Mineral metabolism and haemoglobin concentration among haemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS)

Naoki Kimata1, Takashi Akiba1, Ronald L. Pisoni2, Justin M. Albert2, Sudtida Satayathum2, José M. Cruz3, Tadao Akizawa4, Vittorio E. Andreucci5, Eric W. Young6 and Friedrich K. Port2

1 Division of Blood Purification, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan, 2 University Renal Research and Education Association, Ann Arbor, MI, USA, 3 Hospital General Universitario ‘La Fe’ Servicio de Nefrología, Valencia, Spain, 4 Center of Blood Purification Therapy, Wakayama Medical University, Wakayama, Japan, 5 Cattedra di Nefrologia, Universitá Federico II di Napoli, Naples, Italy and 6 Division of Nephrology, University of Michigan, Department of Veterans Affairs Medical Center, Ann Arbor, MI, USA

Correspondence and offprint requests to: Friedrich K. Port, MD, MS, 315 W. Huron, Suite 260, Ann Arbor, MI 48108, USA. Email: fport{at}urrea.org



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Bone and mineral metabolism is abnormal in most chronic haemodialysis patients and is associated with a high mortality risk. Because of possible pathogenic links between anaemia and intact parathyroid hormone (iPTH), the present study evaluated associations of mineral metabolism indicators with haemoglobin (Hb).

Methods. Data were collected from 317 facilities (12 089 haemodialysis patients) in Australia, Belgium, Canada, France, Germany, Italy, Japan, New Zealand, Spain, Sweden, the United Kingdom and the United States by the Dialysis Outcomes and Practice Patterns Study (DOPPS). The major outcome studied was probability of haemodialysis patients having a target Hb, per guidelines, of ≥11 g/dl at baseline. Major predictor variables were patient characteristics and laboratory markers of mineral metabolism: albumin-corrected serum calcium (calciumAlb), serum phosphorus (PO4) and iPTH. Analyses were adjusted for demographics, 15 comorbidity classes, baseline laboratory values, body mass index, years on dialysis, erythropoietin dose, vitamin D and catheter use, cause of end-stage renal disease and country.

Results. The adjusted odds ratio (AOR) of having Hb ≥11 g/dl was significantly higher (P<0.0001) in patients with higher calciumAlb (AOR = 1.32 per 1 mg/dl), higher PO4 (AOR = 1.08 per 1 mg/dl) and lower iPTH (AOR = 0.96 per 100 pg/ml). Furthermore, 4 month intrapatient changes in Hb concentration were significantly (P<0.0001) related to 4 month changes in calciumAlb (0.17 g/dl Hb rise per 1 mg/dl higher calciumAlb) and PO4 (0.11 g/dl Hb rise per 1 mg/dl higher PO4). Mean weekly recombinant human erythropoietin (rHuEpo) doses were higher for patients with high PO4 or iPTH levels, but lower for patients with calciumAlb >9.5 mg/dl, after patient mix and Hb concentration adjustments.

Conclusions. The results of this study indicate that higher serum calciumAlb and PO4 levels are each independently associated with better anaemia control. This relationship is independent of vitamin D use, PTH levels and prescribed rHuEpo dose. Despite this benefit of better anaemia control at higher serum calciumAlb and PO4 concentrations, lower calcium and PO4 levels, as recommended by the K/DOQI guidelines, should still serve as the long-term goal for HD patients in order to minimize tissue calcification and mortality risk.

Keywords: calcium and anaemia; haemodialysis guidelines; parathyroid hormone and anaemia; parathyroidectomy; phosphorus and anaemia; practice patterns



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Bone and mineral metabolism is abnormal in most patients with chronic renal failure, particularly those with end-stage renal disease (ESRD). Abnormal mineral metabolism is associated with complex alterations in intact parathyroid hormone (iPTH), calcium, phosphorus, 1,25 (OH)2 vitamin D3, acidosis and bone physiology [1–3]. For example, hyperphosphataemia directly increases iPTH secretion and stimulates parathyroid cell proliferation and hyperplasia. Parathyroid gland weight and iPTH level are increased in animal models of renal failure and a high-phosphate diet results in a further increase [1]. Furthermore, calcium is an important regulator of PTH secretion and by controlling serum calcium levels or through the use of calcimimetics, progression of secondary hyperparathyroidism can be managed [4]. Importantly, for chronic haemodialysis (HD) patients, alterations in mineral metabolism leading to secondary hyperparathyroidism, hyperphosphataemia and hypercalcaemia have been shown to be strongly associated with increased mortality risks for this patient population [5–7].

Anaemia accompanies abnormal mineral metabolism during progressive renal failure, largely due to erythropoietin deficiency, marrow fibrosis, blood loss, malnutrition and shortened red blood cell survival. Several investigators have suggested a link between mineral metabolism and anaemia [2,3,8]. Hyperparathyroidism is usually listed as a contributor to renal anaemia and as a possible reason for impaired response to recombinant human erythropoietin (rHuEpo) in patients with renal disease [2]. Possible pathogenic links between anaemia and iPTH include reduced erythropoiesis due to calcitriol deficiency, direct or indirect effects of iPTH on erythropoietin release and shortened red blood cell survival [2,3,8]. However, other authors have failed to observe an association between anaemia and iPTH [9] and factors other than iPTH may directly influence haemoglobin (Hb) production.

Several clinical studies have shown that dialysis patients with severe secondary hyperparathyroidism either require a higher dose of rHuEpo to correct anaemia than do euparathyroid dialysis patients or have significant improvements in anaemia after medical or surgical correction of their secondary hyperparathyroidism [2,3].



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Study design and sample
The present study—undertaken to improve the understanding of the relationship between mineral metabolism and Hb concentration—used a large sample of randomly selected HD patients in 12 countries from the Dialysis Outcomes and Practice Patterns Study (DOPPS II) [10,11], an international, prospective, observational study of HD practice patterns and associated outcomes. The data were collected from 20 facilities (679 patients) in Australia–New Zealand, 19 facilities (770 patients) in Canada, 138 facilities (5374 patients) in Europe (Belgium, France, Germany, Italy, Spain, Sweden and the United Kingdom), 65 facilities (2189 patients) in Japan and 75 facilities (3077 patients) in the United States. DOPPS II began collecting data in 2002 for all 12 countries using a uniform data collection instrument. Nationally representative samples were obtained using a stratified random selection of dialysis units in each country. This selection method provided facility samples proportional to the major types of dialysis units and geographic regions within each country. Within each dialysis unit, patients were selected randomly for study participation. Detailed patient data were collected at study entry (baseline) and at 4 month intervals thereafter [11]. Furthermore, information regarding prescribed medications and their dosage was collected for each study patient at the time of study entry and after 1 year of study participation. Each facility collected data on 20–40 prevalent HD patients (depending on facility size) and up to 15 patients initiating therapy for ESRD. The total number of patients for whom full data were available was 12 089.

A prevalent cross-section (n = 8857) of HD patients dialysing at the time of each facility's entry into the DOPPS was used to describe patient characteristics. However, analytical models used detailed data collected from the 12 089 patients for whom full data were reported. For all study patients, clinical data were abstracted from their medical records. Dialysis facility personnel, usually dialysis nurses, performed data abstraction. Comorbidity and patient demographic data were collected at the time of study entry.

Statistical analysis
Means and SDs were used at the patient level to describe indicators of mineral metabolism among the prevalent cross-section of patients (n = 8857). The major study outcome was the probability of patients having Hb concentration ≥11 vs <11 g/dl at study entry (i.e. baseline), which was modelled by logistic regression analysis. This target corresponds to the guideline recommended by the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQITM) [5, available at http://www2.ajkd.org/scripts/om.dll/serve?web=/ajkd/kdoqi.html&id=ajkd] and the European Best Practice Guidelines for Haemodialysis [12]. The major predictor variables were patient characteristics and laboratory markers of mineral metabolism, including albumin-corrected serum calcium (calciumAlb), serum phosphorus (PO4), iPTH and prior parathyroidectomy (PTX). Each mineral metabolism variable was evaluated in separate models and together in a combined model. The analysed PTH data were based upon iPTH measurements. Approximately 95% of dialysis units in the DOPPS II reported results based upon measurement of iPTH.

CalciumAlb was calculated as [(4 – albumin) x 0.8] + total serum calcium, with serum albumin expressed in g/dl and total serum calcium in mg/dl. Models also were adjusted for age, sex, race, years on dialysis, body mass index (BMI), single-pool dialysis dose (spKt/V), rHuEpo dose (units/week), whether the patient was receiving vitamin D, diagnosis of malnourishment and 15 summary comorbid conditions present at study entry [coronary artery disease, congestive heart failure, other cardiac disease, hypertension, cerebrovascular disease, peripheral vascular disease, diabetes mellitus, lung disease, cancer (excluding skin), human immunodeficiency virus/acquired immunodeficiency syndrome, gastrointestinal bleeding, neurological disease, psychiatric disease, recurrent cellulitis and prior PTX]. The models also were adjusted for several factors recently shown by the DOPPS to be significantly related to Hb control: laboratory values for serum albumin, ferritin and transferrin saturation; polycystic kidney disease as cause of ESRD; and facility-level catheter use [13]. Logistic models were adjusted for country and accounted for facility clustering effects, using generalized estimating equations [14], thereby allowing results to reflect the average effect across all 12 DOPPS II countries. Logistic regression results were expressed as adjusted odds ratios (AOR).

Mixed linear regression models were used to determine how intrapatient changes in serum calcium and PO4 levels related to changes in patient Hb concentrations over a 4 month period. Mixed linear regression models also were used to investigate the relationship between patient rHuEpo dose levels and iPTH. All mixed linear regression models were adjusted for age, sex, race, polycystic kidney disease as cause of ESRD, years on dialysis, BMI, diagnosis of malnourishment, 15 comorbid conditions, spKt/V, ferritin, transferrin saturation, rHuEpo dose (units/week), calciumAlb, PO4, iPTH, prior PTX, facility catheter use, whether receiving vitamin D and country. These models also accounted for facility clustering effects.

All statistical analyses were performed with SAS software, version 8.2 (SAS Institute, Inc., Cary, NC, USA).



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Table 1 shows the baseline characteristics of a prevalent cross-section of HD patients who participated in DOPPS II during 2002–2003 (n = 8857). This international patient sample displayed high levels of cardiovascular disease, with 26–45% of patients having coronary artery disease, congestive heart failure, other cardiac disease, diabetes mellitus or peripheral vascular disease and 79% having hypertension. The mean concentration for selected patient laboratory values was 11.3 g/dl for Hb, 9.6 mg/dl for calciumAlb, 5.6 mg/dl for serum PO4 and 268 pg/ml for iPTH.


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Table 1. Selected baseline socio-demographic variables, laboratory values and comorbidity conditions for a prevalent cross-section of HD patients (n = 8857)

 
The relatively large SD for each of these measures indicated large variation among patients in the management of anaemia and mineral metabolism. A large variation was also seen among dialysis facilities (n = 309; this number excludes facilities with fewer than five patients having a reported Hb measure) in the percentage of patients with Hb ≥11 g/dl at baseline (Figure 1). In nearly 70% of the dialysis units, over half the patients had Hb ≥11 g/dl. However, in 10% of the dialysis units, ≤20% of patients had Hb ≥11 g/dl.



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Fig. 1. Distribution of the percentage of a prevalent cross-section of patients, by facility, having Hb ≥11 g/dl, using baseline data. Excludes facilities with fewer than five patients having a reported Hb measure (n = 309 facilities).

 
Table 2 shows associations between the odds of patients having Hb ≥11 g/dl and four mineral metabolism indicators: serum PO4, serum iPTH, calciumAlb and prior PTX. The results were from a logistic model that simultaneously adjusted for all four mineral metabolism indicators, patient mix and selected patient laboratory measurements previously shown to be significantly related to patient Hb levels [13]. The AOR of having the target Hb concentration (≥11 g/dl) was strongly and positively associated with a patient's calciumAlb concentration. The AOR of having Hb ≥11 g/dl was 32% higher for every 1 mg/dl increment in calciumAlb (P<0.0001). Higher serum PO4 also appeared to be positively associated with increased odds of having Hb ≥11 g/dl. However, the magnitude of the effect for PO4 (AOR of Hb ≥11 vs <11 g/dl = 1.08 per 1 mg/dl higher PO4; P<0.0001) was one-quarter that seen for calciumAlb. In contrast to calciumAlb and PO4, the odds of having Hb ≥11 g/dl declined with increasing iPTH (AOR = 0.96 per 100 pg/ml higher iPTH; P<0.0001). PTX prior to study entry was noted for 6.9% of patients, who tended to have a higher odds of having Hb ≥11 g/dl, although this observation was not statistically significant (AOR = 1.16, P = 0.16). The relationship between mineral metabolism indicators and having the target Hb concentration displayed similar trends when analyses were limited to patients who had been on dialysis >180 days (n = 7563): calciumAlb (AOR = 1.20, P<0.0001), serum PO4 (AOR = 1.09, P<0.0001) and iPTH (AOR = 0.97, P = 0.002). The simultaneous logistic model adjustment for all mineral metabolism indicators allowed for an estimate of the effect of each mineral metabolism measure independent of the other measures. Adjusting for vitamin D use or restricting the analysis to patients not receiving vitamin D had no effect on the relationship between each mineral metabolism measure and odds of a patient having the target Hb concentration. Furthermore, the strong relationship between mineral metabolism measures and having the target Hb concentration was observed to be virtually unaffected by adjusting the analysis for four measures of facility practice: facilities' percentage of patients with single pool Kt/V >1.2; with serum albumin ≥4 g/dl; dialysing with either an arteriovenous (AV) fistula or an AV graft; and with iPTH in the K/DOQI range of 150–300 pg/ml.


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Table 2. AOR for having Hb concentration ≥11 vs <11 g/dl by baseline patient measures of mineral metabolism indicatorsa

 
Categorical analyses indicated a strong dose-dependent relationship between calciumAlb and patients having Hb ≥11 g/dl (Figure 2). This relationship was seen across the entire range of patient calciumAlb concentrations. The steep association between calciumAlb and patient target Hb was independent of differences in weekly rHuEpo doses, since models were adjusted for patient rHuEpo dose and route of rHuEpo administration. Sensitivity analyses demonstrated that the relationship between calciumAlb and the odds of a patient having the target Hb did not differ for patients with PO4 >5.5 vs ≤5.5 mg/dl. Similarly, the relationship between calciumAlb and the odds of a patient having the target Hb did not differ for patients with serum iPTH >300 vs ≤300 pg/ml.



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Fig. 2. AOR of having target Hb ≥11 vs <11 g/dl, by categories of patient-level albumin-corrected serum calcium. Model adjusted for age, sex, black race, cause of ESRD, years on dialysis, BMI, 15 comorbid conditions, spKt/V, ferritin, transferrin saturation, rHuEpo dose (units/week), serum albumin, serum phosphorus (PO4), iPTH, prior PTX, catheter use, whether receiving vitamin D, diagnosis of malnourishment and country, accounting also for facility clustering effects. The inset table shows the odds of patients having Hb ≥11 g/dl per 1 mg/dl higher albumin-corrected serum calcium as a continuous variable, overall and for the following patient subgroups analysed separately: patients with iPTH >300 pg/ml, iPTH ≤300 pg/ml, PO4 >5.5 mg/dl and PO4 ≤5.5 mg/dl.

 
A patient subgroup analysis was performed to examine the relationship between calciumAlb and having the target Hb for HD patients on dialysis >90 vs ≤90 days. The association between calciumAlb and odds of a patient having the target Hb was of slightly greater magnitude for HD patients on dialysis ≤90 days (AOR = 1.32, P<0.0001) than for HD patients on dialysis >90 days (AOR = 1.27, P<0.0001). The difference between these two patient groups was statistically significant (P = 0.006).

Categorical analyses with serum PO4 indicated a significantly greater likelihood of patients having Hb ≥11 g/dl with higher concentrations of serum PO4 (≤7 mg/dl; Figure 3). However, the odds of patients having Hb ≥11 vs <11 g/dl were not substantially higher at concentrations >7 vs 5.5–7 mg/dl, suggesting that most of the effect in the relationship between PO4 and the target Hb level occurred at PO4 levels ≤7 mg/dl. The PO4 reference group (AOR = 1.0) was chosen to correspond to the K/DOQI recommendation of a PO4 range of 3.5–5.5 mg/dl [5]. Having the target Hb level was significantly more likely for patients with PO4 levels >5.5 vs 3.5–5.5 mg/dl in the fully adjusted model (AOR = 1.26, P<0.0001).



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Fig. 3. AOR of having target Hb ≥11 g/dl vs. <11g/dl by patient-level serum phosphorus. Model adjustments were the same as in Figure 2.

 
Figure 4 shows an inverse association between target Hb and categories of iPTH, with the reference group (AOR = 1.0) chosen to correspond to the K/DOQI recommendation of an iPTH range of 150–300 pg/ml [5]. Compared with the iPTH reference group, the likelihood of a patient having the target Hb level was significantly lower for patients with serum iPTH levels of 301–600 pg/ml (AOR = 0.77, P = 0.0002) and iPTH levels >600 pg/ml (AOR = 0.69, P<0.0001).



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Fig. 4. AOR of having target Hb ≥11 vs <11 g/dl by patient-level iPTH. Model adjustments were the same as in Figure 2.

 
The longitudinal patient laboratory data collected by the DOPPS II every 4 months were used to evaluate how changes in a patient's mineral metabolism levels related to changes in that patient's Hb concentration during that same time. Analyses were restricted to patients on dialysis >180 days (n = 7563) to avoid the known variation in patient Hb associated with patients adapting to the first 6 months of HD therapy. Even though these analyses were adjusted for numerous patient characteristics [4 month changes in calciumAlb, PO4, iPTH, serum albumin and rHuEpo dose; baseline Hb, ferritin, transferrin saturation, use of vitamin D (yes vs no) and other factors listed in Table 1], the intrapatient analyses allow patients to serve as their own control for patient mix. This ability greatly enhances these types of analyses by markedly diminishing confounding by patient mix.

Table 3 shows that an increase in patient calciumAlb over 4 months was accompanied by a significant rise in patient Hb concentration of 0.17 g/dl per 1 mg/dl rise in calciumAlb (P<0.0001). Furthermore, the change in patient Hb concentration over the 4 month period also was significantly related to rises in serum albumin (0.20 g/dl higher per 0.3 g/dl; P<0.0001) and serum PO4 (0.11 g/dl higher per 1 mg/dl; P<0.0001). In this analysis, a 4 month change in iPTH levels was not significantly related to the 4 month change in patient Hb concentration. Because the analysis was adjusted for the Hb concentration at the start of the 4 month interval, the observed results are independent of the starting Hb concentration.


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Table 3. Intrapatient time-trend analysisa: mean change in patient Hb concentration over a 4 month period, adjusted for patient characteristics

 
The question arises whether vitamin D could be involved in the relationship seen between the 4 month rise in calciumAlb and the 4 month rise in patient Hb concentrations. To investigate this possibility, two different statistical approaches were employed for adding interactions with vitamin D use to the model described in Table 3. The first approach was to add to the model an interaction between whether the patient was receiving vitamin D and the patient's calciumAlb level at the start of the 4 month study period; using this approach, the strong association of a 1 mg/dl rise in calciumAlb over a 4 month period and a 0.17 g/dl rise in patient Hb (P<0.001) was essentially unaffected. The second approach applied an interaction between whether the patient was receiving vitamin D (yes vs no) and the 4 month change in calciumAlb. In this second approach, the 4 month rise in calcium was still significantly related to the 4 month rise in Hb for patients not receiving vitamin D, although the relationship (0.12 g/dl rise in Hb over 4 months for every 1 mg/dl rise in calciumAlb; P = 0.02) was somewhat lower than in the overall model. The interaction term between patients receiving vitamin D and calcium change during the 4 month period indicated that patients receiving vitamin D may have a slightly larger 4 month rise in Hb (0.21 g/dl rise in Hb over 4 months per 1 mg/dl rise in calciumAlb). However, for patients receiving vs not receiving vitamin D, the difference in 4 month Hb rise associated with the 4 month change in calciumAlb concentration was not statistically significant (interaction; P = 0.18). These results indicate that even for patients not receiving vitamin D, a rise in Hb over a 4 month period is significantly related to a concurrent rise in calciumAlb. The significant relationships between 4 month rise in serum phosphorus and 4 month rise in serum albumin with rise in patient Hb concentrations were unaffected by inclusion of the vitamin D/calciumAlb interaction terms in the above models.

Since patient mineral metabolism levels were observed to be significantly associated with patient Hb concentrations, we examined the relationship between patient mineral metabolism levels and weekly rHuEpo dose levels for patients on dialysis >180 days (n = 7563). Figure 5 indicates a significant association between a patient's weekly rHuEpo dose and certain levels for each mineral metabolism measure for calciumAlb, PO4 and iPTH, after adjusting for differences in patient Hb concentrations, patient mix and other factors. The reference groups for these analyses were chosen to correspond to the K/DOQI guidelines. The overall mean rHuEpo dose was 10 386 units/week for the reference group in each case. Notably, the mean rHuEpo dose per week was >1700 units/week higher for patients with serum iPTH levels >600 pg/ml (P = 0.001) compared with patients with an iPTH of 150–300 pg/ml. Furthermore, patients with PO4 >5.5 mg/dl displayed mean weekly rHuEpo doses 1087–1323 units higher than patients with PO4 of 3.5–5.5 mg/dl (P = 0.001). In contrast, mean weekly rHuEpo doses were 743–857 units per week lower for patients whose calciumAlb exceeded the K/DOQI target of 8.4–9.5 mg/dl (P = 0.03).



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Fig. 5. Association between patient mineral metabolism levels and weekly rHuEpo dose concentration, after adjusting for differences in patients' Hb levels, patient mix and other factors. Model adjustments were the same as in Figure 2 plus Hb concentration. Overall adjusted mean rHuEpo dose for each reference group was 10 386 units/week.

 


   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The results of this investigation demonstrate the complex interrelationships between commonly used measures of mineral metabolism and anaemia management in HD patients. Higher serum calciumAlb and PO4 levels were found to be significantly related to a greater likelihood of patients having Hb concentration ≥11 g/dl. On an mg/dl basis, the effect of calciumAlb was 2–4-fold greater than that of PO4. An opposite association was seen for iPTH, as patients with iPTH levels >300 pg/ml had a significantly lower odds of having Hb ≥11 g/dl, which was similar to results from previous studies [2]. Observing these differing relationships between individual mineral metabolism measures and patient Hb levels was made possible through simultaneous adjustment for all mineral metabolism measures and patient mix in the analytical statistical models. Sensitivity analyses further confirmed the relationships between mineral metabolism measures and anaemia control for different patient subgroups. For example, the strength of the association between higher calciumAlb levels and higher odds of patients having Hb ≥11 g/dl was similar for patients with iPTH values >300 vs ≤300 pg/ml, for patients with PO4 >5.5 vs ≤5.5 mg/dl and for patients on dialysis >90 vs ≤90 days.

Intrapatient 4-month changes in Hb: relationships with mineral metabolism measures
The strong relationship between changes in calciumAlb and PO4 over 4 months with concurrent changes in the same patient's Hb concentration provide strong additional support for claiming that calcium and phosphorus are each significantly and independently linked with control of Hb levels in HD patients (Table 3). On average, every 1 mg/dl rise in calciumAlb over 4 months correlated with a 0.17 g/dl rise in patient Hb and a 1 mg/dl 4-month rise in PO4 correlated with a 0.11 g/dl rise in patient Hb (Table 3). A major strength of these analyses correlating intrapatient changes in mineral metabolism measures with Hb levels over a short interval was the adjustment for case mix inherent in the study design, with each patient serving as his or her own control for both measurements. Furthermore, these analyses controlled for vitamin D use, rHuEpo dose and Hb concentration at the start of the 4 month interval and the change in erythropoietin dose during the 4 month study period. Although the multivariate (non-intrapatient) analyses indicated a significant inverse relationship between iPTH and target Hb levels, the intrapatient analyses failed to demonstrate a significant relationship between changes in iPTH over 4 months with concurrent changes in the same patient's Hb concentration. This observation suggests that the effect of high iPTH on patient Hb may occur over a longer period than 4 months.

Malnutrition and inflammation have been shown to be associated with poorer anaemia control. All of the present analyses of the relationships between mineral metabolism measures and Hb concentrations used numerous adjustments to account for differences in malnutrition and inflammation among patients. These adjustments included serum albumin (a marker for nutrition and inflammation), BMI, ferritin (high values may indicate inflammation), serum phosphorus, transferrin saturation, erythropoietin dose and whether the patient had a diagnosis of malnourishment, coronary artery disease, peripheral vascular disease or cellulitis/gangrene. Although these factors may not completely explain all levels of malnutrition and inflammation, we expect that these adjustments represent much of the malnutrition and inflammation within the DOPPS HD patient sample. As a sensitivity analysis, C-reactive protein and neutrophil count data were reported for some patients in the DOPPS (12% and 52% of patients, respectively). Adjustment for these covariates did not alter the observed relationship between mineral metabolism measures and the likelihood of patients having Hb ≥11 g/dl.

Role for extracellular calcium in supporting the proliferation and differentiation of erythroid cells
A number of prior studies support the possible direct role of calcium in stimulating the proliferation of erythrocyte progenitor cells. Misiti and Spivak [15] have shown that adding extracellular calcium to cultures of mouse erythroid progenitor cells stimulates the proliferation of these cells, with this effect abrogated by EGTA chelation of extracellular calcium. Furthermore, erythropoietin is thought to stimulate proliferation and differentiation of erythroid cells by increasing the influx of calcium into them. Increasing calcium influx is an early and necessary step in the commitment to differentiation of murine erythroleukaemia cells and is observed at specific stages of human erythroid burst-forming unit differentiation [16]. Furthermore, Chu et al. [17] recently provided evidence that erythropoietin can stimulate calcium influx by modulating the activity of TRPC2 and TRPC8 voltage-independent, calcium-permeable channels. This modulation of calcium influx by erythropoietin was completely dependent upon extracellular calcium. Thus, the finding of higher patient Hb concentrations associated with higher calciumAlb levels in the present study is consistent with the biological evidence of a role for extracellular calcium in promoting the proliferation of erythroid cells and modulation of calcium influx by erythropoietin.

Mineral metabolism measures and rHuEpo dosing
The present investigation also revealed higher calciumAlb to be significantly associated with lower mean rHuEpo doses in analyses adjusted for patient mix, other mineral metabolism measures and patient Hb. This finding may indicate that higher serum calcium levels support the action of rHuEpo in stimulating erythropoiesis. Similar to several previous studies [2,3], we observed an association of high iPTH levels with patients being given a significantly higher mean rHuEpo dose, suggesting that hyperparathyroidism is associated with anaemia through poor response to rHuEpo therapy, as reported by Drüeke [2]. Possible explanations for this phenomenon include the development of marrow fibrosis [3] and the direct effect of iPTH in suppressing erythroid colony growth [8].

Higher calciumAlb levels were associated with higher Hb concentrations and lower rHuEpo doses and iPTH, >600 pg/ml was associated with lower Hb concentrations and higher rHuEpo doses in the present study. However, PO4 displayed the more peculiar pattern of being associated with a higher Hb concentrations and higher rHuEpo doses (when adjusted for the same Hb concentration across PO4 levels). Since the proliferation and differentiation of red blood cell precursors into mature erythrocytes and determinants of mature erythrocyte cell lifetimes are multistep processes, it is conceivable that the observed relationship of PO4 with higher Hb and higher rHuEpo doses may reflect PO4 affecting multiple processes that contribute to the determination of Hb levels in HD patients. Consistent with the present findings, Tonelli et al. [18] recently reported significantly higher rHuEpo doses associated with low calcium, high PO4 and high iPTH concentrations in a study of 135 HD patients. This low calcium relationship was not significant after adjustment for various HD patient characteristics, perhaps due to the relatively small sample size of the Tonelli study. The present DOPPS II analyses, based upon more than 12 000 patients, provide adjustments for numerous patient characteristics, thereby greatly increasing the ability to observe meaningful and independently significant associations.

The calcium–phosphorus paradox
There are many examples in therapeutic medicine in which a drug, procedure or metabolite may have beneficial effects in one regard but be deleterious in other respects. This appears to be the case for calcium and phosphorus control in HD patients. The present study indicates that higher serum calcium and serum phosphorus levels are each associated with a higher Hb concentration, which in turn has been shown to be associated with lower mortality and hospitalization risks [13,19]. Thus, with regard to anaemia control, higher serum calcium and serum phosphorus appear to be beneficial. However, DOPPS and other studies have shown that high calcium and phosphorus levels are associated with higher mortality risks, especially cardiovascular mortality in HD patients [6,12,20]. These results indicate that, even though higher serum calcium and PO4 may be beneficial for anaemia control, this benefit ultimately is outweighed by the deleterious consequences of a high-calcium PO4 state–which promotes tissue calcification–and its consequential higher mortality risk and poorer cardiovascular outcomes. Other DOPPS work by Young et al. [7] indicates that adherence to the K/DOQI and European Best Practice Guidelines appears to provide the lowest mortality risk in consideration of serum calcium, PO4 and iPTH levels for HD patients, with the possible modification that calcium levels below the current K/DOQI guideline are related to even lower mortality risks. Therefore, striving to maintain mineral metabolism measures within the K/DOQI guideline ranges would appear to provide the best overall outcome for HD patients in terms of mortality and hospitalization risks, even though levels of calcium and phosphorus above the K/DOQI guidelines are associated with higher Hb concentrations.

The results of the present study provide strong support from a very large international sample of HD patients for the possible involvement of calcium, phosphorus and PTH in processes involved in anaemia control in HD patients. Further delineation of these mechanisms may provide avenues for future enhancements in anaemia management to improve patient outcomes, especially with the advent of site-specific calcimimetic therapeutic approaches. The present study does not disagree with HD practices and guidelines that focus on decreasing hypercalcaemia and hyperphosphataemia in HD patients, since guidelines are based on reducing overall morbidity and mortality. Our results provide indications of several independent relationships between measures of mineral metabolism and anaemia control. The wide variation in anaemia control across dialysis units may not only be a reflection of use of rHuEpo and intravenous iron, nutrition, inflammation and patient comorbidity, but may be explained in part by the broad variability in levels of mineral metabolism indicators. These observations suggest the need for additional research to better understand the underlying mechanisms relating mineral metabolism markers with Hb levels and the need to consider how changes in mineral metabolism practices may affect anaemia control in HD patients.



   Acknowledgments
 
The authors express appreciation to members of the DOPPS Study Committee for contributions during the design and implementation of the DOPPS. For a full listing of committee members, please see [10]. The authors thank Tom Bowden and Miles P. Finley for editorial assistance with this manuscript.

Conflict of interest statement. The DOPPS is supported by research grants from Amgen Inc. and Kirin Brewery without restrictions on publications.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Slatopolsky E, Brown A, Dusso A. Role of phosphorus in the pathogenesis of secondary hyperparathyroidism. Am J Kidney Dis 2001; 37 [Suppl 2]: S54–S57
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Received for publication: 12. 5.04
Accepted in revised form: 14. 1.05





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