Chronic renal failure

Renal bone disease

roliferative activity (Figure 1). Failure of vitamin D bioactivation

p
also leads to a lower extracellular fluid (ECF) calcium concentration, providing a further stimulus to the parathyroid glands.
Calcitriol has a direct inhibitory effect on PTH gene transcription, mediating its effects via a nuclear vitamin D receptor (VDR)
which is present in parathyroid glands, osteoblasts and intestinal
epithelial cells, as well as in many other tissues. The parathyroid
glands also express the calcium sensing receptor (CaR), a Gprotein coupled receptor which mediates rapid minute-to-minute
responses to changes in extracellular calcium concentration.
At the level of bone, PTH at physiological or just supraphysiological concentration is anabolic. In contrast, sustained elevation
of PTH is catabolic, increasing the activity of both osteoblasts
and osteoclasts, accelerating bone turnover and ultimately leading to significant resorptive damage. This is hyperparathyroid
bone disease.6

John Cunningham

Abstract
Sustained loss of kidney function leads to the evolution of progressive secondary hyperparathyroidism associated with a characteristic high-turnover
form of metabolic bone disease. The drivers to hyperparathyroidism include
the failure of renal bioactivation of vitamin D, phosphate retention and in
some cases hypocalcaemia. As renal impairment becomes more severe,
some patients, particularly under the influence of treatment, evolve in a
different direction with the development of low-turnover adynamic bone
disease associated with relative suppression of the parathyroid glands.
Uraemic patients also develop an internal milieu that favours soft tissue
calcification involving peri-articular tissue and the vasculature. Arterial calcification is associated closely with arterial stiffening, left ventricular disease
and increased cardiovascular morbidity and mortality. Current therapies aim
to minimize disturbances to skeletal integrity by setting calcium, phosphate
and parathyroid hormone within defined target ranges. It is hoped, but
not yet established, that these measures will also result in a reduction of
cardiovascular events in this vulnerable population.

Low-turnover bone disease

A somewhat different scenario develops in some patients, particularly those who are subjected to treatment with pharmacological doses of active vitamin D metabolites and high exposure to
calcium derived from the diet or dialysate fluids. In these individuals, there is relative suppression of PTH (mediated by the high
calcium inflow and calcitriol), with the result that the skeleton
lacks stimulatory anabolic input from PTH. Abnormally low bone
turnover develops, with low cellular activity. This is associated
with increased skeletal morbidity and, as a result of an associated
increase in the tendency to develop vascular calcification, with
increased cardiovascular morbidity and mortality as well.

Keywords calcimimetics; chronic kidney disease; hyperparathyroidism;

vascular calcification; vitamin D

Extra-skeletal calcification
Soft tissue calcification, especially that involving large arteries
with a predominantly conduit function, is a frequent complication in patients with chronic kidney disease.5 This calcification

The onset of a significant and sustained reduction in renal function

is invariably associated with the development of metabolic bone
disease, disturbances to the metabolism of calcium and phosphorous, and with abnormalities of the principal calcium-regulating
hormones, calcitriol and parathyroid hormone (PTH).1,2 In addition, there are important links between these disturbances of mineral metabolism and adverse cardiovascular outcomes in patients
with chronic kidney disease.35

Stimulation of the parathyroid glands

Ca (chronic)
Pi (chronic)
Calcitriol

Ca (acute)

Augment parathyroid
cell proliferation

Hyperparathyroidism and high-turnover bone disease

Reduction of renal cell mass and glomerular filtration rate (GFR)
leads to progressive phosphate retention and the failure of the
renal bioactivation of vitamin D. These abnormalities powerfully stimulate the parathyroid glands to synthesize and release
increased amounts of parathyroid hormone and to increase

Increased PTH
release via CaR

Increase PTH
synthesis
per cell

Circulating PTH
John Cunningham BA DM FRCP is Professor of Nephrology at The Royal
Free Hospital and University College London, London, UK. His training
was in Cambridge (pre-clinical) and Oxford (clinical) and subsequently
in London and the USA. He has remained an active researcher and
clinician in nephrology and in general internal medicine. Competing
interests: none declared.

MEDICINE 35:8

Acute minute-to-minute regulation is controlled by calcium acting via the

calcium sensing receptor (CaR). Sustained stimulation by any combination
of low calcium, high phosphate (Pi) and low calcitriol leads to increased
parathyroid hormone (PTH) synthesis per cell and increased parathyroid
proliferative activity.

Figure 1

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2007 Elsevier Ltd. All rights reserved.

Chronic renal failure

occurs in the vascular media and, as such, is distinct from the

intimal calcification seen in patients with atheromatous disease.
Medial calcification in uraemia is closely associated with loss of
vascular compliance, arterial stiffening and increased pulse wave
velocity, abnormalities that increase ventricular afterload and
which may be important in the genesis of uraemic cardiac disease
and the high cardiovascular mortality seen in these patients.

25-hydroxylation in the liver, yielding the active hormonal form

of vitamin D, calcitriol.
These treatments are generally very effective in the control of
secondary hyperparathyroidism, but are prone to cause hypercalcaemia and probably vascular calcification as well. This has
led to a search for alternative and more selective ways of treating
hyperparathyroidism, avoiding the excessive calcaemic actions
of vitamin D and calcium therapy as outlined above. Three
approaches have been used.
First, there has been a substantial move away from calciumbased phosphate binders to calcium-free resins and salts. These
agents, which still suffer from relative lack of potency, are much
less prone to cause hypercalcaemia and there is some evidence
that there may be less tendency to vascular calcification as well.
Sevelamer hydrochloride and lanthanum carbonate are the two
non-calcaemic phosphate binders most commonly used.
Second, new active vitamin D compounds have been developed, some of which exhibit the potential for more selective
action on the parathyroid glands with less tendency to raise calcium via actions on intestine and bone. Laboratory and other
experimental work using these agents has sometimes shown
very impressive evidence of target organ selectivity, but in clinical practice little significant difference has emerged from the
relatively few good-quality comparative studies that have been
completed.8 Vitamin D compounds of this category include
22-oxacalcitriol (maxacalcitol), widely used in Japan, and paricalcitol, which is widely used in the USA and to a lesser extent in
some European countries.
The third approach is to use calcimimetic agents to modulate
the action of the CaR on parathyroid cells.9 These compounds
bind to the transmembrane domain of the receptor, resulting in
an allosteric modification that increases its sensitivity to calcium.
As a result, the parathyroid cell perceives extracellular calcium
concentration as being higher than it really is. Predictably, this
leads to simultaneous reduction of PTH and calcium (and to a
lesser extent phosphate as well). These agents have proved an
extremely effective means of moving PTH, calcium and phosphate into desired target ranges when given to patients with
hyperparathyroidism and chronic kidney disease.

Assessment of osteodystrophy
The typical derangement seen in a biochemical snapshot of the
untreated patient with advanced chronic kidney disease (CKD)
shows high phosphate and low calcium with resulting secondary
hyperparathyroidism. Calcitriol, if measured, is invariably low.
Skeletal X-rays are frequently normal, except in cases of severe
hyperparathyroidism in which subperiosteal erosion and cortical
tunnelling may be seen (Figure 2).

Management
The pathogenesis described above implies that management
should include measures to increase serum calcium, decrease
phosphate and replace deficient calcitriol. This forms the central core of management of the disturbed mineral metabolism in
most patients with chronic kidney disease. Available therapies
are illustrated in Table 1.
Hyperphosphataemia is managed using a combination of
dietary phosphate restriction and oral phosphate binders. The
latter bind dietary phosphate in the intestinal lumen, rendering
it unavailable for absorption. Several agents are used, including calcium carbonate, calcium acetate or aluminium hydroxide
(now rarely used on account of unpredictable neurotoxicity and
skeletal toxicity). Sevelamer, an exchange resin, and lanthanum
carbonate, are newer and safer alternatives.7 Unfortunately, all
these agents have limited efficacy, suffering from relatively low
potency and the need to take large doses timed to coincide with
meals. Patient compliance is frequently poor.
Deficient calcitriol is replaced either by giving calcitriol as
an oral or injectable formulation, or in many cases by giving a
calcitriol prodrug, alfacalcidol. This agent is then subjected to

Biochemical targets in patients with chronic kidney disease

Observational studies have led to the development of several
sets of guidelines and biochemical targets relating to bone and
mineral metabolism in CKD. Central to these guidelines is the
hope that, if achieved, improved clinical outcomes will result.
Several sets of such guidelines have been developed, all broadly
similar and recommending that calcium should be maintained
in the normal and perhaps low-normal range, hyperphosphataemia should be minimized, and finally that PTH should be
maintained at a level between 3 and 6 times the upper limit of
normal.10 This last recommendation may seem surprising. It is
based on a number of observational studies showing that PTH
within this target range is associated with the highest probability
of bone turnover being normal. PTH below 150 pg/ml predicts
low-turnover adynamic bone disease whereas, conversely, PTH
above 300 pg/ml is increasingly associated with high-turnover
hyperparathyroid bone disease. Unfortunately the use of PTH
as a surrogate marker in this way is quite imprecise, although it

Figure 2 Severe hyperparathyroid bone disease in phalanges. Note

subperiosteal resorption and cortical tunnelling.

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2007 Elsevier Ltd. All rights reserved.

Chronic renal failure

Therapeutic levers in CKD. The arrows depict the expected response(s) of serum biochemical parameters

Calcium binder
Calcium-free binder
Vitamin D
Calcimimetic
Dialysate Ca++

Calcium

Phosphate

Calcium phosphate

Parathyroid hormone

Table 1

remains the best compromise of utility and feasibility in clinical

practice.

4 Block GA, Cunningham J. Morbidity and mortality associated with

abnormalities in bone and mineral metabolism in CKD. In: OlgaardK,
ed. A clinical guide to bone and mineral metabolism in CKD.
National Kidney Foundation, 2006.
5 Ketteler M, Gross ML, Ritz E. Calcification and cardiovascular
problems in renal failure. Kidney Int 2005; 94: S12027.
6 Malluche H, Faugere M. Renal bone disease 1990: an unmet
challenge for the nephrologist. Kidney Int 1990; 38: 193211.
7 Fan LS, Cunningham J. Hyperphosphatemia management. Semin Dial
2002; 15: 13.
8 Cunningham J. New vitamin D analogues for osteodystrophy in
chronic kidney disease. Pediatr Nephrol 2004; 19: 70508.
9 Steddon SJ, Cunningham J. Calcimimetics and calcilyticsfooling the
calcium receptor. Lancet 2005; 365: 223739.
10 National Kidney Foundation. K/DOQI clinical practice guidelines:
bone metabolism and disease in chronic kidney disease. Am J
Kidney Dis 2003; 42(suppl 4): S1S201.
11 Teng M, Wolf M, Ofsthun N, et al. Activated injectable vitamin D and
hemodialysis survival: a historical cohort study. Am Soc Nephrol
2005; 16: 111525.
12 Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R.
Survival of patients undergoing hemodialysis with paricalcitol or
calcitriol therapy. N Engl J Med 2003; 349: 44656.
13 Cunningham J, Danese M, Olson K, Klassen P, Chertow G. Effects of
the calcimimetic cinacalcet HCl on cardiovascular disease, fracture
and health-related quality of life in secondary hyperparathyroidism.
Kidney Int 2005; 68: 1793800.

Clinical outcomes
Very large cohort studies have looked at the influence of vitamin D therapies on survival and other outcomes. Somewhat
surprisingly, quite good evidence has emerged that treatment
with active vitamin D compounds is associated with a significant
increase in life expectancy amongst dialysis patients.11 There is
somewhat less convincing evidence that some vitamin D meta
bolites may be better than others in this respect.12 In the case
of calcimimetics, analysis of data from a series of comparative
studies has shown a tenfold reduction in parathyroidectomy rate
and 50% reduction in fracture rate amongst patients treated with
the calcimimetic agent, cinacalcet, compared with those treated
conventionally.13 These are potentially very important findings
which, both in the case of vitamin D therapies and calcimimetics, require confirmation (or otherwise) by means of adequately
powered prospective studies.

Conclusion
Disturbed mineral and bone metabolism in chronic kidney disease is a major therapeutic target in the overall management of
these patients. It is now clear that there is substantial overlap
between the pathogeneses that lead to bone disease and those
that are associated with accelerated vascular disease in this
patient group. The perceived advances in the therapeutic tools
available have not yet led to demonstrably enhanced clinical
outcomes. Further prospective studies are needed to shed light
on these important questions.

Practice points
Hyperparathyroidism develops early in CKD, so treat early
There are important links between metabolic bone disease
and CV disease in CKD patients when treating the bone,
keep an eye on the CV issues as well
Uraemic bone disease is heterogeneous. High-turnover
hyperparathyroid bone disease and low-turnover adynamic
bone disease dominate the two ends of the spectrum
Parathyroid hormone measurement is a reasonable surrogate
for the severity and type of bone disease

References
1 Feinfeld DA, Sherwood LM. Parathyroid hormone and 1,25(OH)2D3 in
chronic renal failure. Kidney Int 1988; 33: 104958.
2 Steddon SJ, Fan SL, Cunningham J. New prospects for the
management of renal bone disease. Nephron Clin Pract 2005;
99: c17.
3 Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, ChertowGM.
Mineral metabolism, mortality, and morbidity in maintenance
hemodialysis. J Am Soc Nephrol 2004; 15: 220818.

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2007 Elsevier Ltd. All rights reserved.