Chronic Kidney Disease-Mineral Bone Disease

Agenda
Overview.
Pathogenesis.
Clinical Features.
KDIGO Diagnosis Guidelines of CKD-MBD.
Laboratory Target Levels.
Treatment of CKD-MBD.
Treatment Failure and Surgical Intervention.
KDIGO Treatment Guidelines.
Conclusion.
Waleed El-Refaey CKD-MBD 21/2/2016

Overview
• As kidney function declines in chronic kidney disease
(CKD), there is a progressive deterioration in mineral
homeostasis, with a disruption of normal serum and
tissue concentrations of phosphorus and calcium, and
changes in circulating levels of hormones.
• These include parathyroid hormone (PTH), 25-
hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D
(1,25(OH)2D), fibroblast growth factor-23 (FGF-23),
and growth hormone.
Introduction and definition of CKD-MBD and the development of the guideline
statements. Kidney Int 2009; 76:S3.

Overview
• Beginning in CKD stage 3, the ability of the kidneys to
appropriately excrete a phosphate load is diminished,
leading to hyperphosphatemia, elevated PTH, and
decreased 1,25(OH)2D with associated elevations in
the levels of FGF-23.
• The kidney fails to respond adequately to PTH, which
normally promotes phosphaturia and calcium
reabsorption, or to FGF-23, which also enhances
phosphate excretion.

Overview
• The mineral and endocrine functions disrupted in CKD
are critically important in the regulation of both initial
bone formation during growth (bone modeling) and
bone structure and function during adulthood (bone
remodeling).
• Numerous cohort studies have shown associations
between disorders of mineral metabolism, fractures
and cardiovascular disease (the leading cause of death
in patients at all stages of CKD).

Overview
KDIGO defined CKD-MBD as a systemic disorder of
mineral and bone metabolism due to CKD,
manifested by either one or a combination of the
following three components:
●Abnormalities of calcium, phosphorus, PTH, or
vitamin D metabolism.
●Abnormalities in bone turnover, mineralization,
volume linear growth, or strength.
●Extraskeletal calcification.

Pathogenesis
• The pathophysiology of this disorder is complex
and involves a number of feedback loops
between the kidney, bone, intestine, parathyroid
glands and the vasculature.
• The main goal of this system is maintenance of
calcium and phosphorus balance, often at the
expense of abnormalities in other components of
the system.
Fang Y, Ginsberg C, Sugatani T, et al. Early chronic kidney disease-mineral bone
disorder stimulates vascular calcification. Kidney Int 2014; 85:142.
.

Pathogenesis
1. ABNORMALITIES OF CALCIUM, PHOSPHORUS, PTH,
AND VITAMIN D METABOLISM.
2. ABNORMALITIES IN BONE TURNOVER,
MINERALIZATION, VOLUME LINEAR GROWTH, OR
STRENGTH.
3. EXTRASKELETAL CALCIFICATION.
Extraskeletal
Calcification

Pathogenesis
PLAYERS
CKD-MBD is A State of Target Organs Resistance In The Face
of Positive and Negative Feedback Loops.
PTH
FGF-23

Pathogenesis

Pathogenesis
1-Elevated PTH:
• Secondary hyperparathyroidism (SHPT) begins early in
the course of CKD, and the prevalence increases as kidney
function declines (eGFR <60 mL/min per 1.73 m2).
• The main abnormalities that contribute to the
pathogenesis of SHPT are:
- PO4 retention - Decreased iCa.
- Decreased calcitriol. - Increased FGF-23.
- The reduced expression of vitamin D receptors (VDRs),
calcium-sensing receptors (CaSRs), fibroblast growth factor
receptors, and klotho in the parathyroid glands.
Cunningham J, Locatelli F, Rodriguez M. Secondary hyperparathyroidism: pathogenesis, disease
progression, and therapeutic options. Clin J Am Soc Nephrol 2011; 6:913.

Pathogenesis
• Skeletal resistance to the calcemic action of PTH is
primarily due to downregulation of PTH receptors induced
by the high circulating PTH concentrations.
• Although both calcitriol deficiency and
hyperphosphatemia may play a contributory role.
• Tertiary hyperparathyroidism reflects severe parathyroid
hyperplasia, with autonomous secretion of PTH that is no
longer adequately responsive to the plasma calcium
concentration.
Rodriguez M, Felsenfeld AJ, Llach F. Calcemic response to parathyroid hormone in renal
failure: role of calcitriol and the effect of parathyroidectomy. Kidney Int 1991; 40:1063.

Pathogenesis
• In patients with tertiary hyperparathyroidism, decreased
expression of CaSR and VDRs results in a lack of
suppression of PTH by increasing calcium or vitamin D
analogs.
• Nodular parathyroid glands do not undergo involution,
despite resolution of some of the triggering mechanisms.
• This is best illustrated by the high PTH concentrations and
hypercalcemia that may persist in CKD patients after
receiving renal transplant.
Grzela T, Chudzinski W, Lasiecka Z, et al. The calcium-sensing receptor and vitamin D
receptor expression in tertiary hyperparathyroidism. Int J Mol Med 2006; 17:779.

Pathogenesis
2-Hyperphosphatemia:
• Three major theories have been proposed to explain how
phosphate retention initially promotes PTH release:
 The induction of hypocalcemia.
 Decreased formation or activity of calcitriol.
 Increased PTH gene expression.
• The initial elevation in PTH secretion is appropriate since
the ensuing increase in phosphate excretion lowers the
plasma phosphate concentration toward normal.
Llach F. Secondary hyperparathyroidism in renal failure: the trade-off hypothesis
revisited. Am J Kidney Dis 1995; 25:663.

Pathogenesis
2-Hyperphosphatemia:
• In ESRD patients, PTH inhibits proximal tubule phosphate
reabsorption from the normal 80 to 95% to as low as 15%
of the filtered phosphate.
• Continued PTH-induced release of phosphate from bone
can actually exacerbate the hyperphosphatemia.
• Hyperparathyroidism also tends to correct both the
hypocalcemia (by increasing bone resorption) and the
calcitriol deficiency (by stimulating the 1-hydroxylation of
calcidiol [25-hydroxyvitamin D] in the proximal tubule).
Cunningham J, Locatelli F, Rodriguez M. Secondary hyperparathyroidism: pathogenesis,
disease progression, and therapeutic options. Clin J Am Soc Nephrol 2011; 6:913.

Pathogenesis
3-Decreased calcitriol activity:
• Plasma calcitriol concentrations generally fall below
normal when the GFR is <60 mL/min per 1.73 m2.
• Initially, the decline in calcitriol concentration is likely to
be due to the increase in FGF-23 concentration (inhibiting 1-
alpha-hydroxylase activity) rather than the loss of functioning
renal mass.
• However, in advanced CKD, hyperphosphatemia and loss
of renal mass may also contribute to the decline in
calcitriol synthesis.
Gutierrez O, Isakova T, Rhee E, et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but
accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 2005; 16:2205.

Pathogenesis
• Low calcitriol concentrations increase PTH secretion by
indirect and direct mechanisms.
• Indirect: effects on PTH are achieved through decreased
intestinal absorption of calcium and calcium release from
bone, both of which promote the development of
hypocalcemia, which stimulates PTH secretion.
Denda M, Finch J, Brown AJ, et al. 1,25-dihydroxyvitamin D3 and 22-oxacalcitriol prevent the
decrease in vitamin D receptor content in the parathyroid glands of uremic rats.
Kidney Int 1996; 50:34.

Pathogenesis
• Direct: Calcitriol normally acts on the VDR in the
parathyroid gland to suppress PTH transcription, but not
PTH secretion.
• A decrease in calcitriol concentrations also lowers the
number of VDRs in the parathyroid cells, both promote
parathyroid chief cell hyperplasia and nodule formation.
Denda M, Finch J, Brown AJ, et al. 1,25-dihydroxyvitamin D3 and 22-oxacalcitriol prevent the
decrease in vitamin D receptor content in the parathyroid glands of uremic rats.
Kidney Int 1996; 50:34.

Pathogenesis
4-Hypocalcemia and calcium-sensing receptor:
• Calcium is a major regulator of PTH secretion.
• Minute changes in the serum ionized calcium are sensed
by a specific membrane receptor, the CaSR, which is highly
expressed on the surface of the chief cells of the
parathyroid glands, tightly regulating PTH secretion.
Rodriguez M, Nemeth E, Martin D. The calcium-sensing receptor: a key factor in the
pathogenesis of secondary hyperparathyroidism. Am J Physiol Renal Physiol 2005; 288:F253.

Pathogenesis
• Total serum calcium concentration decreases during the
course of CKD due to:
1. phosphate retention,
2. decreased calcitriol concentration, and
3. resistance to the calcemic actions of PTH on bone.

Pathogenesis
• In CKD, the number of CaSRs may be reduced in
hypertrophied parathyroid glands, particularly in areas of
nodular hypertrophy.
• The change in receptor number can lead to inadequate
suppression of PTH secretion by calcium, resulting in
inappropriately high PTH concentrations in the setting of
normal or high calcium concentrations.
Yano S, Sugimoto T, Tsukamoto T, et al. Association of decreased calcium-sensing receptor expression
with proliferation of parathyroid cells in secondary hyperparathyroidism. Kidney Int 2000; 58:1980.

Pathogenesis
5-Fibroblast growth factor-23:
• FGF-23 is a circulating peptide that plays a key role in the
control of serum phosphate concentrations.
• FGF-23 is secreted by bone osteocytes and osteoblasts in
response to calcitriol, increased dietary phosphate load,
PTH, and calcium.
• Klotho, a transmembrane protein produced by osteocytes,
is required for FGF-23 receptor activation.
Liu S, Quarles LD. How fibroblast growth factor 23 works. J Am Soc Nephrol 2007; 18:1637.

Pathogenesis
• FGF-23's primary function is to maintain normal serum
phosphate concentration by reducing renal phosphate
reabsorption and by reducing intestinal phosphate
absorption through decreased calcitriol production.
• In renal proximal tubular cells, FGF-23 binds to the FGF
receptor (FGFR) and its coreceptor, klotho, causing
inhibition of the expression of the Na/Pi IIa cotransporter .
Miyamoto K, Ito M, Tatsumi S, et al. New aspect of renal phosphate reabsorption: the type IIc
sodium-dependent phosphate transporter. Am J Nephrol 2007; 27:503.

Pathogenesis
• FGF-23 also suppresses PTH secretion by the parathyroid
gland.
• However, among CKD patients, the presence of high PTH
concentrations, despite high FGF-23 concentrations,
suggests that the parathyroid is relatively resistant to the
elevated concentrations of FGF-23 in uremia.
• This may be related to the markedly decreased expression
of FGFR 1 and klotho protein in the hyperplastic
parathyroid gland.
Komaba H, Goto S, Fujii H, et al. Depressed expression of Klotho and FGF receptor 1 in
hyperplastic parathyroid glands from uremic patients. Kidney Int 2010; 77:232.

Pathogenesis
• Definition of renal osteodystrophy
-Renal osteodystrophy is an alteration of bone morphology in
patients with CKD.
-It is one measure of the skeletal component of the systemic
disorder of CKD–MBD that is quantifiable by
histomorphometry of bone biopsy.
• Kidney Disease: Improving Global Outcomes (KDIGO)
recommended that three parameters be used to assess
bone pathology. These parameters include bone turnover,
mineralization, and volume (TMV system).
Introduction and definition of CKD-MBD and the development of the guideline statements.
Kidney Int 2009; 76:S3.

Pathogenesis
TMV characteristics of the major CKD-related bone diseases
are as follows:
• Osteitis fibrosa cystica is characterized by high bone
turnover due to secondary hyperparathyroidism.
• Adynamic bone disease is characterized by low bone
turnover. Most current cases result from excessive
suppression of the parathyroid glands due to increased
and earlier use of vitamin D analogs and calcium-
containing phosphate binders. This represents the major
bone lesion in peritoneal dialysis and hemodialysis
patients.

Pathogenesis
• Osteomalacia is characterized by low bone turnover in
combination with abnormal mineralization.
 The incidence of osteomalacia has decreased with the
abandonment of aluminum-based phosphate binders and
the introduction of more efficient techniques for
treatment of water used in preparing the dialysate.
Moe SM, Drüeke TB. A bridge to improving healthcare outcomes and quality of life. Am J
Kidney Dis 2004; 43:552..

Pathogenesis
• Mixed uremic osteodystrophy is characterized by either
high or low bone turnover and by abnormal
mineralization.
• A fifth, but different, type of uremic bone disease, with a
unique pathogenesis, occurs in patients on long-term
dialysis and presents as bone cysts, which result from
beta2-microglobulin-associated amyloid deposits.

Pathogenesis
• The prevalence of high-turnover bone disease (osteitis
fibrosa cystica) among dialysis patients has markedly
decreased, while non-aluminum-induced low-turnover
bone disease (adynamic bone disease) has increased, with
variations based in part upon geographic region
evaluated.
Martin KJ, Olgaard K, Coburn JW, et al. Diagnosis, assessment, and treatment of bone turnover
abnormalities in renal osteodystrophy. Am J Kidney Dis 2004; 43:558.

Pathogenesis
• 56 dialysis patients from Thailand followed between 1996
and 1998, bone biopsy in combination with other analyses
revealed that low-turnover (adynamic) bone disease was
present in 41%, and high-turnover (osteitis fibrosa cystica)
disease was present in 29% of patients.

Pathogenesis
• In this study, bone biopsies revealed low-turnover disease
in 59% of 119 hemodialysis patients.
• This high prevalence was observed despite treating most
patients in accordance with K/DOQI guidelines and having
serum mineral parameters within recommended ranges.

Pathogenesis
• Extraskeletal calcification is common in patients with CKD,
particularly those on dialysis, and it contributes to
cardiovascular mortality.
• VC results from both passive and active processes
implicating a variety of mediator and effector proteins.
London GM, Guérin AP, Marchais SJ, et al. Arterial media calcification in end-stage renal disease:
impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 2003; 18:1731.
.
Extraskeletal
Calcification

Pathogenesis
• Calciphylaxis (Calcific uremic arteriolopathy) is a rare and
serious disorder characterized by systemic medial
calcification of the arterioles that leads to ischemia and
subcutaneous necrosis.
• Calciphylaxis most commonly occurs in patients with ESRD
who are on hemodialysis or who have recently received a
renal transplant, but may also occur in non-ESRD patients
Fine A, Zacharias J. Calciphylaxis is usually non-ulcerating: risk factors, outcome and therapy.
Kidney Int 2002; 61:2210.
.
Extraskeletal
Calcification

Extraskeletal
Calcification
calcific uremic arteriolopathy
calcific Aortic valve
Pathogenesis

Pathogenesis
Extraskeletal
Calcification

Extraskeletal
CalcificationPathogenesis

Clinical Features
Piraino B, Chen T, Cooperstein L, et al. Fractures and vertebral bone mineral density in patients
with renal osteodystrophy. Clin Nephrol 1988; 30:57.
.
.
Bone Disease
• Although frequently asymptomatic, this disorder can
result in weakness, fractures, bone and muscle pain,
and avascular necrosis (especially in dialysis).
• Bone pain is the predominant symptom among
patients with adynamic bone disease. Pain results from
low bone turnover, which in turn leads to an impaired
ability to repair microdamage.

Clinical Features
Raggi P, Boulay A, Chasan-Taber S, et al. Cardiac calcification in adult hemodialysis patients. A link
between end-stage renal disease and cardiovascular disease? J Am Coll Cardiol 2002; 39:695.
Vascular Calcifications
• Both intimal and medial calcification have been closely
associated with increased mortality.
• Intimal calcification is a marker for an advanced
atherosclerotic plaque and has been used for
screening for coronary disease.
• Medial calcification is strongly associated with loss of
arterial distensibility and thereby systolic
hypertension, left ventricular hypertrophy, and
impaired coronary artery perfusion.

Diagnosis of CKD-MBD

Diagnosis of CKD–MBD: biochemical abnormalities

Diagnosis of CKD–MBD: bone

Diagnosis of CKD–MBD: vascular calcification

Cardiovascular calcification
Aortic Calcifications
Digital Arteries
Calcification

Laboratory Target levels
Calcium and phosphorus levels
For those with stage 3 & 4 CKD, the following treatment
goals were recommended:
●Serum level of phosphorus should be maintained
between 2.7 mg/dL - 4.6 mg/dL.
●The serum levels of corrected total calcium should be
maintained within the "normal" range for the laboratory
used
●The serum calcium-phosphorus product should be
maintained at <55 mg2/dL2

Calcium and phosphate levels
For those with stage 5 & 5D CKD, the following are
recommended:
●Serum levels of phosphate should be maintained
between 3.5 and 5.5 mg/dL
●Serum levels of corrected total calcium should be
maintained between 8.4 and 9.5 mg/dL
●The serum calcium-phosphate product should be
maintained at <55 mg2/dL2

Parathyroid hormone levels
• Stage 3 CKD: 35 to 70 pg/mL.
• Stage 4 CKD: 70 to 110 pg/mL.
• Stage 5 & 5D CKD: 150 to 300 pg/mL

• Calcium and phosphorus levels
For patients with stage 3 to 5D CKD, the KDIGO working
group suggest:
● Maintaining serum calcium and phosphorus in the
normal range.
● Evaluating individual values of serum calcium and
phosphorus together, rather than the calcium-
phosphorus product.
• Parathyroid hormone levels
In CKD 5D it is recommended to maintain PTH
level in the range of approximately 2-9 times
the upper limit of normal for the assay.

Treatment
The treatment of patients with CKD-MBD varies
depending upon the prevailing metabolic
abnormality, the characteristic bone disease, and the
severity of underlying kidney dysfunction.

Treatment
1) Dietary phosphate restriction and phosphate binders:
Dietary restriction
• Limiting phosphate intake is difficult to achieve unless
protein intake is limited, which could contribute to protein
malnutrition without resulting in a decreased rate of
progression of renal dysfunction.
• Among patients with PTH or serum phosphate levels greater
than target levels, it is suggested to restrict dietary
phosphate intake to 900 mg/day.
Llach F, Massry SG. On the mechanism of secondary hyperparathyroidism in moderate
renal insufficiency. J Clin Endocrinol Metab 1985; 61:601.
.

Treatment
Dietary restriction
• Dietary phosphorus should be derived from sources of high
biologic value, such as meats and eggs. Phosphorus from
food additives should also be estimated and restricted.
• A decrease in serum PTH levels plus improvements in bone
histology with dietary phosphate restriction among patients
with mild CKD was noted.
Llach F, Massry SG. On the mechanism of secondary hyperparathyroidism in moderate
renal insufficiency. J Clin Endocrinol Metab 1985; 61:601.
.

Treatment
BMC Nephrology
2015, 16:9

Treatment
Phosphate binders
• However, hyperparathyroidism and hyperphosphatemia are
unlikely to be prevented by dietary phosphorus restriction
alone in the setting of progressive renal insufficiency.
• Thus, most patients will require the addition of a phosphate
binder (calcium- or non-calcium-based).

Treatment
Phosphate binders
Sucroferric oxyhydroxide (Velphoro) is a chewable
phosphate binder that has received approval from the US
Food and Drug Administration (FDA) and is now available
in the United States for treatment of hyperphosphatemia
in patients with estimated glomerular filtration rate
(eGFR) <15 mL/min/1.73 m2.
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Dr
ugDetails (Accessed on February 28, 2014

Treatment
• Various doses of sucroferric oxyhydroxide were
compared with sevelamer in a randomized,
multicenter, open-label study that included 154
hemodialysis patients.

Treatment
• At six weeks, sucroferric oxyhydroxide at doses of 5,
7.5, 10, and 12.5 g/day (which provided 1.0, 1.5, 2.0,
and 2.5 g/day elemental iron), but not 1.25 g/day
(which provided 250 mg elemental iron), decreased
the serum phosphorus.
• Doses of 5 and 7.5 g/day produced decreases in serum
phosphorus similar to sevelamer dosed at 4.8 g/day.
There was no difference between sucroferric
oxyhydroxide and sevelamer in the rate of adverse
events (61 versus 58 percent, respectively).

Treatment
• In a phase-III study of dialysis patients, sucroferric
oxyhydroxide was noninferior to sevelamer in reducing
serum phosphate and was associated with a lower pill
burden (three tablets versus eight of sevelamer).
• Although adherence was better for sucroferric
oxyhydroxide, more patients stopped taking sucroferric
oxyhydroxide because of adverse effects (15.7 versus
6.6 percent for sevelamer).

Treatment
• The most common adverse effects were
gastrointestinal (diarrhea, nausea, abnormal product
taste, constipation, and vomiting).
• The starting dose of sucroferric oxyhydroxide is 2.5 g
(500 mg elemental iron) three times daily with meals.

Treatment
Phosphate binders
Dosing and administration
• For all phosphate buffers, the lowest dose that is
effective should be used with meals.
• If calcium-containing buffers are selected, the amount
of elemental calcium contained in the phosphate
binder should not exceed 1500 mg per day.

Treatment
Phosphate binders
Choice of agent:
● Hypocalcemic patients: we generally use calcium-containing
phosphate binders. Hypocalcemic patients are less likely to
become hypercalcemic with calcium-containing binders.
● Normocalcemic patients: we generally use calcium-
containing phosphate binders for normocalcemic patients who
have no evidence of vascular calcification or adynamic bone
disease.

Treatment
Phosphate binders
Choice of agent:
● Hypercalcemic patients: we generally use noncalcium-
containing phosphate binders for hypercalcemic patients.
● Patients with adynamic bone disease or vascular
calcification: we generally use noncalcium-containing
phosphate binders for these patients.

Treatment
2) Vitamin D, calcitriol, and vitamin D analogs:
Terminology
• Vitamin D includes both vitamin D2 (ergocalciferol) and
vitamin D3 (cholecalciferol).
• Vitamin D derivatives include:
1. the naturally occurring vitamin D metabolite, calcitriol
(1,25-dihydroxycholecalciferol [1,25(OH)2D]), and
2. synthetic vitamin D analogs such as doxercalciferol,
paricalcitol, alfacalcidol, falecalcitriol, and 22-oxacalcitriol
(or maxacalcitol [1,25 dihydroxy-22-oxavitamin D3]).

Treatment
Vitamin D supplementation
(ergocalciferol and cholecalciferol) are not usually given to
dialysis patients, despite a high prevalence of nutritional
vitamin D deficiency, as defined by 25(OH)D levels <30 ng/mL.

Treatment
• The effect of cholecalciferol 25,000 international units per
week was compared with placebo among 55 25(OH)D-
deficient hemodialysis patients in a double-blind,
randomized trial.

Treatment
• At 13 weeks, compared with placebo, more cholecalciferol-
treated patients had normal levels of 25(OH)D (7.4 versus
61.5 percent, respectively); 1,25(OH)2D (12 versus 54
percent, respectively); and calcium (44 versus 77 percent,
respectively).

Treatment
• In a placebo-controlled, multicenter trial, 105 hemodialysis
patients with 25(OH)D concentrations ≤32 ng/mL were
randomly assigned to receive oral ergocalciferol 50,000
international units either weekly or monthly, or receive
placebo.

Treatment
• At 12 weeks, vitamin D sufficiency (defined as 25(OH)D
concentration >32 ng/mL) was achieved in 91, 66, and 35
percent of patients administered weekly ergocalciferol,
monthly ergocalciferol, or placebo, respectively. There was
no difference among groups in serum ca, PO4, or PTH.

Treatment
Calcitriol and synthetic vitamin D analogs
• Most dialysis patients with increased plasma iPTH levels
(>300 pg/mL) require treatment with calcitriol or vitamin D
analogs.
• Because calcitriol increases gastrointestinal absorption of
calcium and phosphate, more selective vitamin D analogs
have been developed that may reduce the risk of
hypercalcemia and hyperphosphatemia.

Treatment
Choice of agent
• There are six active (ie, 1-hydroxylated) vitamin D
derivatives currently available. These include calcitriol and
five synthetic vitamin D analogs including paricalcitol,
doxercalciferol, alfacalcidol (not available in the United
States), falecalcitriol (not available in the United States), and
22-oxacalcitriol (not available in the United States).
• Paricalcitol and doxercalciferol are predominantly used in
the United States,
• whereas calcitriol and alfacalcidol are more frequently used
in other countries.

Treatment
Choice of agent
• This prospective, randomized trial has directly compared
calcitriol with a synthetic vitamin D analog (paricalcitol).
• No significant difference was observed in the primary
endpoint (lowering of PTH values) and secondary endpoints
(the single incidence of hypercalcemia or elevated Ca x P
product).

Treatment
There is no convincing evidence, including the result from the
one large, prospective, randomized comparative trial,
supporting the use of a specific derivative of the six analogs
currently available over another.

Treatment
Dose
• The optimal dose of calcitriol or synthetic vitamin D analogs
has not been established and depends upon the concurrent
use of calcimimetics, the dose of concomitant calcium-
based phosphate binders, and the potency/selectivity of the
vitamin D analog.
• The current approach has been empiric, with the goal of
administering increasing doses of vitamin D analogs, along
with phosphate binders, to achieve target plasma levels of
Ca, PO4 and PTH.

Treatment
Dose
• The continued up-titration with active vitamin D to
supraphysiologic levels, if necessary to suppress PTH, is
often successful in lowering PTH, but frequently achieves
this one goal at the expense of hypercalcemia and
hyperphosphatemia.

Treatment
Dose

Treatment
Dose
• Patients who are responsive to calcitriol supplementation
typically show significant reductions in plasma PTH
concentrations during the first three to six months of
therapy.
• In general, the dose of calcitriol or synthetic vitamin D
analogs should be reduced by 50% or stopped with plasma
calcium levels at the upper normal range or with mild
hypercalcemia (between 9.5 and 10.2 mg/dL).
• Calcitriol or the synthetic analog should be discontinued for
frank hypercalcemia (>10.2 mg/dL).

Treatment
Contraindications
1- Calcitriol or synthetic vitamin D analogs should not be given
until the serum phosphorus concentration has been controlled
(<5.5 mg/dL) and the serum calcium is <9.5 mg/dL.
2- Low plasma PTH concentration, possibly <150 pg/mL,
because of the association with adynamic bone disease.
• Empiric observations suggest that somewhat higher than
normal PTH levels are required for normal bone formation
rates in patients with kidney disease, presumably due to the
end-organ resistance to PTH observed in uremia.

Treatment
Resistance
Up to one-half of patients with severe hyperparathyroidism
show little or no decline in plasma PTH levels with calcitriol
therapy. Limiting factors include:
1. large functioning gland mass with nodular hyperplasia
(marked reduction in calcitriol receptors ),
2. altered calcium sensitivity of parathyroid cells, and
3. failure of high-dose vitamin D derivatives because of
hypercalcemia and/or hyperphosphatemia.
Katoh N, Nakayama M, Shigematsu T, et al. Presence of sonographically detectable
parathyroid glands can predict resistance to oral pulsed-dose calcitriol treatment of
secondary hyperparathyroidism. Am J Kidney Dis 2000; 35:465.

Treatment
3) Calcimimetics:
• Calcimimetics are agents that increase the sensitivity of the
calcium-sensing receptor (CaSR) in the parathyroid gland to
calcium, regulating PTH secretion and the gland hyperplasia.
• Studies have found that the addition of cinacalcet to current
treatment regimens increases the percentage of patients
who are able to attain PTH, calcium, and phosphate target
levels.
Nemeth EF, Bennett SA. Tricking the parathyroid gland with novel calcimimetic agents.
Nephrol Dial Transplant 1998; 13:1923.

Treatment
3) Calcimimetics:

Treatment
3) Calcimimetics:
• The administration of a calcimimetic agent increases the
sensitivity of the receptor to extracellular calcium and can
lower PTH secretion from the parathyroid gland indirectly.
• Calcimimetic agents also mediate reductions in serum PTH
concentrations by directly decreasing PTH gene expression
and by increasing the VDR expression in the parathyroid
glands.

Treatment
3) Calcimimetics:
• In this large trial (which was the combination of three
phase-III studies), 1136 dialysis patients with iPTH levels of
>300 pg/mL were randomly assigned to traditional therapy
plus cinacalcet HCl or placebo for 26 weeks.
• To achieve the target iPTH levels of between 100 to 250
pg/mL, the dose was adjusted from 30 to 180 mg/day.

Treatment
3) Calcimimetics:
Compared with placebo, the following benefits with cinacalcet
in terms of achieving K/DOQI target levels were reported:
● A significant increase in the likelihood of achieving a mean iPTH
level of <300 pg/mL (56 versus 10%).
● Significantly more likely to achieve serum calcium levels between
8.4 to 9.5 mg/dL (42 versus 24%); serum phosphorus levels between
3.5 to 5.5 mg/dL (46 versus 33%); and a Ca x P product <55 mg2/dL2
(65 versus 36%).
● Compared with placebo, cinacalcet lowered the risk of
parathyroidectomy, fracture, and cardiovascular hospitalization.

Treatment
3) Calcimimetics:
Evaluation of Cinacalcet Hydrochloride Therapy to
Lower Cardiovascular Events [EVOLVE]
• In this trial, 3883 patients were randomly assigned to
receive cinacalcet or placebo in addition to conventional
therapy including phosphate binders and/or vitamin D.

Treatment
3) Calcimimetics:
Evaluation of Cinacalcet Hydrochloride Therapy to
Lower Cardiovascular Events [EVOLVE]
• At a median follow-up of less than two years, there was no
difference between groups in the primary composite
endpoint that included time until death or the first nonfatal
cardiovascular event (myocardial infarction, hospitalization for
unstable angina, heart failure, or a peripheral vascular event).
• Cinacalcet reduced the rate of parathyroidectomy by
approximately half.

Treatment
3) Calcimimetics:
• Indications: may be indicated in dialysis patients with PTH
levels >300 pg/mL who have serum calcium levels >8.4
mg/dL.
• Dose: Cinacalcet is initiated at a dose of 30 mg/day, with
stepwise increments to 60, 90, and 180 mg/day. The dose
can be increased every four weeks until goals are achieved.
• Contraindications: Cinacalcet should not be started if serum
calcium is <8.4 mg/dL. Frequent monitoring of plasma
calcium and PTH levels is needed.
Amgen Sensipar label prepares for off-label use in pre-dialysis population.
Pharmaceutical Approvals Monthly 2004; 9:28.

Treatment
Treatment of
Adynamic Bone Disease (ABD):
• The initial approach to treatment of adynamic bone
disease is to allow PTH secretion to rise.
• This can be achieved by:
1. decreasing the doses of calcium-based phosphate
binders,
2. using non-calcium-based phosphate binders;
3. decreasing or stopping active vitamin D analogs; and,
4. for patients on dialysis, possibly by using a low-
dialysate calcium concentration.

Treatment
Dialysate Calcium:

Treatment
Treatment failures include:
1. dialysis patients with tertiary hyperparathyroidism,
which is defined as elevated PTH levels and
spontaneous hypercalcemia or
2. patients with persistent and progressive elevations of
serum PTH that cannot be lowered to levels <300
pg/mL despite treatment with vitamin D analogs and
cinacalcet (180 mg/day).
Failure

Treatment
Treatment failure
Several interrelated factors are thought to be involved in
the pathogenesis of refractory hyperparathyroidism.
These include:
1. Delayed or inadequate therapy.
2. Persistent hyperphosphatemia.
3. An increase in parathyroid gland mass.
Failure

Treatment
Indications for surgery
• ESRD patients who have markedly elevated, medical
therapy-refractory PTH levels and related signs and
symptoms are generally referred for
parathyroidectomy.
• Parathyroidectomy should not be performed unless
high PTH levels (>800 pg/mL) have been documented.

Treatment
Indications for surgery
The following signs and symptoms warrant
parathyroidectomy in the setting of elevated PTH values in
the absence of another known etiology:
1. Severe hypercalcemia.
2. Progressive and debilitating hyperparathyroid bone
disease.
3. Refractory pruritus.
4. Progressive extraskeletal calcification or calciphylaxis.
5. Otherwise unexplained myopathy.

Treatment
Treatment of CKD–MBD targeted at lowering
high serum phosphorus and maintaining
serum calcium

Treatment
Treatment of abnormal PTH levels in CKD–MBD

Treatment
Treatment of bone with bisphosphonates, other
osteoporosis medications, and growth hormone

Treatment
Treatment options of Osteoprosis:
1. Bisphosphonates
2. Intermittent administration of 1–34 PTH
(teriparatide{Forteopen}): might be useful in
patients with surgical hypoparathyroidism and
adynamic bone disease.
3. Raloxifene {Ralox} is a selective estrogen receptor
modulator.

Conclusion
• Disorders of mineral and bone metabolism are
common sequelae of CKD, with Secondary
hyperparathyroidism encompassing most of the
biochemical abnormalities.
• There is an increased risk of all-cause and
cardiovascular mortality in patients with disorders of
mineral metabolism.
• Among dialysis patients with elevated PTH levels, a
stepped approach to the management of
hyperparathyroidism and bone mineral abnormalities
is recommended.

Conclusion
• This approach requires a complex balance of four
medications, namely calcium-containing binders, non-
calcium-containing binders, calcimimetics, and either
calcitriol or synthetic vitamin D analogs.
• Most current ABD cases result from excessive
suppression of the parathyroid glands due to
increased and earlier use of vitamin D analogs and
calcium-containing phosphate binders.
• Among patients with refractory hyperparathyroidism,
prompt parathyroidectomy is suggested.

Chronic Kidney Disease-Mineral Bone Disease

Chronic Kidney Disease-Mineral Bone Disease

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