Magnitude and Impact of Abnormal Mineral Metabolism in

Hemodialysis Patients in the Dialysis Outcomes and

Practice Patterns Study (DOPPS)
Eric W. Young, MD, MS, Takashi Akiba, MD, PhD, Justin M. Albert, BA, James T. McCarthy, MD,
Peter G. Kerr, MD, David C. Mendelssohn, MD, FRCPC, and Michel Jadoul, MD

● Background: Mineral metabolism has emerged as an important predictor of morbidity and mortality in dialysis
patients, independent of bone and muscle concerns. Several expert panels have issued management guidelines for
mineral metabolism. Methods: The state of mineral metabolism (serum parathyroid hormone [PTH], phosphorus,
calcium, and calcium-phosphorus product) was described for representative samples of patients and facilities from
7 countries (France, Germany, Italy, Japan, Spain, United Kingdom, and United States) participating in the Dialysis
Outcomes and Practice Patterns Study (DOPPS I, 1996-2001; DOPPS II, 2002-2004). Results: A relatively modest
percentage of patients fell within the guideline range for PTH (21.4% in DOPPS I, 26.2% in DOPPS II), serum
phosphorus (40.8%, 44.4%), albumin-corrected serum calcium (40.5%, 42.5%), and calcium-phosphorus product
(56.6%, 61.4%). Results were not dramatically different across countries. The majority of patients not within
guideline ranges had high serum levels of phosphorus (51.6% in DOPPS I, 46.7% in DOPPS II), calcium (50.1%,
48.6%), and calcium-phosphorus product (43.4%, 38.6%) and low (<150 pg/mL) concentrations of PTH (52.9%,
47.5%). It was rare for patients to fall within recommended ranges for all indicators of mineral metabolism; 23% to
28% fell within guideline for at least 3 measures and only 4.6% to 5.5% of patients were within range for all 4. The
risks of all-cause and cardiovascular mortality were directly and independently associated with each of the 4
indicators. Conclusion: The DOPPS provides a useful comparison benchmark for the state of mineral metabolism
management of patients with kidney disease; it also affirms the association between mineral metabolism and
important patient outcomes. Am J Kidney Dis 44(S2):S34-S38.
© 2004 by the National Kidney Foundation, Inc.

INDEX WORDS: Mineral metabolism; parathyroid hormone; phosphorus; calcium; calcium-phosphorus product;
hemodialysis; Dialysis Outcomes and Practice Patterns Study (DOPPS).

E ND-STAGE RENAL disease is usually ac-

companied by profound changes in min-
eral metabolism that lead to clinical problems
such as bone disease, musculoskeletal symp-
toms, and growth retardation. In addition, sev-
eral recent studies have found a strong associa-
From the University of Michigan/Veterans Administration
Medical Center, Ann Arbor, MI; Tokyo Women’s Medical
University, Tokyo, Japan; University Renal Research and
Education Association, Ann Arbor, MI; Mayo Clinic,
Rochester, MN; Monash Medical Centre, Melbourne, Victoria,
Australia; University of Toronto/Humber River Regional
Hospital, Weston, Ontario, Canada; and Université
Catholique de Louvain Cliniques Universitaires St-Luc, Brux-
elles, Belgium.
The Dialysis Outcomes and Practice Patterns Study is
supported by research grants from Amgen and Kirin without
restrictions on publications. The NKF gratefully acknowl-
edges the support of Amgen, founding and principal sponsor
of K/DOQI. The publication of this supplement was sup-
ported by the DOPPS.
Address reprint requests to Eric W. Young, MD, MS, VA
Medical Center (11), 2215 Fuller Road, Ann Arbor, MI
48105. E-mail: dopps@urrea.org
© 2004 by the National Kidney Foundation, Inc.
0272-6386/04/4405-0106$30.00/0
doi:10.1053/j.ajkd.2004.08.009
tion between mortality and abnormal mineral
metabolism, presumably mediated by vascular
calcification and atherosclerotic occlusive dis-
ease.1,2 Several professional bodies have promul-
gated guidelines for the management of altered
mineral metabolism in dialysis patients, partly in
response to growing evidence about the relation-
ship with vascular morbidity and mortality.3,4
The Dialysis Outcomes and Practice Patterns
Study (DOPPS) provides a useful description of
guideline achievement among representative
samples of hemodialysis patients in 7 countries
at 2 time points. In addition, the DOPPS has
confirmed and extended observations about the
associations between outcomes and laboratory
markers of mineral metabolism.
METHODS
The overall DOPPS study design has been presented
elsewhere.5,6 Briefly, a sample of dialysis facilities was
selected in each participating country so as to represent the
distribution of facilities by type and geography. Within each
facility, a sample of 20 to 40 patients was randomly selected.
The resulting prevalent patient cross-section represented the
characteristics of patients in the facility and country at the
time of sampling. Clinical data were abstracted from the
medical record by a study coordinator at each site, usually a
dialysis nurse. Longitudinal follow-up data were acquired

S34 American Journal of Kidney Diseases, Vol 44, No 5, Suppl 2 (November), 2004: pp S34-S38
MINERAL METABOLISM S35

Table 1. Percentage of Patients With Laboratory Values Within K/DOQI Guideline Range, by Country and Year

Laboratory Measure PTH Serum Phosphorus Serum CalciumAlb Ca ⫻ P

Country (n1/n2) DOPPS I DOPPS II DOPPS I DOPPS II DOPPS I DOPPS II DOPPS I DOPPS II

France (540/512) 23.1 20.5 44.2 39.1 35.2 35.4 61.9 64.5
Germany (505/571) 24.0 28.6 26.0 39.5 54.9 52.0 43.6 57.8
Italy (561/576) 21.7 29.6 48.8 46.8 35.9 47.8 65.2 68.2
Japan (2,168/1,802) 21.4 27.5 40.6 45.9 42.7 45.7 56.8 61.2
Spain (491/613) 21.4 25.9 43.8 48.6 37.1 26.3 56.9 59.3
UK (493/544) 20.7 16.4 38.0 39.6 32.7 31.5 55.0 60.1
US (3,853/2,246) 20.7 26.9 41.2 44.4 41.1 46.1 56.3 60.8
Overall 7 countries
(8,611/6,864) 21.4 26.2 40.8 44.4 40.5 42.5 56.6 61.4

NOTE. Among prevalent cross-sections in each region: DOPPS I: US ⫽ 1996, Europe ⫽ 1998, Japan ⫽ 1999; DOPPS II: 2002.
Includes data from France, Germany, Italy, Japan, Spain, UK, and US only. n1/n2 ⫽ sample size from DOPPS I/DOPPS II. K/DOQI
guideline ranges: PTH 150-300 pg/mL, serum phosphorus 3.5-5.5 mg/dL, serum calciumAlb 8.4-9.5 mg/dL, Ca ⫻ P ⬍55 mg2/dL2.
To convert PTH in pg/mL to ng/L, multiply by 1; serum phosphorus in mg/dL to mmol/L, multiply by 0.3229; serum calcium in mg/dL
to mmol/L, multiply by 0.2495.

for a period of at least 2 years. The study was approved by
national and local institutional review boards, and individu-
alized consent requirements were followed for each country
and facility.
DOPPS I, conducted from 1996 to 2001, involved France
(20 facilities, 540 patients in the initial cross-section),
Germany (21 facilities, 505 patients), Italy (20 facilities, 561
patients), Japan (65 facilities, 2,168 patients), Spain (20
facilities, 491 patients), the United Kingdom (20 facilities,
493 patients), and the United States (142 facilities, 3,853
patients). DOPPS II, conducted from 2002 to 2004, included
the same 7 countries: France (20 facilities, 512 patients in
the initial cross-section), Germany (20 facilities, 571 pa-
tients), Italy (20 facilities, 576 patients), Japan (60 facilities,
1,802 patients), Spain (20 facilities, 613 patients), the United
Kingdom (19 facilities, 544 patients), and the United States
(79 facilities, 2,246 patients). Data from the additional
countries that joined DOPPS II (Australia, Belgium,
Canada, Sweden, and New Zealand) were not included in
the current study because of the lack of an earlier time for
comparison.
The variables of interest in this study were common
laboratory indicators of mineral metabolism: parathyroid
hormone (PTH) concentration, serum phosphorus concentra-
tion, serum calcium concentration corrected for the serum
albumin concentration, and the calcium-phosphorus product
(Ca ⫻ P). Throughout the DOPPS, the majority of PTH
measurements were based on an intact molecule assay;
values measured with other assays were excluded from this
analysis. The mineral metabolism values were evaluated in
reference to practice guidelines issued by the Kidney Dis-
ease Outcomes Quality Initiative (K/DOQI) program of the
National Kidney Foundation and the European Best Practice
Guidelines (EBPG) drafted by the European Best Practice
Guidelines Working Group. Time and location trends were
evaluated by using basic descriptive statistics. In addition,
patient all-cause and cardiovascular survival were modeled
using Cox regression with adjustment for patient demograph-
ics and clinical characteristics, including 14 summary comor-
bidity measures. Cardiovascular mortality was defined as
deaths attributed to acute myocardial infarction, cardiac
arrhythmia, cardiac arrest (cause unknown), and atheroscle-
rotic heart disease. Mineral metabolism indicators were
entered as the predictor variables of primary interest. Robust
techniques were used to correct for facility clustering ef-
fects.7
RESULTS
Table 1 shows the percentage of patients within
K/DOQI guideline values by DOPPS country at
2 points in time. DOPPS I measurements were
performed between 1996 and 1999, before the
introduction of guidelines. DOPPS II measure-
ments were made just as the relevant K/DOQI
and EBPG were finalized and disseminated. The
patterns are striking and consistent across coun-
tries. A minority of patients fell within the guide-
line range for PTH (150-300 pg/mL [150-300
ng/L]), phosphorus (3.5-5.5 mg/dL [1.13-1.78
mmol/L]), and calcium (8.4-9.5 mg/dL [2.10-
2.37 mmol/L]). A slight majority of patients fell
within the guideline range for the calcium-
phosphorus product (⬍55 mg2/dL2). There was a
trend toward improvement for all measurements
in most of the countries. There was no consistent
pattern to the relatively modest variation ob-
served across countries.
Given the large fraction of patients who did
not fall within the guideline ranges, it is impor-
tant to understand the distribution of measure-
ments outside the guidelines. Table 2 shows
that among patients outside the guideline range
S36 YOUNG ET AL

Table 2. Overall Distribution of Mineral Metabolism Laboratory Values by Time (DOPPS I and DOPPS II)

Patients (%)

Measurement (n1/n2) Range DOPPS I DOPPS II P Value

PTH (pg/mL) (n1/n2 ⫽ 5,439/4,261) ⬍150 52.9 47.5

150-300 21.4 26.2 ⬍0.001
⬎300 25.7 26.3
Serum calciumAlb (mg/dL) (n1/n2 ⫽ 6,892/5,780) ⬍8.4 9.4 8.9
8.4-9.5 40.5 42.5 0.06
⬎9.5 50.1 48.6
Serum phosphorus (mg/dL) (n1/n2 ⫽ 8,263/6,383) ⬍3.5 7.6 9.0
3.5-5.5 40.8 44.4 ⬍0.001
⬎5.5 51.6 46.7

NOTE. Among prevalent cross sections in each region: DOPPS I: US ⫽ 1996, Europe ⫽ 1998, Japan ⫽ 1999; DOPPS II: 2002.
Includes data from France, Germany, Italy, Japan, Spain, UK, and US only. n1/n2 ⫽ sample size from DOPPS I/DOPPS II. To
convert PTH in pg/mL to ng/L, multiply by 1; serum phosphorus in mg/dL to mmol/L, multiply by 0.3229; serum calcium in mg/dL to
mmol/L, multiply by 0.2495. P values indicate DOPPS I versus DOPPS II for each set of laboratory value measurements.

for PTH, more than twice as many fell in the
low (⬍150 pg/mL [150 ng/L]) than the high
(⬎300 pg/mL [300 ng/L]) range. Over time,
the percentage of patients with low PTH de-
clined and the percentage with high PTH in-
creased. Most patients outside of the serum
phosphorus guideline range fell in the high-
phosphorus category. The time trend shows a
reduction in patients with hyperphosphatemia
and an increase in patients with “normal” and
low phosphorus. For calcium, most of the
patients outside the guidelines had high concen-
trations. The percentages of patients with both
low and high concentrations of serum calcium
have declined modestly over time.
Table 3 illustrates that patients rarely fall within
guideline range for combinations of the 4 labora-
tory markers of mineral metabolism (PTH, phos-
phorus, calcium, and calcium-phosphorus prod-
uct). In DOPPS I (1996-2001), approximately
Table 3. Percentage of Patients Within Guidelines for
Varying Numbers of Laboratory Values
Number of Measurements in
Guideline Range DOPPS I DOPPS II P Value*
0 20.7 17.8
At least 1 79.3 82.2
At least 2 54.0 57.6 ⬍0.001
At least 3 23.1 27.5
All 4 4.6 5.5
*P value is chi-square for overall distribution of number
of target values met in DOPPS I versus DOPPS II (n ⫽
4,679/3,565)
21% of patients fell outside the guideline range
for all 4 measures and only 4.6% of patients fell
within the guideline range for all 4 values. By the
time of data collection for DOPPS II (2002-
2004), there was only a slight increase in the
percentage of patients falling within guidelines
for multiple measurements.
Table 4 illustrates the potential consequences
associated with falling outside the recommended
ranges for markers of mineral metabolism. All-
cause and cardiovascular mortality risks were
significantly and positively associated with the
PTH, serum phosphorus, serum calcium, and the
calcium-phosphorus product.
DISCUSSION
The DOPPS confirms and extends the state of
knowledge about the adverse impact of abnor-
malities of mineral metabolism on the health of
hemodialysis patients. The DOPPS is one of the
largest observational studies to describe the state
and consequences of mineral metabolism for
representative samples of hemodialysis facilities
and patients from 7 countries at 2 discrete time
points. The current study paints an informative
picture of mineral metabolism in the recent past
and provides a benchmark for assessing future
changes.
The mineral metabolism guidelines issued by
the National Kidney Foundation3 and European
Best Practice Guidelines Working Group were
based on evidence and expert opinion.4 A strik-
ing but perhaps unsurprising finding is the univer-
MINERAL METABOLISM S37

Table 4. Association Between Study Outcomes (All-Cause and Cardiovascular Mortality)

and Markers of Mineral Metabolism

Outcome Measure*

All-Cause Mortality Cardiovascular Mortality

Predictor RR (95% CI) P Value RR (95% CI) P Value

Phosphorus (per 1 mg/dL) 1.04 (1.023-1.059) 1.10 (1.067-1.128)

⬍0.0001 ⬍0.0001
Albumin-corrected calcium (per 1 mg/dL) 1.12 (1.079-1.160) 1.13 (1.065-1.196)
⬍0.0001 ⬍0.0001
Calcium-phosphorus product (per 5 mg2/dL2) 1.03 (1.015-1.035) 1.06 (1.041-1.072)
⬍0.0001 ⬍0.0001
PTH (per 100 pg/mL) 1.01 (1.001-1.018) 1.02 (1.005-1.030)
0.03 0.007

NOTE. To convert serum phosphorus in mg/dL to mmol/L, multiply by 0.3229; PTH in pg/mL to ng/L, multiply by 1.
*DOPPS I (1996-2001) and II (2002-04) data; models stratified by country and adjusted for age, sex, black race, duration of
ESRD, prior parathyroidectomy, serum albumin, hemoglobin, dialysis dose (spKt/V), 14 summary comorbid conditions, and
predictors listed in Table 4, and year of enrollment in DOPPS, controlling for effects of facility clustering.

sal frequency with which mineral metabolism
laboratory values fell outside the guideline ranges
proposed by these expert panels (Tables 1 and 2).
A defensible case can certainly be made for each
guideline in isolation. However, our results under-
score the difficulty of simultaneously achieving
guideline targets for all laboratory markers (PTH,
phosphorous, calcium, and calcium-phosphorous
product). Management of mineral metabolism
requires a complex mixture of dialysis therapy,
medications, dietary intervention, patient and
provider education, communication, and patient
adherence. This complexity makes it difficult for
providers to successfully manage mineral metab-
olism with the current therapeutic tools. It will be
important to determine if widespread dissemina-
tion of the guidelines and new therapeutic agents
will result in increased success in achieving
guideline ranges for multiple mineral metabo-
lism indicators.
Several aspects of the distribution of mineral
metabolism laboratory values merit particular
notice. First, there appears to be a trend toward
improvement over the 2- to 4-year period be-
tween DOPPS I and DOPPS II. The improve-
ment is probably not attributable to the guide-
lines, which were only released during DOPPS II
data collection. However, the modest improve-
ments may be attributable to recent studies and
attention on the hypothesized vascular and mor-
tality impact of abnormal mineral metabolism. In
addition, several therapies came into new or
increasing use between DOPPS I and DOPPS II,
including calcium-free phosphorus binder (sevel-
amer), several vitamin D analogs, and cinacalet
HCl. Improvements were seen in some, if not all,
markers of mineral metabolism for patients in all
7 of the DOPPS countries. No country patterns
emerged to suggest dramatically different prac-
tices by region.
Most nephrologists would not be surprised to
find the serum levels of phosphorus, calcium,
and calcium-phosphorus product exceeded the
upper guideline limit for the majority of patients.
These entities accumulate in renal failure, result-
ing in high blood concentrations in the absence
of aggressive management. However, there may
be some surprise that the overwhelming majority
of patients with a PTH level outside the guideline
ranges had a low concentration (Table 2). De-
spite the emphasis on hyperparathyroidism as a
frequent and adverse feature of renal disease,
hypoparathyroidism emerged as the predominant
finding in the current era. Low PTH has been
associated with bone disease but not with mortal-
ity risk per se.
As with other DOPPS analyses and other
observational studies, this study found that these
easily measured laboratory indicators of mineral
metabolism were significantly predictive of mor-
tality (Table 4). All-cause and cardiovascular
mortality were directly associated with higher
concentrations of PTH, phosphorus, calcium, and
calcium-phosphorus product (Table 4). In the
current study, each indicator of mineral metabo-
lism was analyzed as a continuous variable. In a
S38
prior categorical analysis, we found that mortal-
ity risk increased above a PTH of approximately
700 pg/mL (700 ng/L), a phosphorus of 5.5 to
6.0 mg/dL (1.78-1.94 mmol/L), and a calcium-
phosphorus product of 55 to 60 mg2/dL2, all
consistent with the guideline ranges. Mortality
increased steadily with the calcium concentra-
tion, without an apparent plateau. Unlike earlier
reports, there was no evidence of increased mor-
tality at low calcium concentrations. However,
consistent with other studies, mortality risk is
higher at low concentrations of phosphorus. The
higher mortality at low concentrations of serum
phosphorus has been attributed to malnutrition
that is not fully adjusted for in the statistical
models.
Management of mineral metabolism in dialy-
sis patients is unquestionably important for main-
taining musculoskeletal health. However, the re-
peatedly observed associations with mortality
serve to solidify and magnify the importance of
improving the treatment of this problem. Our
findings provide an international baseline for the
results of efforts to improve the management of
mineral metabolism. The possibilities for im-
YOUNG ET AL
provement are substantial given the importance
of mineral metabolism on survival and the recent
availability of several new therapeutic agents.
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