Full text of DOI:10.1046/j.1525-139X.2001.00057-4.x

Dialysis Clinic
Safety of Intravenous Iron During Infections
Given the unanswered questions regarding intrave-
nous iron and infection, is it okay to continue a course of
iron in patients who develop an infection? Is there rea-
son to think it may impair a patient’s immune response
and recovery?
that iron salts such as ferrous sulfate may exacerbate an
infection. For example, a mild infection in animals may
be converted into a severe one when free iron is admin-
istered (1, 2). In humans, certain infections may occur
when iron-overloaded patients are treated with desferri-
oxamine (3). It is likely that this agent binds iron in a
manner that allows bacteria to gain access to the mol-
ecule. But is the same true of intravenous iron? Since
there is no adequate source of published data to help
answer this question. I believe we must err on the side of
caution. I would avoid the use of intravenous iron (and
probably oral iron as well) during episodes of acute in-
fection.
My answer is no, I do not believe that intravenous iron
treatment should be continued when the patient develops
an infection. This answer is based on the low likelihood
that iron treatment would be effective during an acute
infection, and on the risk for worsening the infection.
There is very little in the way of published data to sup-
port this opinion; rather my view is based on theoretical
considerations.
Most microorganisms require iron to survive, and ob-
tain this iron from the infected host. As a result, the
human body “locks away” iron during an infection, trad-
ing a temporary decrease in hemoglobin (this phenom-
enon has been poorly named the anemia of chronic dis-
ease) for the survival benefit of limiting the infecting
organism’s access to iron. A key question is whether
treatment with intravenous iron would provide a new
source of iron to the infecting microorganism. Again,
there are no published data that allow us to critically
answer this question. Experimental evidence suggests
Steven Fishbane
Mineola, NY
References
1. Bullen JJ, Ward CG, Rogers HJ: The critical role of iron in some clinical
infections. Eur J Clin Microbiol Infect Dis 10:613–617, 1991
2. Sokol PA, Woods DE: Relationship of iron and extracellular virulence fac-
tors to Pseudomonas aeruginosa lung infections. J Med Microbiol 18:125–
133, 1984
3. Nouel O, Voisin PM, Vaucel J, Dartois-Hoguin M, Le Bris M: Yersinia
enterocolitica septicemia associated with ideopathic hemochromatosis and
deferoxamine therapy. A case. Presse Med 20:1494–1496, 1991
Bone Mineral Density Measurements in Dialysis Patients
Measuring bone mineral density is increasingly used
in the general population. One would think it might be of
value in dialysis patients, though I haven’t seen recom-
mendations or guidelines for interpretation in this popu-
lation (not to mention what to do with the data thera-
peutically). Can you provide some guidance?
years are thought to be secondary to osteoporosis (3).
The risk of fractures increases progressively as BMD
declines (4, 5). Fracture risk increases 1.4- to 3-fold for
each standard deviation decrease in BMD. In the general
population, hip fracture has been associated with an in-
creased risk of death (6). In the general population, in-
creasing bone mass or reducing bone loss is thought to be
important in the prevention of osteoporotic fractures and
may reduce the associated morbidity and mortality.
The prevalence of low BMD and risk of fracture are
increased among patients with end-stage renal disease
(ESRD) (7–10). Overall the risk of hip fracture is more
than four-fold higher than the general population (8).
While the age-specific relative risk of hip fracture is
highest in the youngest age groups, the added risk of hip
fracture associated with ESRD increases steadily with
increasing age and increases as time since first dialysis
Osteoporosis and secondary fractures have an enor-
mous public health impact. Osteoporosis is defined as
low bone mass and microdeterioration of bone tissue,
leading to enhanced bone fragility and a consequent in-
crease in fracture risk (1). The clinical significance of
osteoporosis is in the increased risk for fracture that ac-
companies reductions in bone mineral density (BMD)
(2). Approximately 1.3 million fractures that occur an-
nually in the United States in people over the age of 45
Dialysis Clinic welcomes questions of general interest to the
journal’s readership. Questions should be typed, double-
spaced and sent to Seminars in Dialysis, Department of
Medicine (Nephrology), 1 Robert Wood Johnson Place,
CN-19, New Brunswick, NJ 08903. Unpublished questions
cannot be answered or returned. Authors of questions will
not be identified unless otherwise requested.
The purpose of Dialysis Clinic is to educate and inform, not
to give medical advice regarding a specific patient. Med-
icine is complex and patient-specific advice requires more
details, both in the question and the answer, than can be
provided. Information offered here should be checked with
appropriate sources before it is used in diagnosis and ther-
apy.
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229
increases. Factors that predict hip fracture among ESRD
patients include increasing age, female gender, Cauca-
sian race, low body mass index, and the presence of
peripheral vascular disease (11). Men and women are
equally affected (8). In studies assessing BMD, cortical
BMD tends to be lower than in age- and sex-matched
controls and is thought to contribute to the increased risk
of fracture (9). Although postulated mechanisms for
bone loss include age, diabetes, aluminum toxicity, hy-
perparathyroidism, and acidosis (12, 13), risk factors for
bone loss are not well defined.
cium balance, hormonal therapy (estrogen, testosterone),
bisphosphonates, calcitonin, posture training, and exer-
cise. Patients who are treated should be monitored yearly
with DEXA.
Catherine Stehman-Breen
Seattle, WA
References
1. Consensus development conference: prophylaxis and treatment of osteopo-
rosis. Am J Med 90:107–110, 1991
There are no separate guidelines for interpretation of
BMD for ESRD patients. BMD is most commonly mea-
sured using dual energy X-ray absorptiometry (DEXA).
BMD is measured in grams per square centimeter and
reported as a T score [standard deviation (SD) from the
mean of peak bone mass] and a Z score (SD from the
mean bone mass of age-, gender-, and race-matched con-
trols). Osteopenia and osteoporosis are defined as they
are in the general population. These definitions are based
on the World Health Organization Study Group recom-
mendations which suggest that BMD more than 1 SD
below the mean of peak bone mass (T < −1) defines
osteopenia and more than 2.5 SD below the mean of peak
bone mass (T < −2.5) defines osteoporosis (14).
There are no reports assessing the impact of screening
ESRD patients for BMD on bone loss or fracture. How-
ever, by screening ESRD patients that are at particular
risk for low bone mass, physicians may identify and treat
patients that are at high risk for fracture and may poten-
tially reduce the risk of fracture and death. This may be
particularly important for those patients who will even-
tually receive a kidney transplant, since the posttrans-
plant period has been associated with significant bone
loss (15). Screening with DEXA should not be per-
formed more frequently than yearly. Unfortunately there
are few data regarding the effectiveness or safety of in-
terventions for bone loss among ESRD patients. Possible
interventions to increase BMD include optimizing cal-
2. Kanis J, Pitt F: Epidemiology of osteoporosis. Bone 31(suppl 1):S7–S15,
1992
3. Erlichman M, Holohan T: Bone densitometry: patients with end stage renal
disease. Health Technol Assess 8:1–27, 1996
4. Cummings S, Black D, Nevitt M, Browner W, Caudley J, Ensrud K, Genant
H, Palmero K, Scott J, Voigt T: Bone density at various sites for prediction
of hip fractures. Lancet 341:72–75, 1993
5. Melton L, Atkinson A, O’Fallon W, Wahner H, Riggs B: Long-term fracture
prediction by bone mineral assessed at different skeletal sites. J Bone Miner
Res 8:1227–1233, 1993
6. Levis S, Altman R: Bone densitometry. Clinical considerations. Arthritis
Rheum 41:577–587, 1998
7. Alem A, Sherrard D, Gillen D, Weiss N, Beresford S, Heckbert S, Wong C,
Stehman-Breen C: Increased risk of hip fracture among patients with end-
stage renal disease. Kidney Int 58:396–399, 2000
8. Stehman-Breen C, Sherrard D, Walker A, Sadler R, Alem A, Lindberg J:
Racial differences in bone mineral density and bone loss among end-stage
renal disease patients. Am J Kidney Dis 33:941–946, 1999
9. Stein M, Packham D, Ebeling P, Ward J, Becker G: Prevalence and risk
factors for osteopenia in dialysis patients. Am J Kidney Dis 28:515–522, 1996
10. Atsumi K, Kushida K, Yamazaki K, Shimizu S, Ohmura A, Inoue T: Risk
factors for vertebral fractures in renal osteodystrophy. Am J Kidney Dis
33:287–293, 1999
11. Stehman-Breen C, Sherrard D, Alem A, Gillen D, Heckbert S, Wong C, Ball
A, Weiss N: Risk factors for hip fracture among patients with end-stage renal
disease. Kidney Int 58:2200–2205, 2000
12. Copley J, Hui S, Leepman S, Slemenda C, Johnson C: Longitudinal study of
bonemass in end-stage renal disease patients: effects of parathyroidectomy
for renal osteodystrophy. J Bone Miner Res 8:415–422, 1993
13. Hutchison A, Whitehouse R, Boulton H, Adams J, Mawer E, Freemont T,
Gokal R: Correlation of bone histology with parathyroid hormone, vitamin
D3, and radiology in end-stage renal disease. Kidney Int 44:1071–1077, 1993
14. Assessment of Fracture Risk and Its Application to Screening for Postmeno-
pausal Osteoporosis. Report of the World Health Organization Study Group.
Geneva: World Health Organization, 1994
15. Julian B, Laskow D, Dubovsky J, Dubovsky E, Curtis J, Quarles L: Rapid
loss of vertebral mineral density after renal transplantation. N Engl J Med
325:544–550, 1991
New Vitamin D Analogs
Two new vitamin D analogs, doxercalciferol (Hec-
torol) and paricalcitrol (Zemplar) have recently become
available. How do they differ from each other (and from
calcitriol)? Are there any clear-cut indications for one or
another of these two agents over calcitriol?
Calcitriol
Calcitriol is the active form of vitamin D3 (1,25-
dihydroxyvitamin D3). It has, for many years, been the
most prescribed therapy for chronic kidney disease
(CKD) patients with vitamin D deficiency. Available
both as an oral supplement and intravenous injection,
synthetic calcitriol is biologically equivalent to calcitriol
that is normally produced in the kidney from its precur-
sor, ␣-hydroxyvitamin D3. Calcitriol has demonstrated
effectiveness in treating the classic disorders caused by
vitamin D deficiency: renal osteodystrophy and SHPT.
However, the effective therapeutic doses of calcitriol
required to treat SHPT can stimulate release of calcium
and phosphorus from bone via osteoclast stimulation and
The ideal therapeutic agent for vitamin D. hormone
replacement should manage parathyroid hormone (PTH),
calcium, and phosphate simultaneously. The first priority
must be to control (or prevent) the cascade of events that
leads to secondary hyperparathyroidism (SHPT). In prac-
tical terms, this means that a suitable vitamin D analog
would effectively suppress PTH without raising the se-
rum levels of calcium and phosphate.

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increase their absorption in the intestine. This process
can lead to both hypercalcemia and hyperphosphatemia,
and increased calcium and phosphorus product.
risk of adynamic bone disease. Calcitriol has a low thera-
peutic index and leads to hypercalcemia and hyperphos-
phatemia, sometimes limiting the treatment options for
patients with SHPT (7). While calcitriol may be indi-
cated to treat hypocalcemia, its use for vitamin D re-
placement is associated with the complications described
above. These limitations have focused attention on ana-
logs of vitamin D2 such as paricalcitrol and doxercalcif-
erol.
Paricalcitrol
Paricalcitrol is a vitamin D analog currently marketed
under the trade name Zemplar (paricalcitrol injection).
This compound (also called 19-nor-D2 or 19-nor-1,25-
dihydroxyvitamin D2) differs from calcitriol in that it is
structurally similar to vitamin D2 and not to vitamin D3.
Paricalcitrol was found to decrease serum PTH levels in
rats with little or no hypercalcemia (1). Animal studies
also showed that paricalcitrol was much less active than
calcitriol in mobilizing calcium and phosphate from bone
(2). Clinical studies in CKD patients confirmed that pari-
calcitrol can effectively control SHPT with minimal hy-
percalcemic and hyperphosphatemic effects (3). How-
ever, paricalcitrol has not been directly compared to cal-
citriol to assess differences in efficacy and safety.
Therapeutic Implications
The deficiency in active vitamin D accompanying kid-
ney failure leads to a broad range of complications, from
secondary hyperparathyroidism to cardiovascular dis-
ease. Early initiation of vitamin D replacement therapy in
patients with renal insufficiency should be considered for
many patients; such therapy may improve outcomes and
minimize the risk of developing complications. Conven-
tional vitamin D therapy suffers from the limitations of
hypercalcemia and hyperphosphatemia as well as result-
ing in nonphysiologic concentrations of D hormone. Evi-
dence suggests that alternatives to conventional vitamin
D offer potential advantages.
Doxercalciferol
Doxercalciferol, like paricalcitrol, is an analog of vi-
tamin D2. This compound, also known as 1␣-
hydroxyvitamin D2, is marketed under the trade name
Hectorol, and is available in oral formulation as well as
intravenous injection. Like alfacalcidol, doxercalciferol
is an out of sequence precursor of active D2 hormone. It
is already hydroxylated at the 1␣-position (normally the
second activation step for D2), and requires only hydrox-
ylation at the 25 position (normally the first activation
step for D2), which is done in the liver. The result is
1,25-dihydroxyvitamin D2 (vitamin D2 hormone). By
avoiding the need for activation in the kidney, doxercal-
ciferol can be used in patients with little or no kidney
function (4). Oral administration of doxercalciferol was
shown to be safe and highly effective for the treatment of
SHPT in hemodialysis patients with minimal hypercal-
cemia and hyperphosphatemia (5, 6).
Jill S. Lindberg
New Orleans, LA
References
1. Slatopolsky E, Finch J, Ritter C, Denda M, Morrissey J, Brown A, DeLuca
H: A new analog of calcitriol, 19-nor-1,25-(OH)2D2, suppresses parathyroid
hormone secretion in uremic rats in the absence of hypercalcemia. Am J
Kidney Dis 26:852–860, 1995
2. Finch JL, Brown AJ, Slatopolsky E: Differential effects of 1,25-dihydroxy-
vitamin D3 and 19-nor-1,25-dihydroxy-vitamin D2 on calcium and phospho-
rus resorption in bone. J Am Soc Nephrol 10:980–985, 1999
3. Martin KJ, Gonzalez EA, Gellens M, Hamm LL, Abboud H, Lindberg J:
19-Nor-1-alpha-25-dihydroxyvitamin D2 (Paricalcitol) safely and effectively
reduces the levels of intact parathyroid hormone in patients on hemodialysis.
J Am Soc Nephrol 9:1427–1432, 1998
4. Coburn JW, Tan AU, Levine BS, Mazess RB, Kyllo DM, Knutson JC,
Bishop CW: 1 alpha-hydroxy-vitamin D2: a new look at an ‘old’ compound.
Nephrol Dial Transplant 11(suppl 3):153–157, 1996
5. Frazao JM, Chesney RW, Coburn JW: Intermittent oral 1-alpha-
hydroxyvitamin D2 is effective and safe for the suppression of secondary
hyperparathyroidism in hemodialysis patients. 1alphaD2 Study Group.
Nephrol Dial Transplant 13(suppl 3):68–72, 1998
Comparison of Treatment Alternatives
6. Tan AU, Levine BS, Mazess RB, Kyllo DM, Bishop CW, Knutson JC,
Kleinman KS, Coburn JW: Effective suppression of parathyroid hormone by
1 alpha-hydroxy-vitamin D2 in hemodialysis patients with moderate to severe
secondary hyperparathyroidism. Kidney Int 51:317–323, 1997
7. Quarles LD, Yohay DA, Carroll BA, Spritzer CE, Minda SA, Bartholomay
D, Lobaugh BA: Prospective trial of pulse oral versus intravenous calcitriol
treatment of hyperparathyroidism in ESRD. Kidney Int 45:1710–1721, 1994
Current forms of vitamin D replacement therapy suffer
from several limitations. Although calcitriol and its ana-
logs have been effective in decreasing the percentage of
patients with severely elevated PTH levels, many pa-
tients still experience poor PTH control and an increased
Hepatitis B Surface Antigen-Positive but
DNA-Negative Patients
It is highly recommended that hepatis B surface anti-
gen (HBSAg)-positive patients be dialyzed in a separate
room in order to prevent the transfer of hepatitis B virus
(HBV). However, some HBSAg-positve patients have a
negative polymerase chain reaction (PCR) test for HBV
DNA, indicating that there is no active replication.
Should these patients still be isolted from the group?
Should HBSAg testing be replaced by HBV PCR testing?
The presence of hepatitis B surface antigen (HBsAg)
should be considered indicative of ongoing hepatitis B
virus (HBV) infection and potential infectiousness, re-

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231
gardless of the patient’s HBV DNA status. All HBsAg-
positive patients should receive dialysis in a room sepa-
rate from HBV-susceptible patients using separate ma-
chines, equipment, instruments, and supplies. Staff
members caring for HBsAg-positive patients should not
care for HBV-susceptible patients at the same time (e.g.,
during the same shift or during patient changeover).
Both qualitative and quantitative tests for detection of
HBV DNA are available. However, these tests are not
U.S. Food and Drug Administration approved, and sub-
stantial variation in results has been reported. Further-
more, the infectious status of patients positive for HBsAg
but negative for HBV DNA is not known. These tests are
most commonly used in patients being managed with
antiviral therapy and should not be used for purposes of
routine screening.
Miriam J. Alter
Atlanta, GA