis patients, preservation of residual renal function is a significant determinant of phosphate control, and the factors associated with phosphate control is different depending on the residual renal function status. In the anuric patients, FGF-23 is most significantly associated with phosphate control; however, glomerular filtration rate and blood urea nitrogen are more important than FGF-23 in the nonanuric HD patients.
Residual renal function (RRF) is an important determinant of mortality and morbidity in chronic dialysis patients. In previous studies, the degree of RRF was found to be inversely associated with the severity of left ventricular hypertrophy and cardiovascular death in peritoneal dialysis patients
Phosphate, which is excreted through urine, is the key molecule in chronic kidney disease-mineral and bone disorder (CKD-MBD). Under normal physiologic conditions, phosphate removal is determined mainly by the expression of type II Na–Pi cotransporters at the tubular epithelium
In this study, we aimed to compare mineral metabolism between anuric and nonanuric chronic HD patients and determine the differences in phosphate control between these groups according to RRF.
From January 2012 to February 2012, a total of 77 HD patients from our dialysis unit were enrolled in this study. All patients were older than 18 years and undergoing maintenance HD therapy for end-stage renal disease for more than 3 months. The participants were dialyzed thrice weekly for more than 4 hours per session, using low-flux membranes. The standard dialysate calcium concentration was 3.5 mEq/L. Exclusion criteria included severe malnutrition, acute infection, hepatic dysfunction, and malignancy. Approval of the local ethics committee was obtained for this study, and all patients provided written informed consent.
Demographics and medical histories were reviewed; dialysis treatment parameters such as dialysis vintage, blood flow rate, and single-pool Kt/V were assessed; and nutritional markers, such as normalized protein nitrogen appearance (nPNA), subjective global assessment (SGA), total protein, albumin, and total cholesterol levels were checked. Biochemical CKD-MBD factors and associated medication histories during the study period were collected. All the predialysis blood samples were obtained for routine laboratory assessment by standard techniques, and a part of these samples was stored at −80°C for performing the enzyme-linked immunosorbent assay (ELISA) study in all patients. Analysis of serum calcium was performed by the ortho-cresolphthalein complexone method using a Roche/Hitachi Modular-DP analyzer (Roche Diagnostics, Basel, Switzerland); calcium levels were corrected for serum albumin. Analysis of serum phosphate was performed by the phosphomolybdate reduction method using a Roche/Hitachi Modular-DP analyzer (Roche Diagnostics). The serum level of intact PTH (iPTH) was assessed by a total iPTH immunoradiometric assay, which quantifies both PTH(1–84) and the N-truncated PTH fragments. Serum 25(OH)D and 1,25(OH)2D3 levels were measured using a radio immunoassay. Serum FGF-23 and serum fetuin A levels were measured using an ELISA kit (ELISA, Immutopics, San Clemente, CA, USA—for FGF-23; ELISA, R&D Systems, Minneapolis, MN, USA—for feutin A), according to the manufacturer’s protocol.
We defined anuria as a 24-hour urine output of <100 mL, and the glomerular filtration rate (eGFR) of the anuric patients was estimated to be 0.00 mL/minute/1.73 m2. For the nonanuric patients, GFR was estimated by the numerical averages of the 24-hour creatinine clearance and urea nitrogen clearance. A 24-hour urine collection was made after the longest interdialysis period. A cardiovascular event was defined as myocardial infarction, stroke, or transient ischemic attack. Single-pool Kt/V (spKt/V) was calculated using the natural logarithm formula
Aortic arch calcifications were calculated based on posterior–anterior plain chest X-rays, using Ogawa et al’s method
Data were analyzed using SPSS for Windows, version 17.0 (SPSS Inc., Chicago, IL, USA). For continuous variables, the mean ± standard deviation was used for normally distributed data; otherwise, the median was shown. Differences between the two groups were assessed using a Student
A total of 77 patients were enrolled in this study. The mean patient age was 59.27±13.95 years, and 59.7% of patients were male. Diabetes was the most common cause of end-stage renal disease, the various causes of which are listed in
In our study, 57.1% (
With the unadjusted analysis, serum phosphate (
We further divided the patients into two groups according to the achievement of optimal phosphate control. Of the patients, 44.1% (
In the univariate analysis, LnFGF-23, 1,25(OH)2D3, GFR, BUN, creatinine, and age were significant factors; however, in the multivariate regression model, LnFGF-23, 1,25(OH)2D3, and GFR were independent factors predictive of optimal phosphate control (
Among the 33 nonanuric patients, 59.4% (
In the univariate analysis, LnFGF-23, BUN, creatinine level, and GFR were statistically significant; however, in the multivariate analysis, GFR [hazard ratio (HR) 0.409, 95% confidence interval (CI) 0.169–0.989,
Only 31.8% (
In the univariate analysis model, LnFGF-23, 1,25(OH)2D3, BUN, and creatinine levels were statistically significant; however, in the multivariate regression analysis, only LnFGF-23 (HR 2.894, 95% CI 1.294–6.474,
Traditionally, the significance of RRF has been emphasized in peritoneal dialysis patients, but its importance has often been overlooked in HD patients. The significance of RRF in CKD-MBD in HD patients was first described by Viaene et al
Our study also demonstrated the significance of RRF for phosphate control in maintenance HD patients. Mineral metabolism was closer to normal physiology in the nonanuric patients than in the anuric patients; phosphate control was better, FGF-23 levels were significantly lower, and 1,25(OH)2D3 levels were significantly higher in the nonanuric patients, and all these factors showed meaningful correlation with eGFR. This superiority of phosphate control in the nonanuric HD patients may be attributed to the occurrence of phosphaturia through the remnant nephron. In the nonanuric patients, excretion of phosphate through urine could inhibit further increase of serum FGF-23, and controlled FGF-23 secretion allowed the conversion of 25(OH)D to 1,25(OH)2D3
The unique point of our study was that factors associated with phosphate control were found to differ according to the RRF status. For optimal phosphate control, FGF-23, as expected, was a significant factor in the anuric patients; however, in the nonanuric patients, BUN and GFR were the independent factors that were predictive of phosphate control, instead of FGF-23. Recently, Wang et al
Traditionally, FGF-23 was regarded as a master regulator of phosphate homeostasis
In this study, BUN was also a determinant of phosphate control in the nonanuric patients. Although BUN has an association with GFR as a filtration marker, it is also an important nutritional marker, especially for dietary phosphate. A higher BUN represents better nutritional status in maintenance HD patients
FGF-23 and PTH stimulate phosphaturia in a similar manner by reducing phosphate reclamation through Na/Pi IIa, IIc cotransporters
In our cross-sectional study, vascular calcification was not affected by RRF. Atherosclerosis is known to have a positive correlation with FGF-23
Our study has several limitations. First, we could not explain the cause and effect relationships between phosphate, RRF, FGF-23, 1,25(OH)2D3, and iPTH, because we did not measure the degree of phosphaturia in the nonanuric HD patients and did not control serum phosphate level in the anuric HD patients. Second, the sample size was small. Third, we did not control dietary phosphate during the study period. However, our results are consistent with previous data, and it is valuable to understand that phosphate metabolism is somewhat different according to RRF in HD patients.
In conclusion, RRF was found to be an important, possibly fundamental, factor for CKD-MBD in maintenance HD patients. In the anuric HD patients, FGF-23 was observed to be an important determinant of phosphate control; however, in nonanuric HD patients, GFR was more important than FGF-23 for phosphate control.
All authors declare no competing interest.
This work was supported by the 2013 Clinical Research Grant from
Causes of end-stage renal disease
Diagnosis | % |
---|---|
Diabetes | 53.25 |
Glomerulonephritis | 20.78 |
Hypertension | 14.28 |
ADPKD | 6.49 |
Neurogenic bladder | 3.89 |
Unknown | 1.29 |
Data are presented as %.
ADPKD, autosomal dominant polycystic kidney disease.
Baseline characteristics according to the urine output status
Variables | Nonanuric patients | Anuric patients | |
---|---|---|---|
33 | 44 | ||
Age (y) | 56.75±14.24 | 62.64±13.00 | 0.986 |
Male | 48 | 61 | 0.737 |
DM | 18.2 | 33.8 | 0.147 |
HT | 75.8 | 61.4 | 0.182 |
Hx of CVE | 37.0 | 38.1 | 0.845 |
GFR (mL/min/1.73 m2) | 6.40±2.65 | 0.00±0.00 | <0.001 |
Dialysis factor | |||
Dialysis vintage (mo) | 20.73±16.87 | 41.73±25.94 | 0.031 |
BFR (mL/min) | 260.00±15.61 | 265.45±21.93 | 0.228 |
Kt/V | 1.55±0.37 | 1.48±0.21 | 0.274 |
Nutrition factors | |||
nPNA (g/kg/d) | 1.02±0.26 | 1.10±0.27 | 0.865 |
SGA | 6.70±0.59 | 6.70±0.83 | 0.728 |
Total protein (g/dL) | 6.75±0.52 | 6.97±0.56 | 0.473 |
Albumin (g/dL) | 3.96±0.48 | 4.14±0.43 | 0.398 |
Total cholesterol (mg/dL) | 147.91±29.73 | 150.09±32.63 | 0.385 |
BUN (mg/dL) | 54.67±19.22 | 64.34±16.79 | 0.867 |
Creatinine (mg/dL) | 7.92±2.78 | 9.53±2.59 | 0.479 |
Hb (g/dL) | 10.29±1.03 | 10.72±1.32 | 0.449 |
Biochemical CKD-MBD factors | |||
Corrected calcium (mg/dL) | 9.09±0.73 | 9.18±0.76 | 0.860 |
Phosphate (mg/dL) | 4.32±1.0 | 5.32±1.66 | 0.017 |
Ca×P (mg2/dL2) | 38.96±9.75 | 49.53±16.06 | 0.025 |
ALP (IU/L) | 73.15±30.37 | 92.48±52.05 | 0.068 |
FGF-23 (pg/mL) | 856.25±2,297.58 | 2,849.09±5,141.40 | 0.002 |
iPTH (pg/mL) | 135.51±105.62 | 156.93±140.24 | 0.238 |
25(OH)D (ng/mL) | 11.45±5.80 | 11.05±3.96 | 0.739 |
1,25(OH)2D3 (pg/mL) | 13.03±7.70 | 9.67±3.46 | 0.020 |
Optimal phosphate group | 59.4 | 31.8 | 0.014 |
Medications for the phosphate control | |||
Calcium acetate | 24.7 | 32.5 | 0.737 |
Sevelamer | 2.6 | 9.1 | 0.183 |
Lanthanum | 0 | 1.3 | 0.383 |
Vitamin D | 5.2 | 6.5 | 0.918 |
Vascular calcification | |||
Presence of AoAC | 17.3 | 25.3 | 0.758 |
AoACS (%) | 12.69±19.85 | 13.95±25.14 | 0.589 |
Fetuin A (µg/mL) | 412.12±93.99 | 429.09±130.59 | 0.770 |
Data are presented as % or mean±SD, unless otherwise indicated.
ALP, alkaline phosphatase; AoAC, aortic arch calcification; AoACS, aortic arch calcification score; BFR, blood flow rate; BUN, blood urea nitrogen; CKD-MBD, chronic kidney disease-mineral and bone disorder; DM, diabetes mellitus; FGF-23, fibroblast growth factor-23; GFR, glomerular filtration rate; Hb, hemoglobin; HT, hypertension; Hx of CVE, history of cardiovascular event; iPTH, intact parathyroid hormone; nPNA, normalized protein nitrogen appearance; SD, standard deviation; SGA, subjective global assessment.
Multivariate analysis that relates to predialysis serum phosphate level, in all patients
Variables | Univariate model | Multivariate model | ||||
---|---|---|---|---|---|---|
HR | 95% CI | HR | 95% CI | |||
LnFGF-23 (pg/mL) | 2.371 | 1.495–3.761 | <0.001 | 1.991 | 1.147–3.458 | 0.014 |
1,25(OH)2D3 (pg/mL) | 0.824 | 0.709–0.957 | 0.004 | 0.777 | 0.641–0.942 | 0.010 |
GFR (mL/min/1.73 m2) | 0.779 | 0.668–0.909 | 0.001 | 0.776 | 0.620–0.970 | <0.001 |
BUN (mg/dL) | 1.075 | 1.034–1.117 | <0.001 | |||
Cr (mg/dL) | 1.542 | 1.211–1.963 | <0.001 | |||
Age (y) | 0.951 | 0.914–0.989 | 0.012 |
BUN, blood urea nitrogen; CI, confidence interval; Cr, creatinine; GFR, glomerular filtration rate; HR, hazard ratio; LnFGF-23, log-transformed fibroblast growth factor-23.
Adjusted age, sex, LnFGF-23, 1,25(OH)2D3, GFR, BUN, and Cr.
Comparisons of phosphate control according to the residual renal function in chronic hemodialysis patients
Variables | Nonanuric patients | Anuric patients | ||||
---|---|---|---|---|---|---|
Optimal P control | Poor P control | Optimal P control | Poor P control | |||
Number | 20 | 13 | 14 | 30 | ||
Age (y) | 66.37±10.54 | 58.23±15.03 | 0.081 | 61.25±7.51 | 54.74±15.98 | 0.078 |
Male | 57.9 | 53.8 | 0.821 | 75.0 | 54.8 | 0.306 |
DM | 47.4 | 38.5 | 0.618 | 75.0 | 54.8 | 0.306 |
HT | 73.7 | 76.9 | 0.835 | 91.7 | 51.6 | 0.032 |
Hx of CVE | 41.7 | 36.7 | 0.763 | 41.7 | 36.7 | 0.763 |
GFR (mL/min/1.73 m2) | 7.28±2.89 | 5.20±1.84 | 0.030 | 0 | 0 | – |
Dialysis factor | ||||||
Dialysis vintage (mo) | 22.58±18.26 | 16.31±13.80 | 0.303 | 45.92±24.24 | 41.35±26.29 | 0.605 |
BFR (mL/min) | 257.37±9.91 | 260.76±18.91 | 0.560 | 265.00±23.16 | 266.13±22.01 | 0.886 |
Kt/V | 1.58±0.42 | 1.52±0.30 | 0.648 | 1.46±0.21 | 1.50±0.21 | 0.517 |
Nutrition factors | ||||||
nPNA (g/kg/d) | 1.02±0.31 | 1.02±0.19 | 0.999 | 1.03±0.19 | 1.13±0.29 | 0.246 |
SGA score | 6.74±0.56 | 6.64±0.67 | 0.664 | 6.42±1.16 | 6.81±0.65 | 0.171 |
Total protein (g/dL) | 6.64±0.41 | 6.90±0.63 | 0.169 | 7.06±0.64 | 6.94±0.54 | 0.510 |
Albumin (g/dL) | 3.99±0.39 | 3.92±0.60 | 0.071 | 4.01±0.32 | 4.18±0.46 | 0.246 |
Total cholesterol (mg/dL) | 145.32±30.49 | 151.69±29.36 | 0.560 | 147.33±23.18 | 151.16±35.90 | 0.735 |
BUN (mg/dL) | 46.68±14.89 | 67.27±19.16 | 0.002 | 55.67±14.84 | 68.10±16.54 | 0.028 |
Creatinine (mg/dL) | 6.73±2.35 | 9.47±2.63 | 0.004 | 8.39±2.14 | 10.09±2.58 | 0.048 |
Hb (g/dL) | 10.37±1.14 | 10.16±0.92 | 0.581 | 10.47±1.52 | 10.82±1.27 | 0.456 |
Biochemical CKD-MBD factors | ||||||
Corrected calcium (mg/dL) | 9.48±0.66 | 9.51±0.73 | 0.905 | 9.63±0.72 | 9.42±0.64 | 0.364 |
Phosphate (mg/dL) | 3.59±0.58 | 5.35±0.60 | <0.001 | 3.43±0.56 | 6.13±1.24 | <0.001 |
Ca×P (mg2/dL2) | 32.52±5.46 | 48.37±6.24 | <0.001 | 31.78±6.29 | 56.39±13.11 | <0.001 |
ALP (IU/L) | 79.05±27.58 | 67.77±32.93 | 0.302 | 105.50±54.65 | 87.10±51.83 | 0.310 |
FGF-23 (pg/mL) | 314.23±456.39 | 658.31±375.96 | 0.045 | 372.12±304.20 | 3919.32±5846.95 | 0.003 |
LnFGF-23 (pg/mL) | 4.92±1.33 | 6.21±0.92 | 0.009 | 5.50±1.12 | 7.09±1.71 | 0.007 |
iPTH (pg/mL) | 163.75±115.07 | 101.92±81.05 | 0.105 | 117.19±101.73 | 167.61±151.45 | 0.295 |
1,25(OH)2D3 (ng/mL) | 15.27±8.71 | 10.48±5.08 | 0.100 | 11.19±4.21 | 8.76±2.65 | 0.047 |
Medications for the phosphate control | ||||||
Calcium acetate | 63.2 | 53.8 | 58.3 | 64.5 | ||
Average dose (mg/d) | 597.89±542.95 | 1301.67±1625.64 | 0.598 | 650.83±769.37 | 1088.67±1082.94 | 0.210 |
Sevelamer | 0±0 | 15.4 | 0 | 22.6 | ||
Average dose (mg/d) | 0 | 369.23±901.28 | 0.157 | 0±0 | 541.94±1020.06, | 0.006 |
Lanthanum | 0 | 0 | 0 | 3.2 | ||
Average dose (mg/d) | 0±0 | 0±0 | 0±0 | 48.39±269.41 | 0.540 | |
Calcitriol | 21.1 | 0 | 8.3 | 12.9 | ||
Average dose (mcg/d) | 0.05±0.13 | 0±0 | 0.128 | 0.02±0.07 | 0.02±0.06 | 0.854 |
Vascular calcification | ||||||
Presence of AoAC | 47.4 | 30.8 | 0.348 | 41.7 | 45.2 | 0.836 |
AoACS score | 15.78±22.76 | 8.17±14.29 | 0.294 | 9.37±13.19 | 15.72±28.45 | 0.464 |
Fetuin A (µg/mL) | 381.68±93.15 | 459.89±81.49 | 0.030 | 409.89±95.03 | 439.27±142.92 | 0.551 |
Data are presented as % or mean ± SD.
ALP, alkaline phosphatase; AoAC, aortic arch calcification; AoACS, aortic arch calcification score; BFR, blood flow rate; BUN, blood urea nitrogen; CKD-MBD, chronic kidney disease-mineral and bone disorder; DM, diabetes mellitus; FGF-23, fibroblast growth factor-23; GFR, glomerular filtration rate; Hb, hemoglobin; HT, hypertension; Hx of CVE, history of cardiovascular event; iPTH, intact parathyroid hormone; nPNA, normalized protein nitrogen appearance; SD, standard deviation; SGA, subjective global assessment.
Regression analysis of factors relate to predialysis serum phosphate level, according to the residual renal function
Variables | Univariate model | Multivariate model | ||||
---|---|---|---|---|---|---|
HR | 95% CI | HR | 95% CI | |||
Nonanuric patients | ||||||
LnFGF-23 (pg/mL) | 2.539 | 1.170–5.511 | 0.018 | |||
GFR (mL/min/1.73 m2) | 0.633 | 0.403–0.996 | 0.048 | 0.409 | 0.169–0.989 | 0.047 |
BUN (mg/dL) | 1.090 | 1.020–1.164 | 0.011 | 1.090 | 1.014–1.172 | 0.019 |
Creatinine (mg/dL) | 1.542 | 1.101–2.160 | 0.012 | |||
Anuric patients | ||||||
LnFGF-23 (pg/mL) | 2.064 | 1.135–3.754 | 0.018 | 2.894 | 1.294–6.474 | 0.010 |
1,25(OH)2D3 (pg/mL) | 0.793 | 0.621–1.013 | 0.063 | |||
BUN (mg/dL) | 1.055 | 1.003–1.110 | 0.039 | |||
Creatinine (mg/dL) | 1.408 | 0.984–2.014 | 0.061 |
BUN, blood urea nitrogen; CI, confidence interval; GFR, glomerular filtration rate; HR, hazard ratio; LnFGF-23, log-transformed fibroblast growth factor-23.
Adjusted age, sex, LnFGF-23, GFR, BUN, Cr, and fetuin A, in nonanuric patients. Adjusted age, sex, HT, LnFGF-23, BUN, Cr, 1.25(OH)2D3 and use of sevelamer in anuric patients.