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porter 2b (Npt2b)
䡩 Stimulated by calcitriol
1α-hydroxylase
PTH acvity FGF-23
Renal Handling
● Inorganic phosphorus is filtered by glomeruli, Increased Decreased
1,25(OH)2D 1,25(OH)2D
then 70%-80% is reabsorbed in proximal tubule
through the Npt2a cotransporter
● Npt2a is moved to or removed from the brush
increased renal
border to facilitate phosphorus reabsorption or phosphorus
excreon
excretion, respectively
● 20%-30% of filtered phosphorus is reabsorbed in
distal tubule
●
Figure 1. Regulation of serum phosphorus. A solid line indi-
Renal phosphorus excretion is sensitive to serum cates stimulation; a dashed line indicates inhibition. Abbrevia-
phosphorus levels; PTH and FGF-23 increase tions: 1,25(OH)2D3, calcitrol; FGF-23, fibroblast growth factor 23;
phosphorus excretion PTH, parathyroid hormone. Adapted with permission of Elsevier
●
from Moe SM, Sprague SM. Mineral bone disorders in chronic
Phosphorus depletion decreases its own excretion kidney disease. In: Brenner and Rector’s The Kidney. 8th ed.
Philadelphia, PA: WB Saunders Company; 2007:1784-1807.
Fibroblast Growth Factor 23
● Belongs to a group of molecules called phospha-
y PTH increases 1␣-hydroxylase and there-
tonins fore production of calcitriol, which in turn
䡩 Phosphatonins are hormones that regulate phos-
inhibits further PTH release
phorus excretion
y In contrast, FGF-23 inhibits 1␣-hydroxylase
䡩 Three phosphatonins have been identified:
and decreases calcitriol production, which
sFRP-4, MEPE, and FGF-23 (the most studied)
● Produced almost exclusively in osteocytes and
will inhibit FGF-23 secretion
䡩 Hypocalcemia stimulates PTH and therefore in
bone-lining cells, but also found in heart, liver,
low-calcium high-phosphorus states, the action
thyroid/parathyroid, intestine, and skeletal muscle
● FGF-23 receptor on the proximal tubule requires
of PTH predominates
䡩 In high-calcium high-phosphorus states, the
a coreceptor (klotho) for signal transduction
䡩 Klotho is found in the distal renal tubule and
action of FGF-23 predominates
parathyroid gland
䡩 Klotho is downregulated in aging and CKD Phosphorus, FGF-23, and PTH in CKD
● FGF-23 has the following actions
CKD and Phosphorus
䡩 Downregulates luminal sodium/phosphate
● Phosphorus homeostatic control is impaired at a
cotransporters in the proximal tubule, decreas-
ing phosphorus reabsorption and therefore in- glomerular filtration rate (GFR) as high as 60
creasing its excretion mL/min (well before frank hyperphosphatemia
䡩 Inhibits 1␣-hydroxylase (CYP27B1), decreas- develops)
ing the conversion of 25-hydroxyvitamin D
● As GFR decreases to ⬍60 mL/min, there is a
(25[OH]D) to 1,25-dihydoxyvitamin D gradual increase in serum phosphorus levels
● During this period, “normal” phosphorus levels
(1,25[OH]2D3; calcitriol)
䡩 Stimulates 24-hydroxylase (CYP24), leading to are maintained by continual increases in FGF-23
vitamin D degradation and PTH levels
䡩 Inhibits PTH secretion ● Eventually, this compensatory mechanism is over-
● FGF-23 gene expression in bone is stimulated by whelmed when GFR decreases to ⬍30 mL/min,
elevated phosphorus, PTH, and calcitriol levels, and measured serum phosphorus levels may
even in uremic animals increase to higher than the reference range
● Local bone proteins also regulate synthesis ● Hyperphosphatemia also leads to inhibition of
● Figure 1 shows the regulation of serum phospho- calcitriol synthesis, which stimulates further PTH
rus levels by PTH and FGF-23 production; together, these processes trigger sec-
䡩 Both FGF-23 and PTH lead to increased phos- ondary hyperparathyroidism in CKD to develop
phorus excretion ● Observational data suggest that hyperphos-
䡩 Regulatory feedback loops for both PTH and phatemia is connected to increased morbidity and
FGF-23 are dependent on calcitriol mortality (all cause and cardiovascular) in CKD
● In different analyses of patients with CKD stage 䡩 The rest is reabsorbed through transcellular
5D, the phosphorus level associated with in- pathways in the distal convoluted tubule, con-
creased mortality varies from ⬎5.5-⬎7 mg/dL necting tubule, and cortical collecting duct
● Even in the non-CKD population, serum phospho- through TRPV5 and TRPV6 calcium channels
rus level in the high-normal ranges is associated 䡩 TRPV6 predominates in the intestine, whereas
with increased risk of cardiovascular and all- TRPV5 predominates in the kidney
cause mortality ● Calcium-sensing receptor (CaSR)
● No interventional study has shown that decreas- 䡩 G-protein–coupled protein that binds calcium
ing phosphorus to a certain “target” level is to sense small changes in ionized calcium
associated with better outcomes levels; decreased ionized calcium stimulates
PTH secretion
CKD, FGF-23, and PTH 䡩 CaSR is expressed in parathyroid cells, thyroid
● In early CKD, FGF-23 levels start increasing C cells, intestine, kidney, and likely bone
● This coincides with its effects on increasing 䡩 In the kidney, CaSR is in mesangial cells and
phosphorus excretion, decreasing calcitriol syn- throughout tubules
thesis (thereby stimulating PTH), and facilitating y Activation of CaSR on the thick ascending limb
the development of secondary hyperparathyroid- decreases paracellular calcium reabsorption
ism y Upregulation of CaSR in hypercalcemia inhibits
● In humans, FGF-23 and PTH levels appear to antidiuretic hormone (ADH)-induced free water
increase as GFR decreases reabsorption, leading to urinary dilution
● Dialysis patients have FGF-23 levels that may be y Renal effects of CaSR are both dependent
up to 1,000-fold greater than in non-CKD popula- and independent of PTH
tions
● In dialysis patients, serum FGF-23 levels are
Calcium Abnormalities in CKD
associated with mortality even when adjusted for
serum phosphorus levels and can predict the ● In CKD stages 2-3, serum calcium levels are
development of secondary hyperparathyroidism maintained in the reference range at the cost of
and responsiveness to calcitriol therapy secondary elevations in PTH levels
● Intestinal calcium absorption is impaired in CKD
Calcium due to decreased calcitriol levels, but still propor-
Physiologic Levels and Dietary Sources tional to calcium intake
● Urinary calcium excretion decreases as CKD pro-
● Serum calcium levels are controlled tightly in the
Box 2. Vitamin D Nomenclature Used by the KDIGO Work Group vitamin D3 (cholecalciferol; nomenclature of
Vitamin D: cholecalciferol and/or ergocalciferol vitamin D compounds listed in Box 2)
25-Hydroxyvitamin D: the 25-hydroxylated metabolites of ● Vitamin D2 (ergocalciferol) is obtained from
vitamin D; also known as ercalcidiol or calcidiol; abbreviated as
25(OH)D
dietary sources
● D2 and D3 are hydroxylated by CYP27A1 in the
Calcitriol: 1,25-dihydroxycholecalciferol; abbreviated as
1,25(OH)2D3 liver to 25(OH)D2 (ercalcidiol) and 25(OH)D3
Vitamin D analogs: derivatives of vitamin D2 and vitamin (calcidiol), together termed 25(OH)D
D3, of which the clinically investigated synthetic derivatives
include doxercalciferol, paricalcitol, alfacalcidol, falecalcitriol,
● Ercalcidiol and calcidiol have a half life of ⬃3
and 22-oxacalcitriol (maxacalcitol) weeks and are the best assessment of vitamin D
intake from sun and food
Abbreviation: KDIGO, Kidney Disease: Improving Global Outcomes.
Reproduced from the KDIGO Clinical Practice Guideline for
● 25(OH)D is converted by 1␣-hydroxylase in the
the Diagnosis, Evaluation, Prevention, and Treatment of Chronic kidney to calcitriol (1,25-dihydroxycholecalcif-
Kidney Disease-Mineral and Bone Disorder (Kidney Int 2009; erol, or 1,25[OH]2D3; Fig 2)
76[suppl 113]), with permission of Nature Publishing Group. ● 1,25(OH)2D3 actions:
䡩 Increase TRPV5 and TRPV6, the calcium
based phosphate binders in this setting, but no adenosine triphosphatase and sodium/calcium
absolute limit is given due to the lack of hard data transporters in the intestine and kidney
● Observational studies in dialysis patients show an 䡩 This increases oral calcium absorption and
increase in risk of all-cause mortality with high calcium reabsorption in renal tubules
serum calcium levels 䡩 Decreases PTH synthesis by binding to the
䡩 Levels at which this becomes significant vary vitamin D receptor in the parathyroid gland,
in different analyses from ⬎9.5-⬎11.4 mg/dL inhibiting PTH gene expression, and decreas-
䡩 There are no studies that have treated patients ing PTH cell proliferation
to different calcium levels to determine mortal-
ity benefit Recommended Levels and Health Effects
● In many studies, 25(OH)D deficiency is defined
Vitamin D as ⬍10 ng/mL, and insufficiency, as ⱖ10 ng/mL,
Sources and Role but ⬍20-32 ng/mL
● Cholesterol is converted to 7-dehydrocholesterol, ● The Institute of Medicine (IOM) published a
which in the presence of sunlight is converted to report on vitamin D in 2010
Cholesterol 7-dehydrocholesterol
Sunlight
UVB DIET
plants +
vitamin D2 yeasts
vitamin D3 Vitamin D fay fish,
Binding
Bi di P Protein
i vitamin D3 fish oils
D3-VDBP/D2-VDBP
CYP27A1
24,25(OH)2D 25(OH)D
that vitamin D’s effects outside of bone ● 1,25(OH)2D levels in CKD are variable depend-
health are not yet reliably studied and there
ing on whether calcitriol or one of its analogues is
are no definitive randomized controlled trials
administered because paricalcitol can suppress
(RCTs) levels
● It is not recommended that 1,25(OH)D3 levels be
Vitamin D and CKD measured routinely
● In observational studies of CKD, low 25(OH)D
level has been associated with progression to Parathyroid Hormone
dialysis therapy, cardiovascular events, and mor- Physiologic Role
tality ● PTH is secreted by the parathyroid glands in
● However, no study has shown a clinical benefit of response to hypocalcemia, hyperphosphatemia,
treating patients with CKD to a specific vitamin and/or calcitriol deficiency
D level ● Minute-to-minute concentrations of PTH are most
● Many patients with CKD have decreased sensitive to low ionized calcium concentrations
1,25(OH)2D levels ● The sensitivity of this response may be blunted in
● Reduced phosphorus excretion leads to an in- the presence of hyperphosphatemia in CKD
crease in serum phosphorus and FGF-23 levels,
which suppress 1␣-hydroxylase activity and Intact PTH
thereby decrease 1,25(OH)2D levels ● This 84–amino acid protein is cleaved from
● Lower 1,25(OH)2D levels decrease intestinal pre-pro PTH in the parathyroid gland
calcium absorption, and the lower serum calcium ● Intact PTH (iPTH) has a short half-life (2-4
level stimulates PTH release, which restores minutes)
1,25(OH)2D levels (providing kidney function is ● Cleaved into amino-terminal, carboxy-terminal,
still adequate) and increases phosphorus excre- and midlength fragments, which are metabolized
tion in the liver and kidney
● As CKD progresses, these compensatory mecha- ● Amino-terminal fragments remain active; car-
nisms fail (see Fig 1) boxy-terminal fragments accumulate in CKD
● KDIGO guideline recommendations
䡩 25(OH)D levels should be measured at base- PTH Assays
line in patients with CKD and then further ● First-generation assays (Fig 3)
testing as needed, individualized based on 䡩 Radioimmunoassays using an antibody against
replacement or treatment the midregion or carboxy-terminal end
䡩 Deficiency and insufficiency are to be cor- 䡩 Detects full-length PTH and the multiple car-
rected using treatment strategies recommended boxy- and amino-terminal fragments
for the general population 䡩 Unreliable
may not correlate with bone remodeling, which BONE DISEASE IN CKD
occurs over several months
䡩 Also, significant assay-to-assay variability ex-
Bone Biology
ists, even in the same individual ● Cancellous bone is present in the epiphyses, and
● PTH is associated significantly with mortality in fibers (90%) and proteoglycans, osteopontin,
observational studies at levels varying from ⬎400- osteocalcin, osteonectin, and other noncollag-
⬎600 pg/mL, depending on the population ana- enous proteins
lyzed ● Cells in bone are cartilage cells, osteoblasts, and
whom PTH levels were maintained in the range tiated to form osteoprogenitor cells and eventu-
of 150-300 pg/mL recommended by KDOQI ally mature osteoblasts
guidelines ● After bone formation, osteoblasts may undergo
● Given these issues, recent KDIGO guidelines apoptosis or become a part of mineralized bone
recommend extremes of risk for PTH at less than as osteocytes
2 times the lower-limit and greater than 9 times ● Osteoclasts are formed from hematopoietic cells,
the upper-limit values of the specific assay used fusing at bone to become multinucleated cells
䡩 However, trends of PTH levels within that that reabsorb bone using enzymes
range should be evaluated and medications ● At any time, ⬍20% of bone surface undergoes
䡩 Patients are given tetracycline 3 weeks and 3-5 best available noninvasive tools for the assess-
days before bone biopsy ment of renal osteodystrophy
䡩 Tetracycline binds to hydroxyapatite and labels ● Overall, impaired bone quality (altered architecture,
bone for visualization by fluorescence microscopy remodeling, mass, and volume) is seen in CKD
䡩 The amount of bone formed between the 2 䡩 This can be superimposed on pre-existing
tetracycline labels is used to calculate bone age-related changes in bone, such as loss of
turnover bone mass due to osteoporosis
䡩 Three key parameters are used to assess bone 䡩 This translates to an increased prevalence of
(turnover, mineralization, and volume; TMV sys- fractures in dialysis patients compared with
tem) and replace the terms adynamic bone, mild age-matched general population
hyperparathyroidism, osteitis fibrosa, mixed ure-
mic osteodystrophy, and osteomalacia (Fig 4) SUGGESTED READING
● Biomarkers such as PTH and bone alkaline » Bakkaloglu SA, Wesseling-Perry K, Pereira RC, et al. Value of
phosphatase are only modestly predictive of the new bone classification system in pediatric renal osteodystro-
underlying bone histology, but currently are the phy. Clin J Am Soc Nephrol. 2010;5(10):1860-1866.
» Barreto FC, Barreto DV, Moyses RM, et al. Osteoporosis in
hemodialysis patients revisited by bone histomorphometry: a
new insight into an old problem. Kidney Int. 2006;69(10):
1852-1857.
» Malluche HH, Mawad HW, Monier-Faugere MC. Renal
osteodystrophy in the first decade of the new millennium-
analysis of 630 bone biopsies in black and white patients.
J Bone Miner Res. 2011;26(6):1368-1376.
» Ott SM. Review article: bone density in patients with chronic
kidney disease stages 4-5. Nephrology (Carlton). 2009;14(4):
395-403.
» Ott SM. Bone histomorphometry in renal osteodystrophy.
Semin Nephrol. 2009;29(2):122-132.
CKD
● Vascular calcification prevalence in dialysis pa-
Figure 4. Turnover mineralization volume (TMV) classification
system for bone histomorphometry. The TMV system provides tients ranges from 50%-90% in more than 20
more information than the previously used classification scheme. studies that have addressed this using different
Each axis represents one of the descriptors in the TMV classification:
turnover (from low to high), mineralization (from normal to abnor-
modalities and is even present in children on
mal), and bone volume (from low to high). Individual patient param- dialysis therapy
eters can be plotted on the graph, or mean values and ranges of ● Vascular calcification appears to start early in
grouped data can be shown. For example, many patients with renal
osteodystrophy cluster in areas shown by the bars. The red bar
CKD and ⬎50% of patients initiated on hemodi-
(osteomalacia [OM]) previously was described as low-turnover alysis (HD) therapy already have evidence of
bone with abnormal mineralization. Bone volume may be low to coronary artery calcification (CAC)
medium, depending on the severity and duration of the process and ● Age and dialysis vintage are consistently associ-
other factors that affect bone. The green bar (adynamic bone
disease [AD]) previously was described as low-turnover bone with ated with CAC
normal mineralization, and bone volume in this example is at the ● Use of calcium-based phosphate binders and
lower end of the spectrum, but other patients with normal mineraliza-
tion and low turnover will have normal bone volume. The yellow bar elevated phosphorus levels are risk factors in
(mild hyperparathyroid-related bone disease [HPT]) and purple bar some studies
(osteitis fibrosa [OF], or advanced hyperparathyroid-related bone ● Two types of vascular calcification
disease) previously were considered distinct categories, but in
䡩 Intimal calcification leads to calcific plaques or
actuality represent a range of abnormalities along a continuum of
medium to high turnover and any bone volume depending on the circumferentially calcified atherosclerosis
duration of the disease process. Finally, the blue bar (mixed uremic 䡩 Medial calcification is nonocclusive and leads
osteodystrophy [MUO]) is variably defined internationally. In the
present graph, it is shown as high-turnover, normal bone volume, to vascular stiffening; it can cause local isch-
with abnormal mineralization. In summary, the TMV classification emia and also affect the capacity of the vascula-
system more precisely describes the range of pathologic abnormali- ture to dampen increases in arterial pressure
ties that can occur in patients with chronic kidney disease. Repro-
duced with permission of Nature Publishing Group from Figure 1 in with each ventricular systole, leading to left
Moe et al. Kidney Int. 2006;69(11):1945-1953. ventricular hypertrophy
Figure 5. Pathogenesis of vascular calcification. Normally, mesenchymal stem cells differentiate to adipocytes, osteoblasts, chondro-
cytes, and vascular smooth muscle cells (VSMCs). In the setting of chronic kidney disease (CKD), diabetes, aging, inflammation, and multiple
other toxins, these VSMCs can dedifferentiate or transform into osteo/chondrocytic-like cells by upregulation of transcription factors such as
RUNX-2 and MSX2. These transcription factors are critical for normal bone development and thus their upregulation in VSMCs is indicative of
a phenotypic switch. These osteo/chondrocytic-like VSMCs then become calcified in a process similar to bone formation. These cells lay
down collagen and noncollagenous proteins in the intima or media and incorporate calcium and phosphorus into matrix vesicles to initiate
mineralization and further mineralize into hydroxyapatite. The overall positive calcium and phosphorus balance of most dialysis patients feeds
both the cellular transformation and the generation of matrix vesicles. In addition, the extremes of bone turnover in CKD (low and high or
adynamic and hyperparathyroid bone, respectively) will increase the available calcium and phosphorus by altering the bone content of these
minerals. Ultimately, whether an artery calcifies depends on the strength of the army of inhibitors standing by in the circulation (fetuin A) and
arteries (PPI, pyrophosphate; MGP, matrix Gla protein; OP, osteopontin as examples). Reproduced with permission of the American Society
of Nephrology from Figure 1 in Moe et al. J Am Soc Nephrol. 2008;19:213-216.
● Traditionally, the CAC score obtained by elec- 䡩 The most important stimulus appears to be
tron beam computed tomography (CT) is used to hyperphosphatemia, but other uremic factors,
quantify calcification burden such as inflammation, cytokines, oxidative
● Other available techniques can provide semiquan- stress, and advanced glycation end products,
titative evidence of calcification, including du- also can enhance this transformation
plex ultrasonography, echocardiography, pulse 䡩 Osteo/chondrocytic-like cells lay down colla-
wave velocity, and even plain radiographs gen and noncollagenous proteins (extracellular
● A study of these techniques showed good correlation matrix) in the intima or media
between lateral abdominal aortic radiographs and
䡩 Calcium and phosphorus are incorporated into
electron beam CT in quantifying calcification
matrix vesicles to initiate mineralization in the
Pathogenesis of Vascular Calcification form of hydroxyapatite
● Features a phenotypic switch in which vascular ● When the balance favors promineralizing factors
smooth muscle cells (VSMCs) dedifferentiate to (eg, elevations in calcium and phosphorus) over
osteo/chondrocytic-like cells (Fig 5) inhibitors of calcification (eg, fetuin A, matrix
䡩 Switch associated with upregulation of tran- GLA protein, osteopontin, and pyrophosphate),
scription factors such as RUNX-2 and MSX-2 calcification occurs
䡩 Levels of calcium and phosphorus are influ- » Ketteler M, Biggar PH. Review article: getting the balance
enced by bone status in a particular individual; right: assessing causes and extent of vascular calcification in
chronic kidney disease. Nephrology (Carlton). 2009;14(4):
the extent of bone turnover alters the release of 389-394.
these minerals from bone » Lau WL, Festing MH, Giachelli CM. Phosphate and vascular
䡩 Patients with CKD who have low-turnover calcification: emerging role of the sodium-dependent phos-
bone disease appear to have the greatest risk of phate co-transporter PiT-1. Thromb Haemost. 2010;104(3):
vascular calcification 464-470.
䡩 It is likely that adynamic bone is not able to
» Liu Y, Shanahan CM. Signalling pathways and vascular
calcification. Front Biosci. 2011;16:1302-1314.
take up high calcium loads and this excess » Moe SM, Chen NX. Mechanisms of vascular calcification in
calcium may become deposited in the chronic kidney disease. J Am Soc Nephrol. 2008;19(2):213-
vasculature 216.
● Observational studies have shown increased CAC » Noureddine L, Landis M, Patel N, et al. Efficacy of sodium
thiosulfate for the treatment for calciphylaxis. Clin Nephrol.
and valvular calcification to be associated with 2011;75(6):485-490.
increased mortality in patients with CKD » Pai AS, Giachelli CM. Matrix remodeling in vascular calcifi-
● Calcification of large peripheral arteries also is cation associated with chronic kidney disease. J Am Soc
associated with increased pulse wave velocity, Nephrol. 2010;21(10):1637-1640.
pressure, and mortality » Shao JS, Cheng SL, Sadhu J, et al. Inflammation and the
osteogenic regulation of vascular calcification: a review and
Calciphylaxis perspective. Hypertension. 2010;55(3):579-592.
» Sood AR, Wazny LD, Raymond CB, et al. Sodium thiosulfate-
● Also called “calcific uremic arteriolopathy”; type based treatment in calcific uremic arteriolopathy: a consecutive
of soft-tissue/medial calcification in small skin case series. Clin Nephrol 2011:75(1):8-15.
arterioles leading to tissue ischemia and ulcer-
ation CKD–MINERAL AND BONE DISORDER
● Debilitating, with mortality rates as high as 80%
● Risk factors: hyperphosphatemia, obesity, female Definition
sex, dialysis vintage, warfarin use, and hypoalbu- ● Patients with CKD have biochemical abnormali-
minemia ties of calcium, phosphorus, vitamin D, and PTH;
● Potential treatments: parathyroidectomy, cessa-
bone changes associated with these abnormali-
tion of calcium-containing phosphate-binder use, ties; and extraskeletal calcification
frequent dialysis, hyperbaric oxygen therapy, use ● These 3 interrelated processes account for morbid-
of bisphosphonates or calcimimetics, and use of ity and mortality in CKD and together are called
sodium thiosulfate CKD-MBD
䡩 No randomized trials have been performed for
Phosphorus Maintain in “normal” range (2C) Maintain in “normal” range (2C) Decrease toward the ”normal” range (2C)
Calcium Maintain in “normal” range (2C) Maintain in “normal” range (2C) Maintain in “normal” range (2C)
Intact PTH Ideal level unknown Ideal level unknown Maintain within ⬎2 and ⬍9⫻ the upper limit of
normal (if there is a trend changing within
that range, adjust prescription) (2C)
Note: Grades are given in parentheses (number refers to strength of recommendation; level 1 is strong and level 2 is weak; letter
refers to quality of evidence; A is high, B is moderate, C is low, and D is very low).
Abbreviations: CKD, chronic kidney disease; CKD stage 5D, dialysis-dependent chronic kidney disease stage 5; KDIGO, Kidney
Disease: Improving Global Outcomes; PTH, parathyroid hormone.
Based on the KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney
Disease-Mineral and Bone Disorder (Kidney Int. 2009;76[suppl 113]).
» Sprague SM. Renal bone disease. Curr Opin Endocrinol Phosphate Binders
Diabetes Obes. 2010;17(6):535-539.
» Uhlig K, Berns JS, Kestenbaum B, et al. KDOQI US Background
commentary on the 2009 KDIGO Clinical Practice Guideline ● Dietary restriction often is insufficient to control
for the Diagnosis, Evaluation, and Treatment of CKD-
elevated phosphorus levels in CKD; the next step
Mineral and Bone Disorder (CKD-MBD). Am J Kidney Dis.
2010;55(5):773-799. includes the use of phosphate binders
● An ideal binder should be minimally absorbed in
CONTROL OF HYPERPHOSPHATEMIA the gut, have no side effects, and be effective in
Hyperphosphatemia is associated with poor cardiovas- binding phosphorus at the lowest dose
● Use of aluminum-based binders is now mini-
cular outcomes, mortality, secondary hyperparathy-
roidism, and extraskeletal calcification. Although the mized in CKD due to evidence showing their
benefits of treating to certain target phosphorus levels toxicity in the form of osteomalacia, anemia, and
have not been proved in RCTs, the KDIGO guidelines dialysis encephalopathy
suggested that it is reasonable to treat hyperphos- ● Magnesium carbonate and hydroxide have not
phatemia in patients with CKD (Table 1). Currently been studied well, but there is the risk of magne-
available modalities for normalizing phosphorus lev- sium toxicity in patients with CKD; currently not
els include restriction of dietary phosphorus, use of widely used or recommended due to lack of
phosphorus binders, and attempts to increase phospho- long-term studies
rus removal in dialysis. ● Types of phosphorus binders in common use
include calcium-based binders (calcium carbon-
Diet ate or acetate), anion-exchange resins (eg,
● Dietary phosphorus restriction to 800-1000 mg/d sevelamer hydrochloride and sevelamer carbon-
is recommended ate), and lanthanum carbonate; other binders are
● Difficult to maintain this and consume adequate in development
protein because most foods high in protein tend
to be high in phosphorus Calcium-Based Binders
● Foods with a low phosphorus to protein ratio ● Commonly used forms are calcium acetate (25%
need to be encouraged and formal dietary counsel-
ing may be required to achieve this elemental calcium: 169 mg of calcium/667-mg
䡩 Plant-based foods tend be low in phosphorus to
capsule) and calcium carbonate (40% elemental
protein ratio calcium: 200 mg of elemental calcium/500 mg of
䡩 Additionally, phosphorus in plant-based foods calcium carbonate)
● No studies have examined calcium-based binders
is bound to phytate and may be less bioavail-
able because humans lack the enzymes re- versus placebo or compared the 2 forms of
quired to break the phosphorus-phytate bond calcium-based binders with extraskeletal calcifi-
● Preservatives present in many fast foods and cation or patient-centered outcomes, such as
processed foods tend to be high in phosphorus mortality, fractures, and hospitalizations
● Currently, the US Food and Drug Administration ● Both formulations have the potential to cause
(FDA) does not mandate the reporting of phospho- hypercalcemia as a side effect, but a meta-
rus content on food labels, making it challenging analysis showed that calcium acetate may be less
to counsel patients likely to do so
● Gastrointestinal (GI) intolerance, notably consti- ● There are no studies comparing the effect of
pation, may be a limiting side effect calcium-based binders versus lanthanum or any
of the other non–calcium-, non–sevelamer-based
Non–Calcium-Based Binders
binders with patient-centered outcomes
● Sevelamer ● There are inconsistent data for the beneficial
䡩 Previously formulated as sevelamer hydrochlo-
effect of sevelamer compared with calcium-
ride, but now marketed as sevelamer carbonate based binders on vascular calcification, as shown
䡩 Side effects include GI intolerance
in the following RCTs
䡩 May also decrease low-density lipoprotein
䡩 A study of low-phosphorus diet versus low-
(LDL) cholesterol levels
䡩 Most trials were performed using the hydrochlo-
phosphorus diet plus calcium carbonate ver-
sus low-phosphorus diet plus sevelamer in 90
ride salt
●
predialysis patients showed no progression
Lanthanum carbonate
䡩 Chewable; poorly, although not incompletely,
of calcification in the diet-plus-sevelamer
absorbed; and cleared primarily by the liver group, although calcification progressed in
䡩 Initial concerns included toxicity similar to that
the other 2 groups
䡩 TTG (Treat to Goal) Study assessed the progres-
of aluminum; however, no liver toxicity,
changes in cognition, or bone marrow suppres- sion of calcification in 200 HD patients ran-
sion have been noted in studies of humans domly assigned to sevelamer or calcium-based
䡩 No increased risk of osteomalacia has been binders; showed absolute increases in CAC
noted in studies of humans score in the calcium-treated arm, but not the
sevelamer arm
Calcium- Versus Non–Calcium-Based Binders 䡩 RIND Study also showed a significant increase
● Two studies have examined the effect of calcium- in calcification in the calcium-based binder
based binders versus sevelamer on mortality: arm at 18 months compared with sevelamer
䡩 DCOR (Dialysis Clinical Outcomes Revisited) 䡩 CARE-2 (Calcium Acetate Renagel Compari-
Study son) Study of long-term dialysis patients in the
y 2,103 prevalent HD patients randomly as- United States randomly assigned to calcium
signed to sevelamer or a calcium-based binder acetate plus atorvastatin versus sevalamer plus
(70% acetate and 30% carbonate forms) a statin if needed to achieve LDL cholesterol
y Primary outcome of all-cause or cause- level of 70 mg/dL showed no difference in the
specific mortality was not different between progression of arterial calcification and similar
the 2 arms lipid profiles in both arms
y However, there was a significant dropout 䡩 BRIC (Bone Remodeling and Coronary Cal-
rate of ⬃50% in both arms, with only 1,068 cification) Study (calcium acetate vs
patients completing the study sevelamer in 101 Brazilian dialysis patients)
y When dialysis records were used to deter-
showed that the annual rate of CAC progres-
mine end points, a subgroup analysis of sion was not different between calcium-
participants older than 65 years did show a based binders and sevelamer; however, this
survival advantage for sevelamer
study allowed multiple medication and dialy-
y However, another analysis that used Medi-
sate calcium changes based on baseline bone
care claims to determine end points did not
biopsy studies and thus was subject to consid-
show a mortality benefit in this group
erable bias
y Analysis of Medicare claims also showed
● Effect on bone of calcium-based binders versus
that all-cause hospitalizations were lower
sevelamer
for sevelamer participants
䡩 BRIC Study showed no significant changes in
䡩 RIND (Renagel in New Dialysis) Study
䡩 RCT of 1 year of treatment favored lanthanum phosphorus by this route might complement diet
carbonate over calcium-based binders and binder therapies; further studies are needed
䡩 RCT of 65 patients showed an improvement in to provide more evidence for this
turnover and volume, but worsened mineraliza-
tion in lanthanum arm SUGGESTED READING
䡩 RCT of 20 participants showed that no patient
receiving lanthanum developed low turnover » Barreto DV, Barreto Fde C, de Carvalho AB, et al. Phosphate
compared with 3 patients developing low- binder impact on bone remodeling and coronary calcifica-
turnover bone in the calcium arm tion—results from the BRiC Study. Nephron Clin Pract.
䡩 Therefore, bone changes in response to binder 2008;110(4):c273-c283.
» Block GA, Raggi P, Bellasi A, Kooienga L, Spiegel DM.
therapy are not consistent and are dependent Mortality effect of coronary calcification and phosphate
on the individual patient and initial bone binder choice in incident hemodialysis patients. Kidney Int.
status 2007;71(5):438-441.
● In summary, there are limited data to suggest the » Block GA, Spiegel DM, Ehrlich J, et al. Effects of sevelamer
use of 1 type of binder over another; however, in and calcium on coronary artery calcification in patients new
to hemodialysis. Kidney Int. 2005;68(4):1815-1824.
the presence of arterial calcification or adynamic
» Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the
bone disease, it is prudent to restrict the dose of progression of coronary and aortic calcification in hemodialy-
calcium-based binders until more conclusive data sis patients. Kidney Int. 2002;62(1):245-252.
are available » Chertow GM, Levin NW, Beck GJ, et al. In-center hemodialy-
● In the KDOQI guidelines, the maximal dose of sis six times per week versus three times per week. N Engl
elemental calcium was recommended at 1,500 J Med. 2010;363(24):2287-2300.
» D’Haese PC, Spasovski GB, Sikole A, et al. A multicenter
mg/d, with total calcium intake from diet plus study on the effects of lanthanum carbonate (Fosrenol) and
binders recommended not to exceed 2,000 calcium carbonate on renal bone disease in dialysis patients.
mg/d Kidney Int Suppl. 2003;85:S73-S78.
● KDIGO guidelines recommend avoidance of » Ferreira A, Frazao JM, Monier-Faugere MC, et al. Effects of
calcium-based binders if there is arterial calci- sevelamer hydrochloride and calcium carbonate on renal
osteodystrophy in hemodialysis patients. J Am Soc Nephrol.
fication, PTH level is persistently low, or with
2008;19(2):405-412.
persistent or recurrent hypercalcemia; no daily » Freemont AJ, Hoyland JA, Denton J, et al. The effects of
ceiling was given due to the lack of balance lanthanum carbonate and calcium carbonate on bone abnor-
studies malities in patients with end-stage renal disease. Clin Neph-
rol. 2005;64(6):428-437.
» Malluche HH, Siami GA, Swanepoel C, et al. Improvements
Clearance of Phosphorus in Dialysis
in renal osteodystrophy in patients treated with lanthanum
● Patients receiving nocturnal HD remove twice carbonate for two years. Clin Nephrol. 2008;70(4):284-295.
the amount of phosphorus per week compared » Pierratos A. Daily (quotidian) nocturnal home hemodialysis:
with those on thrice-weekly intermittent HD nine years later. Hemodial Int. 2004;8(1):45-50.
» Qunibi W, Moustafa M, Muenz LR, et al. A 1-year random-
● Intermittent HD removes 1,000 mg of phospho-
ized trial of calcium acetate versus sevelamer on progression
rus per session, and because 1,000 mg also is of coronary artery calcification in hemodialysis patients with
absorbed each day, net phosphorus balance is comparable lipid control: the Calcium Acetate Renagel
about 4,000 mg/wk Evaluation-2 (CARE-2) Study. Am J Kidney Dis. 2008;51(6):
● An RCT of 51 patients randomly assigned to 952-965.
» Russo D, Miranda I, Ruocco C, et al. The progression of
6-times-weekly nocturnal HD versus thrice-
coronary artery calcification in predialysis patients on cal-
weekly intermittent HD showed significant and cium carbonate or sevelamer. Kidney Int. 2007;72(10):1255-
sustained decreases in serum phosphorus levels 1261.
over a 6-month period » St Peter WL, Liu J, Weinhandl E, Fan Q. A comparison of
䡩 Also noted was a significant rate of discontinu- sevelamer and calcium-based phosphate binders on mortality,
ation or lowering of phosphorus-binder dose in hospitalization, and morbidity in hemodialysis: a secondary
analysis of the Dialysis Clinical Outcomes Revisited (DCOR)
the nocturnal HD group randomized trial using claims data. Am J Kidney Dis.
䡩 No significant difference in PTH levels be-
2008;51(3):445-454.
tween groups » Suki WN, Zabaneh R, Cangiano JL, et al. Effects of
● A frequent dialysis study that randomly assigned sevelamer and calcium-based phosphate binders on mortality
245 patients to daily versus thrice-weekly dialy- in hemodialysis patients. Kidney Int. 2007;72(9):1130-1137.
» Walsh M, Manns BJ, Klarenbach S, Tonelli M, Hemmelgarn
sis found a decrease in serum phosphorus levels
B, Culleton B. The effects of nocturnal compared with
in the frequent-HD group (P ⫽ 0.002) conventional hemodialysis on mineral metabolism: a random-
● With the increasing popularity of nonconven- ized-controlled trial. Hemodial Int. 2010;14(2):
tional HD modalities, increased clearance of 174-181.
taining iPTH in the range of approximately 2-9 pre-HD CKD address patient-level outcomes
times limits for the assay” (mortality, hospitalizations, fractures, para-
● Marked changes in PTH levels within that range thyroidectomy, and quality of life) or vascu-
also should be treated lar calcification
䡩 Two studies have shown improvement in bone
● Measures available for this include oral calcium,
Treatment of Elevated PTH in CKD Stages 3-4 of progression to end-stage renal disease
● PTH level increases as an adaptive response to
(ESRD) and death in patients with CKD stages
3-4 using a vitamin D analogue, although no
hyperphosphatemia; in individual patients, this
prospective studies have examined this
becomes maladaptive at a certain point and
● Theoretically, it may be beneficial to correct both
treatments for elevated PTH levels should be
individualized and based on trends vitamin D deficiency and calcitriol deficiency,
● KDIGO guidelines recommend correcting modi- but no studies have been performed to assess this
● Calcimimetics also decrease PTH levels com-
fiable factors: treating hypocalcemia, elevated
phosphorus levels, and vitamin D deficiency to pared with placebo in CKD stages 3-4, but with a
attempt to reverse progressive hyperparathyroid- significant risk of hyperphosphatemia
● Given this risk, further studies need to be per-
ism, however, there is a paucity of evidence to
support this at the present time formed before this can be recommended
● Oral calcium has been used to suppress PTH in
» Shoben AB, Rudser KD, de Boer IH, et al. Association of oral » Tentori F, Hunt WC, Stidley CA, et al. Mortality risk among
calcitriol with improved survival in nondialyzed CKD. J Am hemodialysis patients receiving different vitamin D analogs.
Soc Nephrol. 2008;19(8):1613-1619. Kidney Int. 2006;70(10):1858-1865.
» Sprague SM, Abboud H, Qiu P, Dauphin M, Zhang P, Finn W.
Lanthanum carbonate reduces phosphorus burden in patients
with CKD stages 3 and 4: a randomized trial. Clin J Am Soc
CALCIMIMETICS FOR TREATING ELEVATED PTH IN
Nephrol. 2009;4(1):178-185. CKD STAGE 5D
» Sprague SM, Coyne D. Control of secondary hyperparathy-
● Calcimimetics are allosteric activators of the
roidism by vitamin D receptor agonists in chronic kidney
disease. Clin J Am Soc Nephrol. 2010;5(3):512-518. extracellular CaSR, sensitizing the parathyroid
» Zisman AL, Hristova M, Ho LT, Sprague SM. Impact of gland to extracellular calcium
ergocalciferol treatment of vitamin D deficiency on serum 䡩 This decreases PTH release from the parathy-
parathyroid hormone concentrations in chronic kidney dis- roid
ease. Am J Nephrol. 2007;27(1):36-43. 䡩 These actions are independent of vitamin D
● Cinacalcet is the only FDA-approved calcimi-
CALCITRIOL AND VITAMIN D ANALOGUES FOR metic in the United States
TREATING ELEVATED PTH IN CKD STAGE 5D ● RCTs have shown suppression of PTH, calcium,
● Vitamin D analogues and calcitriol traditionally phosphorus, and calcium-phosphorus product
● Retrospective analyses of pooled data of 1,100
are used for their PTH-lowering effects and are
effective in patients receiving dialysis participants in phase 3 RCTs of cinacalcet showed
● Retrospective data from multiple analyses show reductions in risks of parathyroidectomy, fracture,
survival benefits in patients receiving any vita- cardiovascular hospitalization, and improved qual-
min D analogue ity of life
● An observational study found a significant sur-
● One study showed a survival benefit of paricalci-
tol compared with calcitriol, but another study vival benefit associated with cinacalcet use in
dialysis patients receiving vitamin D analogues
showed no benefit of either paricalcitol or doxer-
● ADVANCE (A Randomized Study to Evaluate
calciferol over calcitriol
●
the Effects of Cinacalcet plus Low-Dose Vitamin
These studies are all retrospective and have not
D on Vascular Calcification in Subjects With
been confirmed in prospective analyses
●
Chronic Kidney Disease Receiving Hemodialy-
Paricalcitol was observed to lead to less sustained
sis Study) showed no reduction in CAC in the
hypercalcemia than calcitriol in a secondary
cinacalcet/low-dose paricalcitol arm versus the
analysis of an RCT, although there was no
flexible dose of vitamin D analogue arm when
difference in number of patients who had one
analyzed by the Agatston method, but showed a
episode of hypercalcemia
reduction using the volumetric method
● No head-to-head comparison of doxercalciferol, ● RCTs are needed for the effects of calcimimetics
paricalcitol, or calcitriol has evaluated vascular on patient-related outcomes and bone histology
calcification or patient-related end points 䡩 EVOLVE (Evaluation of Cinacalcet Therapy to
● Therefore, the KDIGO guidelines do not recom- Lower Cardiovascular Events), a global, phase
mend one vitamin D analogue over another or 3, double-blind, randomized, placebo-con-
over calcitriol at this point trolled trial of 4,000 patients, is examining the
impact of cinacalcet on mortality and cardiovas-
SUGGESTED READING cular events in HD patients with secondary
» Moe SM. Vitamin D, cardiovascular disease, and survival in hyperparathyroidism; EVOLVE is ongoing,
dialysis patients. J Bone Miner Res. 2007;22(suppl 2):V95- with results anticipated in late 2012 or 2013
V99. ● KDIGO guidelines recommend that calcitriol,
» Sprague SM, Coyne D. Control of secondary hyperparathy- vitamin D analogues, or calcimimetics can be
roidism by vitamin D receptor agonists in chronic kidney
used in CKD stage 5D to decrease PTH levels;
disease. Clin J Am Soc Nephrol. 2010;5(3):512-518.
» Sprague SM, Llach F, Amdahl M, Taccetta C, Batlle D. the choice is dependent on serum calcium and
Paricalcitol versus calcitriol in the treatment of secondary phosphorus levels
hyperparathyroidism. Kidney Int. 2003;63(4):1483-1490.
» Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM,
Thadhani R. Survival of patients undergoing hemodialysis
SUGGESTED READING
with paricalcitol or calcitriol therapy. N Engl J Med. 2003; » Block GA, Martin KJ, de Francisco AL, et al. Cinacalcet for
349(5):446-456. secondary hyperparathyroidism in patients receiving hemodi-
» Teng M, Wolf M, Ofsthun MN, et al. Activated injectable alysis. N Engl J Med. 2004;350(15):1516-1525.
vitamin D and hemodialysis survival: a historical cohort » Block GA, Zaun D, Smits G, et al. Cinacalcet hydrochloride
study. J Am Soc Nephrol. 2005;16(4):1115-1125. treatment significantly improves all-cause and cardiovascular
survival in a large cohort of hemodialysis patients. Kidney Int. ● Current KDIGO guidelines recommend no spe-
2010;78(6):578-589. cific PTH level for which parathyroidectomy
» Brown EM. Clinical utility of calcimimetics targeting the
would be an absolute indication
extracellular calcium-sensing receptor (CaSR). Biochem Phar-
macol. 2010;80(3):297-307.
» Cunningham J, Danese M, Olson K, Klassen P, Chertow GM. SUGGESTED READING
Effects of the calcimimetic cinacalcet HCl on cardiovascular
disease, fracture, and health-related quality of life in secondary » Kestenbaum B, Andress DL, Schwartz SM, et al. Survival
hyperparathyroidism. Kidney Int. 2005;68(4):1793-1800. following parathyroidectomy among United States dialysis
» Raggi P, Chertow GM, Torres PU, et al. The ADVANCE patients. Kidney Int. 2004;66(5):2010-2016.
Study: a randomized study to evaluate the effects of cinacal-
cet plus low-dose vitamin D on vascular calcification in
CONCLUSION
patients on hemodialysis [published online ahead of print CKD-MBD includes a constellation of biochemical
December 8, 2010]. Nephrol Dial Transplant. and hormone abnormalities, impaired bone architec-
ture, growth and fragility, and extraskeletal calcifica-
PARATHYROIDECTOMY FOR TREATING ELEVATED tion. Management of CKD-MBD is important to de-
PTH IN CKD STAGE 5D crease morbidity and mortality in patients with CKD.
●
This requires an integrated approach and an under-
Parathyroidectomy is effective in optimizing PTH
standing of physiology because all 3 components are
control and traditionally has been offered to
interrelated and affecting one typically affects the
patients with sustained PTH levels ⬎1,000 pg/mL
others. Studies focused on combination therapy to
● Advantages are the lack of adverse effects from improve all aspects of CKD-MBD simultaneously
continuous vitamin D analogue or cinacalcet will be the challenge of the future.
therapy
● It would be difficult to perform an RCT of
ACKNOWLEDGEMENTS
vitamin D/cinacalcet versus parathyroidectomy,
and to date, no such study has been performed Support: None
Financial Disclosure: Dr Moe is a consultant and received
● A retrospective analysis of US Renal Data Sys- honoraria and/or funding from Genzyme, Amgen, Shire, and
tem (USRDS) data showed lower mortality risk Litholink. Dr Moorthi declares that she has no relevant financial
in patients who underwent parathyroidectomy interests.