Nephrol Dial Transplant (2004) 19 [Suppl 5]: v2–v8
doi:10.1093/ndt/gfh1049
The clinical consequences of secondary hyperparathyroidism: focus on
clinical outcomes
Walter H. Hörl
Division of Nephrology and Dialysis, Department of Medicine III, University Hospital, Vienna, Austria
Abstract
Secondary hyperparathyroidism (SHPT) is a common
occurrence in patients with chronic renal failure and is
characterized by excessive serum parathyroid hormone
(PTH) levels, parathyroid hyperplasia and imbalances
in calcium and phosphorus metabolism. PTH acts as a
uraemic toxin and it may be responsible for the following long-term consequences: renal osteodystrophy;
non-skeletal abnormalities, including severe vascular
and heart valve calcification; alterations in cardiovascular structure and function; immune dysfunction;
and renal anaemia. The risk of developing SHPT is not
the same for all uraemic patients. Black patients
appear to have a higher risk of developing SHPT
than Caucasian patients, and patients with diabetes
have a lower risk than non-diabetic patients. Current
treatments include dietary phosphate restriction, oral
phosphate binders, vitamin D and its analogues, and,
in severe cases, parathyroidectomy. These treatments
do not provide optimal treatment for many patients,
and compounds that directly inhibit PTH secretion
may prove a major step forward in the treatment
of SHPT.
Keywords: chronic renal failure; parathyroid
hormone; secondary hyperparathyroidism; uraemia
Introduction
Secondary hyperparathyroidism (SHPT) is a frequently
observed complication in patients with chronic renal
failure (CRF), and is characterized by increased secretion of parathyroid hormone (PTH) and parathyroid
gland hyperplasia [1,2].
SHPT develops as a consequence of hypocalcaemia, hyperphosphataemia and reduced 1,25
Correspondence and offprint requests to: Professor Walter H. Hörl,
Division of Nephrology and Dialysis, University Hospital, Vienna,
Austria. Email: [email protected]
dihydroxyvitamin D3 [1,25(OH)2D3] production [3]. A
number of other factors, such as aluminium, oestrogens
and catecholamines, may also influence the synthesis
and release of PTH, thereby further contributing to
hyperparathyroidism [4–6]. PTH is a major uraemic
toxin, which acts directly or indirectly to increase
intracellular calcium concentrations. This action results
in a number of serious outcomes, including neurotoxicity, anaemia, immune dysfunction, uraemic
neuropathy, cardiomyopathy, impairment of vascular
reactivity and impaired lipid/carbohydrate metabolism.
This paper discusses the clinical complications associated with elevated PTH, their effect on mortality and
potential therapeutic approaches to their management.
SHPT risk in the uraemic patient
Not all uraemic patients share the same risk of
developing SHPT. Gupta et al. examined PTH levels
in uraemic patients as a function of race, sex, age and
diabetic status [7]. Race was shown to be a major
determinant of SHPT, with severe SHPT occurring
more often in Black uraemic patients than in Caucasian
uraemic patients (Figure 1), and Black patients having
higher circulating PTH levels than Caucasians
(Figure 2)—possibly leading to a higher risk of outcomes. Among the Black population, the parathyroid
gland mass is higher than in the general population, and
this may be a predisposing factor to SHPT when renal
failure develops [8]. One explanation for this may be
that skin pigmentation in Blacks results in decreased
synthesis of 25-hydroxyvitamin D3 [25(OH)D3] in
response to sunlight [9], leading to SHPT and increased
parathyroid gland mass in the Black population [9,10].
In the same study, it was shown that patients with
diabetes have relatively low PTH levels and therefore
a lower risk for developing SHPT in both Black and
Caucasian populations, compared with non-diabetic
patients (Figure 2). This is due to an inhibition of PTH
release as a result of hyperglycaemia and insulin
deficiency. Bone mass is also reduced in the diabetic
Nephrol Dial Transplant Vol. 19 Suppl 5 ß ERA–EDTA 2004; all rights reserved
Clinical consequences of SHPT
v3
Fig. 1. Risk of relative hypoparathyroidism or severe SHPT in Black patients vs Caucasian patients [7]. aMaximum PTH <150 pg/ml;
b
mean PTH >500 pg/ml. OR ¼ odds ratio.
Fig. 2. PTH levels in Black patients vs Caucasian patients and in diabetic vs non-diabetic patients [7]. Results are given as mean values.
patient population due to a lower rate of bone
formation.
It has now been shown that low plasma levels of the
vitamin D metabolite 25(OH)D3 are an independent
risk factor for elevated PTH levels in haemodialysis
patients [11]. This is significant since, historically, limited attention has been paid to the underlying vitamin D
status in these patients.
Clinical consequences of SHPT
SHPT associated with uraemia contributes to a number
of clinical complications. These include hyperphosphataemia and the development of renal osteodystrophy, as either osteitis fibrosa or mixed uraemic bone
disease [12]. Disturbed PTH and mineral metabolism
is also known to result in non-skeletal toxicity that
frequently manifests as cardiovascular morbidity and
mortality [13–15].
Skeletal effects of SHPT—renal osteodystrophy
Renal osteodystrophy leading to bone loss is a significant cause of morbidity in haemodialysis patients.
The risk factors for osteopenia in patients with renal
osteodystrophy are SHPT, 1,25(OH)2D3 deficiency,
previous immunosuppression, chronic acidosis, secondary amenorrhoea, and chronic aluminium and
heparin exposure [12]. There is a close relationship
between osteopenia and the incidence of vertebral
fractures in uraemic patients. Atsumi et al. have studied
this relationship in Japanese male haemodialysis
patients; female patients were eliminated from the
study to exclude the effect of the menopause on bone
density [16]. The prevalence of vertebral fracture was
found to be higher at all ages in the haemodialysis
patients, compared with healthy Japanese men, and
was three times greater for patients in their fifth decade.
When patients were stratified according to PTH tertile,
those in the lowest tertile [(intact parathyroid hormone
(iPTH), 5–61 pg/ml] had an increased risk of fracture
v4
compared with those in the middle tertile (iPTH,
62–202 pg/ml) [relative risk (RR) 2.4; P<0.05].
Patients in the highest PTH tertile (iPTH 203–1818
pg/ml) also had a tendency towards increased fractures
when compared with the ‘middle’ group.
In addition to being a risk factor for PTH elevation
in haemodialysis patients, vitamin D deficiency is also
thought to be a risk factor in itself for bone disease. In a
group of elderly uraemic patients, Looser’s zone lesions
have been observed in patients with low vitamin D
levels (<40 nmol/l), and no bone resorption occurred in
patients with plasma 25(OH)D3 levels >100 nmol/l
(Figure 3).
Non-skeletal effects of SHPT
Calcification. Some authors have suggested a direct
role for elevated PTH in promoting calcification in
dialysis patients; however, this remains to be well
defined. For example, Goldsmith et al. [17] noted
reduced progression of calcification in haemodialysis
patients who underwent parathyroidectomy (PTX).
More robust evidence is available that elevated calcium
and phosphorus levels lead to the development of calcification. Hyperphosphataemia has, for example, been
associated with the formation and deposition of calcium phosphate crystals in soft tissues, heart valves and
peri-articular regions [18,19]. In addition, Raggi et al.
observed a significant correlation between the extent
of coronary calcification in end-stage renal disease
(ESRD) patients and their serum levels of calcium and
phosphorus [20]. Accordingly, several observational
studies have shown a link between an elevated calcium–
phosphorus product (Ca P) and the development of
vascular and/or valvular calcification [21,22].
Fig. 3. Plasma 25(OH)D3 concentration according to radiological
bone lesions. The horizontal dashed lines are drawn at 25, 40 and
100 nmol/l. The 25 nmol/l level corresponds to the usual threshold
below which histological osteomalacia can be seen in the absence
of renal failure, defining a state of vitamin D deficiency; 40 nmol/l
and 100 nmol/l correspond to the thresholds above which no
Looser’s zone lesions and subperiosteal resorption, respectively, are
seen. Reproduced, with permission, from Ghazali et al. [11].
W. Hörl
Severe, non-skeletal calcifications have also been
described in the absence of hyperphosphataemia, and a
recent study has shown that reduced levels of human
fetuin-A (AHSG), an extracellular calcium-regulating
protein, are an important predictor of cardiovascular
mortality [23]. It is thought that AHSG deficiency
may contribute to a decrease in vascular wall elasticity,
an early sign of uraemic vasculopathy, and a potent
cardiovascular risk factor in the dialysis population [23].
Cardiovascular structure and function. A number of
changes in cardiovascular structure and function are
commonly observed in patients with CRF as a result
of elevated levels of circulating PTH (Table 1) [24].
Although acute exposure to PTH in animals produces
hypotension, chronic exposure in animals and humans
increases blood pressure. It has been hypothesized that
the mechanism by which PTH leads to hypertension
is via the accumulation of calcium in vascular smooth
muscle cells. A recent publication by Ogata et al.
demonstrated that the calcimimetic NPS R-568 lowers
blood pressure in subtotally nephrectomized rats to a
level that is comparable with that in normal control
animals [25]. The group found that this compound
also reduced the rate of progression of CRF, although
it is not clear whether this beneficial effect is related
to the drug effect in lowering intracellular calcium, or
to the effect on blood pressure, or both.
Left ventricular hypertrophy (LVH) is seen frequently in patients with ESRD, and is a major cause
of cardiac mortality. Both primary hyperparathyroidism and SHPT are associated with LVH and increased
left ventricular mass index [26,27]. The mechanisms
whereby SHPT leads to LVH are unknown, but it has
been suggested that they may include direct trophic
effects on myocardial myocytes and interstitial fibroblasts, as well as indirect effects of hypertension as
a result of hypercalcaemia, anaemia, and large and
small vessel changes [24]. Elevated PTH has also been
implicated in the development of interstitial fibrosis,
which is independent of hypertension, and this contributes to the diastolic dysfunction and apnoea often
seen in ESRD patients [28].
Elevated PTH is also a contributing factor to the
development of atherosclerosis and ischaemia in
patients with ESRD. Studies suggest that elevated
PTH levels in renal failure patients may contribute to
hyperlipidaemia [29–31]. Impaired carbohydrate tolerance is an independent risk factor for cardiovascular
mortality and is frequently observed in patients with
CRF. The mechanism linking SHPT to carbohydrate
intolerance in uraemia is unknown, but it has been
suggested that excessive PTH levels lower pancreatic
islet cell ATP, thus raising intracellular calcium levels
and impairing insulin secretion [32–34]. However,
increased levels of insulin have also been observed
in haemodialysis patients with SHPT [35]. DeFronzo
et al. [36] observed elevated insulin levels and insulin
resistance in peripheral tissues in CRF patients. Vitamin D is also thought to play a role in this regard as
1,25(OH)2D3 has been shown to correct insulin
Clinical consequences of SHPT
v5
Table 1. Effects of excess PTH on cardiovascular structure and function in patients with chronic renal failure
Blood pressure
Cardiac contractility
" Left ventricular mass, via:
" Atherosclerosis (chronic), via:
#Blood pressure (acute)
"Blood pressure (chronic)
"VSMC [Ca]i
"VSM wall:lumen ratio
"Contractile force and rate (acute)
"Contractile force (chronic)
#Cardiomyocyte mitochondrial energy production (chronic)
Cardiomyocyte hypertrophy
"Interstitial fibrosis
Disturbed lipoprotein metabolism
"Insulin resistance
"VSMC [Ca]i
"Calcium phosphate deposition in vessel wall (mediacalcosis)
Hypertension
But: inhibition of VSMC migration/proliferation by PTH and PTHrP
Myocardial calcification (chronic)
Heart valve calcification (chronic)
VSMC ¼ vascular smooth muscle cells; PTHrP ¼ PTH-related peptide; [Ca]i ¼ intracellular calcium.
Reproduced, with permission, from Rostand and Drüeke [24].
Fig. 4. Adjusted relative risk (RR) of mortality by cause of death for patients with serum phosphorus levels >6.5 mg/dl. PTH levels in the
reference population were in the range 2.4–6.5 mg/dl. *P<0.05; **P<0.005; ***P<0.0005, compared with a RR of 1.0. Reproduced, with
permission, from Ganesh et al. [14]. CAD ¼ coronary artery disease; CVA ¼ cerebrovascular.
resistance and hypertriglyceridaemia in haemodialysis patients, even in the absence of changes in PTH
levels [37].
Cardiovascular morbidity and mortality. SHPT and its
associated disturbances in mineral metabolism increase
the risk of cardiovascular morbidity and death. For
example, PTH levels >495 pg/ml have been associated
with a significantly increased risk of sudden death from
cardiovascular causes in haemodialysis patients compared with a reference group with a mean PTH of
197 pg/ml (RR ¼ 1.06; P<0.05) [14]. Furthermore, in a
recent 6 year prospective study, PTH levels >50 pmol/l
(471 pg/ml) were associated with a greater risk of
cardiovascular death than lower levels of the hormone
(RR ¼ 3.9) [15].
Increased serum phosphorus levels have also been
shown to be significantly associated with death from
coronary artery disease (CAD) and sudden cardiovascular death [13]. Patients with a serum phosphorus level
>6.5 mg/dl had a 41% greater risk of death from CAD
and a 20% greater risk of sudden cardiovascular death,
compared with patients with serum levels of between
2.4 and 6.5 mg/dl (Figure 4) [14]. There are various
mechanisms by which elevated serum phosphorus levels
may contribute to death from CAD, including the
development of vascular calcification and vascular
smooth muscle cell proliferation, compromising blood
flow in the coronary microcirculation [14]. A similar
link between elevated serum levels of calcium and
cardiovascular mortality has been established in a
large-scale observational study [38]. The identification
of serum PTH, calcium and phosphorus levels as
predictors of cardiovascular mortality has important
implications for therapy. As calcium, phosphorus
and PTH levels are modifiable [39], targeted therapy
v6
to reduce these levels in haemodialysis patients could
potentially improve survival.
One possible mechanism for the increased cardiovascular mortality observed as a result of disturbed
PTH and mineral metabolism is vascular calcification,
which has been identified as a key predictor of mortality
in patients with ESRD [40–42].
Immune dysfunction. Immune dysfunction, particularly defective leukocyte function, leading to increased
susceptibility to infection, is frequently observed in
patients with SHPT. Elevated intracellular calcium
levels have been shown to decrease the phagocytic
ability of neutrophils in patients receiving long-term
haemodialysis [43,44]. A similar correlation has been
demonstrated between intracellular calcium levels and
neutrophil phagocytosis in a healthy elderly population [45], probably due to vitamin D deficiency and
the development of SHPT. Research has shown that
intracellular calcium levels can be normalized by treatment with 1,25(OH)2D3 or with calcium channel
blockers [46]. If a calcimimetic such as cinacalcet also
decreases intracellular calcium levels, this drug may
offer an alternative treatment option for normalizing
neutrophil function in patients with SHPT.
Renal anaemia. Anaemia is a recognized complication of hyperparathyroidism, and high levels of PTH
may contribute to the severity of anaemia in uraemic
patients. Patients with SHPT also show an impaired
response to recombinant human erythropoietin
(rHuEPO). The relationship between PTH overproduction and renal anaemia is unclear. Although some
studies have shown that patients with SHPT undergoing dialysis require a higher dose of rHuEPO to
correct anaemia or achieve significant improvement
following PTX [47,48], others have failed to find
any association between SHPT and anaemia [49,50].
Drüeke and Eckardt [51] have suggested that the role of
SHPT in the pathogenesis of anaemia may be small,
compared with other factors such as iron deficiency and
chronic inflammation. Another important aggravating
factor for renal anaemia in SHPT patients may be
vitamin D deficiency, as the administration of calcitriol
can improve anaemia in ESRD patients [52]. It has
been shown that calcitriol upregulates the proliferative
effects of haematopoietic cells, and the effect is greater
when calcitriol is combined with erythropoietin [53].
This additive effect between calcitriol and erythropoietin may be explained by the fact that calcitriol
increases erythropoietin receptor expression at both the
mRNA and protein levels, thereby increasing the
overall number of erythropoietin receptors [53].
Parathyroidectomy as a treatment option?
Current treatment of SHPT involves tight dietary
control of phosphate and the administration of
phosphate binders, vitamin D and its analogues. In
severe cases, a total PTX is performed. PTX is the
W. Hörl
treatment of choice in patients with fulminant
metastatic calcinosis [54], which has a high mortality
rate, and can be cured by total PTX [55,56]. It has
been shown, however, that even after total PTX, twothirds of patients have normal or greater than normal
levels of PTH and only one-third of patients have
undetectable levels of PTH [54]. The reasons for this
are unclear, but ectopic parathyroid tissue has been
found in variable percentages in humans, and this may
be, at least in part, responsible for the recurrence of
SHPT in patients who have undergone total PTX.
Another disadvantage of total PTX is that hypoparathyroidism is frequently observed, and this may
increase the risk of hypocalcaemia and adynamic
bone disease. Thus, although PTX may be necessary
in patients with the most severe form of hyperparathyroidism, the morbidity associated with surgery
and the risks of recurrent SHPT or hypoparathyroidism mean that total PTX is not the optimal treatment
modality for all patients with SHPT.
Conclusion
In summary, SHPT is a major cause of morbidity and
mortality from a number of clinical consequences in
patients with chronic renal disease. PTH is a uraemic
toxin that is responsible for a number of complications,
including renal osteodystrophy, and changes in cardiac
structure and function, which may account for the high
morbidity and mortality from cardiovascular disease
seen in these patients. The abnormal mineral metabolism associated with SHPT, including hyperphosphataemia and increased Ca P, has also been linked to
increased cardiovascular mortality. SHPT is also a
major risk factor for anaemia, and can lead to immune
dysfunction. Current treatment options, including dietary phosphate restriction, phosphate binders, vitamin
D, calcitriol or vitamin D analogues and total PTX,
have only been partially successful in the management of SHPT, and are not always sufficiently effective in lowering PTH and Ca P to a desired level. A
calcimimetic agent such as cinacalcet, which could
directly control the secretion of PTH by acting at
the level of the parathyroid gland, and simultaneously reduce calcium, phosphorus and Ca P,
would represent a major advance in therapy.
Conflict of interest statement. None declared.
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