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could be used as a performance indicator.

Suggestions for future research

1. Mortality studies with newer agents -
sevelamer and lanthanum - in comparison
with calcium salts are urgently required.

2. An audit of serum aluminium levels. Follow-up data on patients with elevated levels should be collected.

3. Cost-benefit analysis of sevelamer vs. calcium salts should be undertaken as the dose of sevelamer needed to control

phosphate will add considerably to the cost of treating end-stage kidney disease.

4. Bone biopsy studies of patients treated long-term with lanthanum should be

undertaken to satisfy safety concerns.

National Kidney Foundation (US)



K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Guideline 5. Use of

Phosphate binders in CKD (2004).

In CKD Patients (Stages 3 and 4):

1. If phosphorus or intact PTH levels
cannot be controlled within the

target range, despite dietary

phosphorus restriction, phosphate
binders should be prescribed.
2. Calcium-based phosphate binders
are effective in lowering serum

phosphorus levels (EVIDENCE) and may be used as the initial binder therapy. (OPINION)

In CKD Patients with Kidney Failure (Stage 5):

3. Both calcium-based phosphate

binders and other noncalcium-,

nonaluminum-, nonmagnesium-

containing phosphate-binding
agents (such as sevelamer HCl)
are effective in lowering serum
phosphorus levels (EVIDENCE)
and either may be used as the
primary therapy. (OPINION)

4. In dialysis patients who remain

hyperphosphatemic (serum
phosphorus >5.5 mg/dL [1.78

mmol/L]) despite the use of either of calcium-based phosphate

binders or other noncalcium-,
nonaluminum-, nonmagnesium-
containing phosphate-binding
agents, a combination of both
should be used. (OPINION)

5. The total dose of elemental calcium

provided by the calcium-based

phosphate binders should not

exceed 1,500 mg/day (OPINION),
and the total intake of elemental
calcium (including dietary calcium)
should not exceed 2,000 mg/day.

6. Calcium-based phosphate binders

should not be used in dialysis

patients who are hypercalcemic

(corrected serum calcium of >10.2
mg/dL [2.54 mmol/L]), or whose

plasma PTH levels are <150 pg/mL (16.5 pmol/L) on 2 consecutive

measurements. (EVIDENCE) 7. Noncalcium-containing phosphate

binders are preferred in dialysis patients with severe vascular and/or other soft tissue

calcifications. (OPINION)

8. In patients with serum phosphorus

levels >7.0 mg/dL (2.26 mmol/L),

aluminum-based phosphate binders may be used as a short-term

therapy (4 weeks), and for one course only, to be replaced

thereafter by other phosphate

binders. (OPINION) In such

patients, more frequent dialysis
should also be considered.

Cannella G, Messa P.

Other reviews


Johnson DW, Craven A-M, Isbel NM.
Modification of cardiovascular risk in

hemodialysis patients: An evidence-

based review. Hemodialysis

International. Vol. 11(1)(pp 1-14),


Cardiovascular disease accounts for 40% to 50% of deaths in dialysis populations.

Overall, the risk of cardiac mortality is 10-
fold to 20-fold greater in dialysis patients than in age and sex-matched controls

without CKD. The aim of this paper is to

review critically the evidence that cardiac
outcomes in dialysis patients are modified
by cardiovascular risk factor interventions.
There is limited, but as yet inconclusive

controlled trial evidence that cardiovascular outcomes in dialysis populations may be improved by antioxidants (vitamin E or

acetylcysteine), ensuring that hemoglobin levels do not exceed 120 g/L (especially in the setting of known cardiovascular

disease), prescribing carvedilol in the setting of dilated cardiomyopathy, and by using

cinacalcet in uncontrolled SHPT. Similarly, there are a number of negative controlled trials, which have demonstrated that statins, high-dose folic acid, angiotensin-converting enzyme inhibitors, multiple risk factor

intervention via multidisciplinary clinics, and high-dose or high-flux dialysis are ineffective in preventing cardiovascular disease.

Although none of these studies could be
considered conclusive, the negative trials to
date should raise significant concerns about
the heavy reliance of current clinical practice
guidelines on extrapolation of findings from
cardiovascular intervention trials in the
general population. It may be that
cardiovascular disease in dialysis
populations is less amenable to intervention,
either because of the advanced stage of
CKD or because the pathogenesis of
cardiovascular disease in dialysis patients is
different from that in the general population.
Large, well-conducted, multicenter
randomized-controlled trials in this area are
urgently required.

Therapy of secondary

hyperparathyroidism to date:
Vitamin D analogs, calcimimetics or both? Journal of Nephrology. Vol. 19(4) (pp 399-402), 2006.

Therapy with i.v. calcitriol (CLT), that had been the mainstay of the cure of severe SHPT for many years, is often hindered by the occurrence of hypercalcemia, that

requires discontinuation of the drug with consequent rebounding of the PTH

oversecretion. To circumvent this

shortcoming, CLT-analogs with less

calcemic effects with respect to CLT have

been developed. One of these analogs,

paracalcitol (PCLT), proved to be at least as powerful as CLT in decreasing serum PTH, but it still remains endowed with some

calcemic effect as the parent compound.
Meanwhile, calcimimetics (CaMs) drugs
targeting the calcium-sensing receptors on
the PTG, have been marketed woldwide.
Cinacalcet (CNC) is a CaM endowed with
the unique prerogative to significantly

decrease serum PTH while aldecreasing serum calcium. Thus, one may attempt to speculate that CaMs may completely

replace vitamin D derivatives from the therapeutic arena. Uremic patients,

however, suffer from severe deprivation of biological vitamin D effects, that puts them in need of highly dosed vitamin D in order to both ameliorate their bone status and to

preserve their general and cardiovascular health. Thus, a combination therapy with PCLT, which has a significant patient-

survival advantage over CLT, and CNC

seems to be more appropriate than only-
one-drug based therapy for SBPT. Such a
combination will hopefully result in a better

control of SHPT, avoidance of cumbersome hypercalcemia and higher life expectancy for uremic patients than ever before.

Gal-Moscovici A, Sprague SM.
The role of calcimimetics in chronic

kidney disease. Kidney

International. Vol. 70(SUPPL. 104)(pp S68-S72), 2006.

SHPT develops in CKD as a consequence of impaired phosphate, calcium, and vitamin D homeostasis. Treatment strategies

directed to reduce the PTH concentrations
have included phosphate binders and active
vitamin D compounds. The over zealous use

of these agents may result in hypercalcemia or overt calcium overload. Severe SHPT, hyperphosphatemia, and total body calcium overload have been implicated in the

pathophysiology of skeletal and
extraskeletal calcification and associated
with increased morbidity and mortality
among the dialysis population. Cinacalcet,
the recently approved agent to lower PTH,
activates the calcium-sensing receptor of the
parathyroid gland amplifying the glands'
sensitivity to extracellular ionized calcium
concentration resulting in suppression of
PTH secretion. Several clinical studies
conducted in dialysis patients, have shown
that cinacalcet in doses from 30 to 180
mg/day, significantly reduce PTH

concentrations while simultaneously

lowering calcium and phosphate levels. Respective to the National Kidney
Foundation-Kidney Disease Outcomes and Quality Initiative (NKF-K/DOQI)

recommended targets for bone and mineral metabolism, 41% of cinacalcet-treated

patients achieved both PTH and calcium-
phosphorus targets. The ability of cinacalcet to reduce PTH secretion, along with

reductions in the serum calcium,

phosphorus, and calcium-phosphate product provide an alternative to the traditional

treatment paradigm, and should be a

welcomed addition to our therapeutic
strategy in the management of SHPT.
Lindberg JS.

Calcimimetics: A new tool for management of

hyperparathyroidism and renal osteodystrophy in patients with chronic kidney disease. Kidney International. Vol. 67(SUPPL. 95)(pp S-33-S-36), 2005.

Epidemiologic, clinical, and basic scientific studies led to an explosion in our

understanding of disorders of mineral
metabolism in the CKD patient. These
advances are not always translated into

improved care of renal osteodystrophy in CKD-5 patients. The introduction of a new class of drugs, calcimimetics, allows

improved control of abnormal
calcium/phosphorus metabolism. The
calcimimetics compliment, rather than
replace, current treatment options for SHPT in the chronic disease patient.
Ogata H, Koiwa F, Ito H, et al.
Therapeutic strategies for

secondary hyperparathyroidism in dialysis patients. Therapeutic

Apheresis & Dialysis. Vol. 10(4)(pp 355-363), 2006.

SHPT leads not only to bone disorders, but also cardiovascular complications in long-

term dialysis patients. Conventional

treatment with calcium (Ca) supplement, phosphate (P) binders and active vitamin D analogs lead in part to amelioration of

SHPT, but are simultaneously associated
with unacceptable side-effects, including
hypercalcemia, hyperphosphatemia, and
increased calcium-phosphate products,

which are the risk factors for cardiovascular disease in dialysis patients. Conventional treatment has been unable to facilitate the attainment of optimal management of SHPT proposed in the K/DOQI guidelines.

Cinacalcet HCl (cinacalcet), a novel
calcimimetic compound, restores the

sensitivity of the Ca-sensing receptor in

parathyroid cells, and decreases serum PTH without introducing hypercalcemia or
hyperphosphatemia. Cinacalcet treatment
enables a significant number of patients to achieve the K/DOQI guideline. Based on
experimental data, calcimimetics could
ameliorate cardiovascular calcification and remodeling in uremic rats with SHPT.
Clinical trials have shown that cinacalcet
significantly reduced the risks of

parathyroidectomy, fracture and

cardiovascular hospitalization among long-
term dialysis patients with SHPT.

Parathyroid intervention therapy

(parathyroidectomy and percutaneous direct injection) is ala useful alternative. In the

present article, we review novel therapeutic strategies for SHPT.

Ix JH, Quarles LD, Chertow GM.
Guidelines for disorders of mineral

metabolism and secondary

hyperparathyroidism should not yet
be modified. Nature Clinical Practice
Nephrology. Vol. 2(6)(pp 337-339),

This brief article is a response to the article by Monge et al. on page 326 entitled

Reappraisal of 2003 NKF-K/DOQI guidelines for management of

hyperparathyroidism in CKD patients. We

contend that there is insufficient evidence to

support the changes to clinical practice and clinical practice guidelines proposed by

Monge and colleagues. We recommend that
clinical trials be conducted to resolve these
points of contention and other critical issues
in the management of disorders of mineral
metabolism in CKD, including SHPT. The
focus should be on evaluating the effects of
alternative strategies on survival, as well as
clinical manifestations of cardiovascular and
bone disease.
Shahapuni I, Monge M, Oprisiu R, et al.
Drug insight: Renal indications of

calcimimetics. Nature Clinical Practice Nephrology. Vol. 2(6)(pp 316-325), 2006.

Calcimimetics suppress the secretion of PTH by sensitizing the parathyroid calcium receptor to serum calcium. Cinacalcet

(Sensipar/Mimpara, Amgen Inc., Thousand Oaks, CA), the first-in-class calcimimetic agent approved for treatment of SHPT in dialysis patients, is, in association with

higher dose of a calcium-based oral
phosphate binder, a well-tolerated and

effective alternative to standard treatments

such as vitamin D derivatives in association
with a non-calcium-based oral phosphate
binder. Here, we present an overview of

evidence in support of this assertion. We extend our discussion to encompass other indications for calcimimetics - SHPT in

predialysis CKD patients, hypercalcemic
hyperparathyroidism in renal transplant

recipients, primary hyperparathyroidism, and hypercalcemia associated with parathyroid carcinoma - as well as providing guidance on optimal usage of this drug.


Cinacalcet. Secondary

hyperparathyroidism: Where are the clinical data? Prescrire International. Vol. 15(83)(pp 90-93), 2006.

Patients who require dialysis for CRF

develop phosphocalcium metabolic

disorders that often lead to SHPT. Standard treatment consists of a phosphate chelator and vitamin D, along with the use of an

appropriate calcium concentration in the
dialysis bath, but is difficult to manage.
Parathyroid cancer is a rare malignancy

frequently associated with hypercalcaemia. Cinacalcet is a calcimimetic agent that

reduces the parathormone level. Clinical
evaluation includes more than a dozen
dose-finding studies and clinical trials. The
optimal dose seems to range from 30 to 180
mg/day and varies widely from one patient
to another. 3 double- blind placebo-
controlled trials, lasting for a maximum of
one year and involving a total of 1136
dialysis patients with CRF, showed no
improvement in quality of life with cinacalcet.
The target parathormone level was reached
by 40% of patients on cinacalcet versus 5%
of patients on placebo, while the effects of
cinacalcet on calcium levels (-7%) and
phosphate levels (-8%) were modest. No
impact on bone complications is mentioned
in available reports. The assessment of
treatment of parathyroid cancer is limited to
one ongoing non comparative trial involving

21 patients. * During clinical trials, 11% of

dialysis patients had low parathormone
levels, creating a risk of adynamic bone

disease and fractures, but available data are sparse. Two-thirds of patients receiving

cinacalcet have episodes of hypocalcaemia, which may in part account for reports of

seizures (1.4% of patients), nausea (31%) and vomiting (27%). Many adverse effects seen in animal studies have not been

adequately investigated in the clinical
setting, such as an increase in the QT
interval, thyroid disorders, and sexual

dysfunction. Cinacalcet is a powerful CYP 2D6 inhibitor and is almetabolised by

isoenzymes CYP 3A4 and CYP 1A2, creating an increased risk of drug

interactions. In practice, treatment with

cinacalcet seems difficult to manage and to
provide only limited benefits. Available
assessment reports leave many questions
unanswered, and this is a further reason not
to use this product outside of clinical trials,
either after failure of phosphate chelator and
vitamin D therapy (especially as an
alternative to surgery) or in parathyroid
Strippoli GFM, Palmer S, Tong A, et al.
Meta-Analysis of Biochemical and

Patient-Level Effects of

Calcimimetic Therapy. American Journal of Kidney Diseases. Vol. 47(5) (pp 715-726), 2006.

Background: Many randomized trials have

now evaluated the effects of calcimimetics in
patients with CKD and SHPT on standard
therapy with vitamin D and/or phosphate

binders. We conducted a meta-analysis to evaluate outcomes of therapy with these novel agents. Methods: MEDLINE,

EMBASE, the Cochrane Controlled Trials
Register, and conference proceedings were
searched for randomized controlled trials
evaluating any calcimimetic against placebo
or another agent in predialysis or dialysis
patients with CKD. Data were extracted for
all relevant patient-centered and surrogate
outcomes. Analysis was by means of a

random-effects model, and results are

expressed as relative risk or weighted mean
difference (WMD) with 95% confidence
intervals (CIs). Results: Eight trials (1,429
patients) were identified that compared a
calcimimetic agent plus standard therapy
with placebo plus standard therapy. End-of-
treatment values for PTH (4 trials; 1,278
patients; WMD, -290.49 pg/mL; 95% CI, -
359.91 to -221.07), serum calcium (3 trials;
1,201 patients; WMD, -0.85 mg/dL; 95% CI,

-1.14 to -0.56), serum phosphorus (3 trials;

1,195 patients; WMD, -0.29 mg/dL; 95% CI,

-0.50 to -0.08), and calcium-phosphate

product (3 trials; 1,194 patients; WMD, -7.90
mg2/dL2; 95% CI, -10.25 to -5.54) were
significantly lower with calcimimetic therapy
compared with placebo. No significant
effects on patient-based end points were
shown. Conclusion: Calcimimetic treatment
of patients with SHPT leads to significant
improvements in biochemical parameters
that observational studies have associated
with increased mortality, cardiovascular risk,
and osteitis fibrosa, but patient-based
benefits have not yet been shown. For
patients with SHPT, the benefits of
calcimimetics over standard therapy remain
uncertain until additional randomized trials
become available.
Reichel H.

Current treatment options in secondary renal

hyperparathyroidism. Nephrology Dialysis Transplantation. Vol.

21(1)(pp 23-28), 2006. No abstract available.

Goodman WG.

Calcimimetics: A remedy for all problems of excess parathyroid hormone activity in chronic kidney disease? Current Opinion in

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