Lang, Susanne M.

Schiffl, Helmut

Stratakis, D.

English

Open Access LMU

iPTH, pg/mlLetter to the EditorNephron 2001;88:391–392Secondary Hyperparathyroidism,Proinflammatory Cytokines and Response toEpoietin in Anemic Maintenance DialysisPatientsH. Schiffl D. Stratakis S.M. LangSection of Nephrology, Department of Internal Medicine, University Munich Innenstadt, Munich, GermanyProf. Dr. H. SchifflMed. Klinik, Klinikum der Universität MünchenZiemssenstrasse 1D–80336 Munich (Germany)Fax +49 89 5705727, E-Mail hschiffl@medinn.med.uni-muenchen.deABCFax + 41 61 306 12 34E-Mail karger@karger.chwww.karger.com© 2001 S. Karger AG, Basel0028–2766/01/0884–0391$17.50/0Accessible online at:www.karger.com/journals/nefDear Sir,There is ample evidence that excess plas-ma parathyroid hormone concentrations(iPTH), especially in the presence of histo-logical ostitis fibrosa, are associated withworsening of anemia or resistance to theaction of erythropoietin. This may be coun-teracted either by treatment with activeforms of vitamin D3 or by parathyroidecto-my. The mechanisms involved in the com-plex relationship between the autonomousparathyroid glands and erythropoiesis arenot fully understood. The early response tosurgery or medical therapy suggests directeffects on hematopoiesis such as suppressionof endogenous erythropoietin secretion, in-hibition of bone marrow erythroid progeni-tors or red cell survival. The continuous im-provement of anemia may be further ex-plained by decreased bone marrow fibrosis.However, data regarding the operating fac-tors are conflicting [1]. Inflammatory cyto-kines such as interleukin-6 (IL-6) blockerythropoiesis by their effects on the devel-opment of erythroblasts [2] and thereby ane-mia and responsiveness to erythropoietin.The question whether parathyroid hormoneexcess affects synthesis of proinflammatorycytokines remains unanswered.We prospectively examined the effects ofparathyroidectomy on IL-6 levels, hemoglo-bin concentrations and epoietin dose in 9anemic patients with end-stage renal disease(5 patients on CAPD, 4 patients on hemodi-alysis) and severe secondary hyperparathy-roidism. There were 5 men and 4 women,aged 28–63 years, and the duration on dialy-sis before surgery was 38–184 months (mean85). The cause of end-stage renal disease waschronic glomerulonephritis in 6 patients,chronic tubulointerstitial nephritis in 2 pa-tients and polycystic kidney disease in 1patient. None of the patients had absolute orrelative iron deficiency, infection, inflam-matory disorders, malignancy, occult gas-trointestinal blood loss, aluminium toxicityor was taking drugs known to interfere witherythropoiesis. They all had normal vitaminB12 and folic acid levels, and weekly Kt/V ofat least 3.6 for hemodialysis and 2.1 forCAPD. The diagnosis of severe secondaryhyperparathyroidism was made on the basisof biochemical, histological (bone biopsy),radiological and clinical parameters. Bloodsamples for determinations of iPTH andother chemical parameters, serum IL-6 lev-els, and hemoglobin concentrations weredrawn prior to surgery (within 1 week) and6 months after surgery.Parathyroidectomy (total parathyroidec-tomy with a forearm transplant) resulted ineach patient in a normalization of excessparathyroid hormone concentration, hyper-calcemia (2.9 B 0.1 vs. 2.4 B 0.1 mmol/l),hyperphosphatemia (6.5 B 0.5 vs. 3.4 B0.5 mg/dl) and alkaline phosphatase (261 B22 vs. 153 B 18 U/l). Compared to pre-operative values, the postoperative epoie-tin doses were significantly lower, althoughTable 1. Effect of parathyroidectomy onresponsiveness to epoietin therapy in 9 ure-mic patientsParathyroidectomyprior post1,582B633 27B9*IL-6, pg/ml 54B18 12B5*CRP, mg/dl 1.3B0.2 0.2B0.1*Hb, g/dl 9.2B0.4 10.8B0.4*EPO dose,U/kg/week 151B35 61B28** p ! 0.05 vs. preoperative values.postoperative hemoglobin levels were signif-icantly higher than corresponding levels be-fore surgical therapy. Parathyroidectomywas also associated with a fall in elevated IL-6 values towards values usually observed inchronic hemodialysis patients. Furthermore,successfully treated patients had significant-ly lower CRP values (table 1).The worsening of anemia and the resis-tance to erythropoietin characterizing severesecondary hyperparathyroidism are causednot by a single pathogenetic mechanism, butmay involve a number of factors operatingsimultaneously at different stages of the de-392 Nephron 2001;88:391–392 Schiffl/Stratakis/Langvelopment of parathyroid gland hyperplasia.The present data disclose a previously un-described link between excess parathyroidhormone and erythropoiesis in hyperpara-thyroidism secondary to end-stage renal dis-ease. Circulating IL-6 levels were found to beincreased in our patients with severe second-ary hyperparathyroidism as well as in 86 ure-mic patients with different degrees of renalosteodystrophy published by Montalban etal. [3]. The authors of the latter series founda strong correlation (r = 0.71) between iPTHconcentrations and corresponding IL-6 lev-els in their 15 patients with severe secondaryhyperparathyroidism (iPTH 1250 pg/ml).Goicoechea et al. [4] described a positivecorrelation between IL-6 or TNF-· valuesand erythropoietin doses in hemodialysis pa-tients, but did not analyze the response toepoietin dose in relation to the severity ofsecondary hyperparathyroidism. Surgicaltreatment of our patients with secondary hy-perparathyroidism or successful parathyroidadenomectomy of patients with primary hy-perparathyroidism [5], resulted in a fall ofelevated IL-6 levels into the normal range.Vitamin D3 metabolites have shown to sup-press elevated IL-6 levels in diseased states[6]. Whether the beneficial effects of activevitamin D3 on anemia in patients with sec-ondary hyperparathyroidism solely reflectthe correction of excess parathyroid hor-mone secretion or, in addition, may also cor-rect PTH or hypercalcemia-induced alter-ations in cytokine synthesis, remains to beshown.In summary, severe secondary hyper-parathyroidism represents an important fac-tor affecting the pathogenesis of anemia inuremic patients and is considered a revers-ible cause of resistance to recombinant hu-man erythropoietin therapy. The complexrelationship between excess parathyroid hor-mone and erythropoiesis seems to involvealterations of the synthesis of proinflamma-tory cytokines.References1 Gallieni M, Corsi C, Brancaccio D: Hyperpara-thyroidism and anemia in renal failure. Am JNephrol 2000;20:89–96.2 Krantz SB: Pathogenesis and treatment of theanemia of chronic disease. Med Sci 1994;307:353–359.3 Montalban C, Garcia-Unzueta MT, De Fran-cisco AL, Amado JA: Serum interleukin-6 inrenal osteodystrophy: Relationship with serumPTH and bone remodeling markers. Horm Me-tab Res 1999;31:14–17.4 Goicocechea M, Martin J, De Sequera P, Qui-roga JA, Ortiz A, Carreno V, Caramelo C: Roleof cytokines in the response to erythropoietinin hemodialysis patients. Kidney Int 1998;54:1337–1343.5 Grey A, Mitnick MA, Shapses S, Ellison A,Gundberg C, Insogna K: Circulating levels ofinterleukin-6 and tumor necrosis factor-alphaare elevated in primary hyperparathyroidismand correlate with markers of bone resorption –A clinical research center study. J Clin Endocri-nol Metab 1996;81:3448–3449.6 Muller K, Bendtzen K: 1,25-Dihydroxyvita-min D3 as a natural regulator of human im-mune function. J Invest Dermatol Symp Proc1996;1:68–71.

Amado JA: Serum interleukin-6 in renal osteodystrophy: Relationship with serum PTH and bone remodeling markers. Horm Metab Res

Bendtzen K: 1,25-Dihydroxyvitamin D3 as a natural regulator of human immune function.

Caramelo C: Role of cytokines in the response to erythropoietin in hemodialysis patients. Kidney Int 1998;54:

Circulating levels of interleukin-6 and tumor necrosis factor-alpha are elevated in primary hyperparathyroidism and correlate with markers of bone resorption – A clinical research center study.

Hyperparathyroidism and anemia in renal failure.

Pathogenesis and treatment of the anemia of chronic disease. Med Sci 1994;307:

Secondary hyperparathyroidism, proinflammatory cytokines and response to epoietin in anemic maintenance dialysis patients

Universität München: Elektronischen Publikationen

iPTH, pg/ml
Letter to the Editor
Nephron 2001;88:391–392
Secondary Hyperparathyroidism,
Proinflammatory Cytokines and Response to
Epoietin in Anemic Maintenance Dialysis
Patients
H. Schiffl D. Stratakis S.M. Lang
Section of Nephrology, Department of Internal Medicine, University Munich Innenstadt, Munich, Germany
Prof. Dr. H. Schiffl
Med. Klinik, Klinikum der Universität München
Ziemssenstrasse 1
D–80336 Munich (Germany)
Fax +49 89 5705727, E-Mail hschiffl@medinn.med.uni-muenchen.de
ABC
Fax + 41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
© 2001 S. Karger AG, Basel
0028–2766/01/0884–0391$17.50/0
Accessible online at:
www.karger.com/journals/nef
Dear Sir,
There is ample evidence that excess plas-
ma parathyroid hormone concentrations
(iPTH), especially in the presence of histo-
logical ostitis fibrosa, are associated with
worsening of anemia or resistance to the
action of erythropoietin. This may be coun-
teracted either by treatment with active
forms of vitamin D3 or by parathyroidecto-
my. The mechanisms involved in the com-
plex relationship between the autonomous
parathyroid glands and erythropoiesis are
not fully understood. The early response to
surgery or medical therapy suggests direct
effects on hematopoiesis such as suppression
of endogenous erythropoietin secretion, in-
hibition of bone marrow erythroid progeni-
tors or red cell survival. The continuous im-
provement of anemia may be further ex-
plained by decreased bone marrow fibrosis.
However, data regarding the operating fac-
tors are conflicting [1]. Inflammatory cyto-
kines such as interleukin-6 (IL-6) block
erythropoiesis by their effects on the devel-
opment of erythroblasts [2] and thereby ane-
mia and responsiveness to erythropoietin.
The question whether parathyroid hormone
excess affects synthesis of proinflammatory
cytokines remains unanswered.
We prospectively examined the effects of
parathyroidectomy on IL-6 levels, hemoglo-
bin concentrations and epoietin dose in 9
anemic patients with end-stage renal disease
(5 patients on CAPD, 4 patients on hemodi-
alysis) and severe secondary hyperparathy-
roidism. There were 5 men and 4 women,
aged 28–63 years, and the duration on dialy-
sis before surgery was 38–184 months (mean
85). The cause of end-stage renal disease was
chronic glomerulonephritis in 6 patients,
chronic tubulointerstitial nephritis in 2 pa-
tients and polycystic kidney disease in 1
patient. None of the patients had absolute or
relative iron deficiency, infection, inflam-
matory disorders, malignancy, occult gas-
trointestinal blood loss, aluminium toxicity
or was taking drugs known to interfere with
erythropoiesis. They all had normal vitamin
B12 and folic acid levels, and weekly Kt/V of
at least 3.6 for hemodialysis and 2.1 for
CAPD. The diagnosis of severe secondary
hyperparathyroidism was made on the basis
of biochemical, histological (bone biopsy),
radiological and clinical parameters. Blood
samples for determinations of iPTH and
other chemical parameters, serum IL-6 lev-
els, and hemoglobin concentrations were
drawn prior to surgery (within 1 week) and
6 months after surgery.
Parathyroidectomy (total parathyroidec-
tomy with a forearm transplant) resulted in
each patient in a normalization of excess
parathyroid hormone concentration, hyper-
calcemia (2.9 B 0.1 vs. 2.4 B 0.1 mmol/l),
hyperphosphatemia (6.5 B 0.5 vs. 3.4 B
0.5 mg/dl) and alkaline phosphatase (261 B
22 vs. 153 B 18 U/l). Compared to pre-
operative values, the postoperative epoie-
tin doses were significantly lower, although
Table 1. Effect of parathyroidectomy on
responsiveness to epoietin therapy in 9 ure-
mic patients
Parathyroidectomy
prior post
1,582B633 27B9*
IL-6, pg/ml 54B18 12B5*
CRP, mg/dl 1.3B0.2 0.2B0.1*
Hb, g/dl 9.2B0.4 10.8B0.4*
EPO dose,
U/kg/week 151B35 61B28*
* p ! 0.05 vs. preoperative values.
postoperative hemoglobin levels were signif-
icantly higher than corresponding levels be-
fore surgical therapy. Parathyroidectomy
was also associated with a fall in elevated IL-
6 values towards values usually observed in
chronic hemodialysis patients. Furthermore,
successfully treated patients had significant-
ly lower CRP values (table 1).
The worsening of anemia and the resis-
tance to erythropoietin characterizing severe
secondary hyperparathyroidism are caused
not by a single pathogenetic mechanism, but
may involve a number of factors operating
simultaneously at different stages of the de-
392 Nephron 2001;88:391–392 Schiffl/Stratakis/Lang
velopment of parathyroid gland hyperplasia.
The present data disclose a previously un-
described link between excess parathyroid
hormone and erythropoiesis in hyperpara-
thyroidism secondary to end-stage renal dis-
ease. Circulating IL-6 levels were found to be
increased in our patients with severe second-
ary hyperparathyroidism as well as in 86 ure-
mic patients with different degrees of renal
osteodystrophy published by Montalban et
al. [3]. The authors of the latter series found
a strong correlation (r = 0.71) between iPTH
concentrations and corresponding IL-6 lev-
els in their 15 patients with severe secondary
hyperparathyroidism (iPTH 1250 pg/ml).
Goicoechea et al. [4] described a positive
correlation between IL-6 or TNF-· values
and erythropoietin doses in hemodialysis pa-
tients, but did not analyze the response to
epoietin dose in relation to the severity of
secondary hyperparathyroidism. Surgical
treatment of our patients with secondary hy-
perparathyroidism or successful parathyroid
adenomectomy of patients with primary hy-
perparathyroidism [5], resulted in a fall of
elevated IL-6 levels into the normal range.
Vitamin D3 metabolites have shown to sup-
press elevated IL-6 levels in diseased states
[6]. Whether the beneficial effects of active
vitamin D3 on anemia in patients with sec-
ondary hyperparathyroidism solely reflect
the correction of excess parathyroid hor-
mone secretion or, in addition, may also cor-
rect PTH or hypercalcemia-induced alter-
ations in cytokine synthesis, remains to be
shown.
In summary, severe secondary hyper-
parathyroidism represents an important fac-
tor affecting the pathogenesis of anemia in
uremic patients and is considered a revers-
ible cause of resistance to recombinant hu-
man erythropoietin therapy. The complex
relationship between excess parathyroid hor-
mone and erythropoiesis seems to involve
alterations of the synthesis of proinflamma-
tory cytokines.
References
1 Gallieni M, Corsi C, Brancaccio D: Hyperpara-
thyroidism and anemia in renal failure. Am J
Nephrol 2000;20:89–96.
2 Krantz SB: Pathogenesis and treatment of the
anemia of chronic disease. Med Sci 1994;307:
353–359.
3 Montalban C, Garcia-Unzueta MT, De Fran-
cisco AL, Amado JA: Serum interleukin-6 in
renal osteodystrophy: Relationship with serum
PTH and bone remodeling markers. Horm Me-
tab Res 1999;31:14–17.
4 Goicocechea M, Martin J, De Sequera P, Qui-
roga JA, Ortiz A, Carreno V, Caramelo C: Role
of cytokines in the response to erythropoietin
in hemodialysis patients. Kidney Int 1998;54:
1337–1343.
5 Grey A, Mitnick MA, Shapses S, Ellison A,
Gundberg C, Insogna K: Circulating levels of
interleukin-6 and tumor necrosis factor-alpha
are elevated in primary hyperparathyroidism
and correlate with markers of bone resorption –
A clinical research center study. J Clin Endocri-
nol Metab 1996;81:3448–3449.
6 Muller K, Bendtzen K: 1,25-Dihydroxyvita-
min D3 as a natural regulator of human im-
mune function. J Invest Dermatol Symp Proc
1996;1:68–71.


H. Schiffl

D. Stratakis

S.M. Lang

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Secondary Hyperparathyroidism, Proinflammatory Cytokines and Response to Epoietin in Anemic Maintenance Dialysis Patients

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Secondary hyperparathyroidism, proinflammatory cytokines and response to epoietin in anemic maintenance dialysis patients

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