Diagnosis, Evaluation, Prevention and Treatment of CKD-MBD

DIAGNOSIS, EVALUATION,
PREVENTION, AND
TREATMENT OF CKD-MBD
KDIGO Clinical Practice Guidelines for the
Dr Abdullah Ansari
SR Nephrology
SGPGIMS Lucknow

Contents
Introduction and definition of CKD–MBD
Diagnosis of CKD–MBD: biochemical abnormalities
Diagnosis of CKD–MBD: bone
Diagnosis of CKD–MBD: vascular calcification
Treatment of CKD–MBD targeted at serum phosphorus and serum calcium
Treatment of abnormal PTH levels in CKD–MBD
Treatment of bone with bisphosphonates, other osteoporosis medications and growth hormone
Evaluation and treatment of kidney transplant bone disease

CHAPTER 1:
INTRODUCTION AND DEFINITION OF
CKD-MBD

Introduction of CKD–MBD
• CKD is an international public health
problem affecting 5-10% of the world
population
• As kidney function declines, there is a
progressive deterioration in mineral
homeostasis and endocrine functions

Introduction of CKD–MBD
• These dysfunctions are critically important in the regulation of both
 Bone modeling: initial bone formation during growth
 Bone remodeling: bone structure and function during adulthood
• Skeletal abnormalities are found almost universally in dialysis patients, and in the
majority of patients with CKD stages 3-5
• An increasing concern of extra-skeletal calcification that may result from the
deranged metabolism itself and from its corrective therapies

Nomenclature and description for rating
guideline recommendations

CHAPTER 3.1:
DIAGNOSIS OF CKD-MBD:
BIOCHEMICAL ABNORMALITIES

Assessment
3.1.1:
• We recommend monitoring serum levels of calcium, phosphate, PTH, and
alkaline phosphatase activity beginning in CKD G3a (1C).
• In children, we suggest such monitoring beginning in CKD G2 (2D).

Assessment
3.1.2:
• In patients with CKD G3a–G5D, it is reasonable to base the frequency of
monitoring serum calcium, phosphate, and PTH on the presence and
magnitude of abnormalities, and the rate of progression of CKD (Not
Graded).

Assessment
3.1.3:
• In patients with CKD G3a–G5D, we suggest that 25(OH)D (calcidiol) levels
might be measured, and repeated testing determined by baseline values
and therapeutic interventions (2C).
• We suggest that vitamin D deficiency and insufficiency be corrected using
treatment strategies recommended for the general population (2C).
Vitamin D deficiency may be an underlying cause of elevated PTH, and thus there is a rationale for
measuring and supplementing in this population
In the general population and in CKD, there is an association of low 25(OH)D levels with mortality
In the absence of knowing the optimum level, the decision of whether to measure, when to
measure, how often, and to what target level needs to be individualized

Assessment
• 3.1.4: In patients with CKD G3a–G5D, we recommend that therapeutic
decisions be based on trends rather than on a single laboratory value,
taking into account all available CKD-MBD assessments (1C).
• 3.1.5: In patients with CKD G3a–G5D, we suggest that individual values of
serum calcium and phosphate, evaluated together, be used to guide clinical
practice rather than the mathematical construct of calcium-phosphate
product (Ca x P) (2D).

 The interpretation requires an understanding of assay type and variability, blood sample
handling, and normal postprandial, diurnal and seasonal variations
 Thus, trends in laboratory values should be preferentially used over single values
The measurement of phosphorus is generally valid and reproducible, but is affected by diurnal
and postprandial variation
Values may differ substantially (eg upto 0.08 mg/dl) in dialysis patients, depending on which shift
or which interdialytic interval is chosen

Assessment
• 3.1.6: In reports of laboratory tests for patients with CKD G3a–G5D, we
recommend that clinical laboratories inform clinicians of the actual assay
method in use and report any change in methods, sample source (plasma
or serum), or handling specifications to facilitate the appropriate
interpretation of biochemistry data (1B).

• Impaired renal excretion of C-terminal
fragments in CKD
• The third-generation assays are not yet widely available and have not been
shown convincingly to improve the predictive value for the diagnosis of
underlying bone disease or other serum markers of bone turnover
• Therefore, the widely available second-generation assays should continue to
be used in routine clinical practice at present
PTH assays

CHAPTER 3.2:
DIAGNOSIS OF CKD-MBD:
BONE

Background: Fractures in CKD patients
• Hip fractures were seen two to three times more often than in persons
without CKD
• Previous fractures are strongly associated with the risk of a subsequent
fracture and this risk is independent of age, bone density, or other
identified risk factors
• Mortality in patients with CKD stage 5 who have had a hip fracture is about
twice as high as that in patients of similar age and gender who have not
had a fracture

Background: BMD measurements
• Noninvasive techniques include DXA and quantitative CT
• Dual-energy X-ray absorptiometry (DXA) cannot differentiate between
cortical and trabecular bone
• These distinctions are important because bone remodeling is different in
trabecular bone compared with cortical bone
• Quantitative CT can separately measure cortical and trabecular bone
because it is a three-dimensional measurement

Distribution of osteoporosis, osteopenia,
and normal bone density by creatinine
clearance in general US population
Klawansky S, Komaroff E, Cavanaugh Jr PF et al. Relationship
between age, renal function and bone mineral density in the US
population. Osteoporos Int 2003;14:570–576.
• The percentage of people with low BMD was
much greater in those with CKD than in those
with normal kidney function

Background: Bone biopsy
• A bone biopsy should also be considered in unexplained fractures,
refractory hypercalcemia, suspicion of osteomalacia, an atypical response,
or progressive decreases in BMD despite standard therapy
• The goal of a bone biopsy would be to
1. rule out atypical or unexpected bone pathology
2. determine whether the patient has high or low-turnover disease, which
may alter the dose of medications
3. identify a mineralization defect that would alter treatment

Classification of renal osteodystrophy by bone biopsy
KDIGO has suggested that bone biopsies in CKD should be characterized by
determining bone turnover, mineralization, and volume (TMV)
• Turnover: A spectrum of turnover rates from osteitis fibrosa to adynamic bone disease
• Mineralization: The classic abnormality is osteomalacia (bone-formation rate is low and
osteoid volume is high)
• Volume: In typical osteoporosis, both cortical and cancellous bone volumes decrease,
these parameters are different in CKD. Eg, in high turnover MBD, cortical bone volume is
decreased but cancellous volume is increased

Testing for CKD-MBD
• 3.2.1: In patients with CKD G3a-G5D with evidence of CKD-MBD and/or
risk factors for osteoporosis, we suggest bone mineral density (BMD)
testing to assess fracture risk if results will impact treatment decisions (2B).
• 3.2.2: In patients with CKD G3a-G5D, it is reasonable to perform a bone
biopsy if knowledge of the type of renal osteodystrophy will impact
treatment decisions (Not Graded).

Comparison: 2017 vs 2009
New 3.2.1: In patients with CKD G3a-G5D
with evidence of CKD-MBD and/or risk
factors for osteoporosis, we suggest BMD
testing to assess fracture risk if results will
impact treatment decisions (2B).
New 3.2.2: In patients with CKD G3a-G5D, it
is reasonable to perform a bone biopsy if
knowledge of the type of renal
osteodystrophy will impact treatment
decisions (Not Graded).
• Old 3.2.2: In patients with CKD G3a–G5D with
evidence of CKD-MBD, we suggest that BMD
testing not be performed routinely, because
BMD does not predict fracture risk as it does
in the general population, and BMD does not
predict the type of renal osteodystrophy (2B).
• Old 3.2.1: In patients with CKD G3a–G5D, it is
reasonable to perform a bone biopsy in
various settings including, but not limited to:
unexplained fractures, persistent bone pain,
unexplained hypercalcemia, unexplained
hypophosphatemia, possible aluminum
toxicity, and prior to therapy with
bisphosphonates in patients with CKD-MBD
(Not Graded).

The 2009 Guideline recommendations
• The 2009 Guideline recommended a bone biopsy prior to antiresorptive therapy
and evidence of biochemical abnormalities of CKD-MBD, low BMD and/or fragility
fractures
• The rationale was that low BMD may be due to CKD-MBD (e.g., high PTH) and
that lowering PTH is a safer and more appropriate therapy than an antiresorptive
• There was also concern that bisphosphonates would induce low-turnover bone
disease
• Studies in patients with CKD have not definitively demonstrated that
bisphosphonates cause adynamic bone disease

Rationale for Update
• Multiple new prospective studies have documented that lower dual-energy
X-ray absorptiometry (DXA) BMD predicts incident fractures in patients
with CKD G3a-G5D
Iimori S, Mori Y, Akita W, et al. Diagnostic usefulness of bone mineral density and biochemical markers of
bone turnover in predicting fracture in CKD stage 5D patients–a single-center cohort study. Nephrol Dial
Transplant. 2012;27:345–351.
Naylor KL, Garg AX, Zou G, et al. Comparison of fracture risk prediction among individuals with reduced and
normal kidney function. Clin J Am Soc Nephrol. 2015;10:646–653.
West SL, Lok CE, Langsetmo L, et al. Bone mineral density predicts fractures in chronic kidney disease. J Bone
Miner Res. 2015;30:913–919.
Yenchek RH, Ix JH, Shlipak MG, et al. Bone mineral density and fracture risk in older individuals with CKD.
Clin J Am Soc Nephrol. 2012;7:1130–1136.

• The growing experience with osteoporosis medications in patients with
CKD, low BMD and a high risk of fracture
• The inability to perform a bone biopsy may not justify withholding
antiresorptive therapy to patients at high risk of fracture
Jamal SA, Ljunggren O, Stehman-Breen C, et al. Effects of denosumab on fracture and bone mineral density
by level of kidney function. J Bone Miner Res. 2011;26:1829–1835
Toussaint ND, Lau KK, Strauss BJ, et al. Effect of alendronate on vascular calcification in CKD stages 3 and 4: a
pilot randomized controlled trial. Am J Kidney Dis. 2010;56:57–68.
Haghverdi F, Farbodara T, Mortaji S, et al. Effect of raloxifene on parathyroid hormone in osteopenic and
osteoporotic post menopausal women with chronic kidney disease stage 5.Iran J Kidney Dis. 2014;8:461–
466.

Meta-Analysis
Bucur RC et al, Osteoporosis International, 26, 449–458 (2015)
• BMD was statistically significantly lower at the femoral neck, lumbar spine, the 1/3 and ultradistal
radius in subjects with fractures compared to those without regardless of dialysis status
• BMD can discriminate fracture status in predialysis and dialysis CKD

Assessment
• 3.2.3: In patients with CKD G3a–G5D, we suggest that measurements of
serum PTH or bone-specific alkaline phosphatase can be used to evaluate
bone disease because markedly high or low values predict underlying bone
turnover (2B).
Bone biopsy remains the gold standard for the assessment of bone turnover
Measurements of circulating PTH or b-ALP have limited sensitivity and specificity, especially in
detecting adynamic bone
There have been several large prospective studies in CKD stage 5D patients relating serum PTH to
fractures, with inconsistent results

Assessment
• 3.2.4: In patients with CKD G3a–G5D, we suggest not routinely measuring
bone-derived turnover markers of collagen synthesis (such as procollagen
type I C-terminal propeptide) and breakdown (such as type I collagen cross-
linked telopeptide, cross-laps, pyridinoline, or deoxypyridinoline) (2C).
• 3.2.5: We recommend that infants with CKD G2–G5D have their length
measured at least quarterly, while children with CKD G2–G5D should be
assessed for linear growth at least annually (1B).

Pediatric Perspective
• Linear height deficit is one of the cardinal features of progressive CKD in
pediatric patients
• The mechanisms include the presence of chronic metabolic acidosis, renal
osteodystrophy, nutrient wasting, chronic inflammation, functional
hypogonadism, and dysregulation of the growth hormone-insulin-like
growth factor 1 endocrine axis
• Thus, recombinant human growth hormone has been licensed by the FDA
since 1988 for the treatment of linear growth failure

CHAPTER 3.3:
DIAGNOSIS OF CKD–MBD:
VASCULAR CALCIFICATION

Assessment
• 3.3.1: In patients with CKD G3a–G5D, we suggest that a lateral abdominal
radiograph can be used to detect the presence or absence of vascular
calcification, and an echocardiogram can be used to detect the presence or
absence of valvular calcification, as reasonable alternatives to computed
tomography-based imaging (2C).
• 3.3.2: We suggest that patients with CKD G3a–G5D with known vascular or
valvular calcification be considered at highest cardiovascular risk (2A).
• It is reasonable to use this information to guide the management of CKD-
MBD (Not Graded).

Rationale for recommendations
• In normal population, the magnitude of coronary artery calcification (CAC)
is a strong predictor of cardiovascular event risk
• In CKD, coronary artery and generalized vascular calcification is exceedingly
more prevalent, more severe and follows an accelerated course
• The reference standard is the CT-based CAC score, but the more easily
available technique may yield comparable information
• However, there is limited evidence from RCTs in CKD that the reduction of
arterial calcification progression impacts mortality

CHAPTER 4.1:
TREATMENT OF CKD–MBD:
TARGETED AT LOWERING HIGH
SERUM PHOSPHATE AND
MAINTAINING SERUM CALCIUM

Phosphate and Calcium
• 4.1.1: In patients with CKD G3a-G5D, treatments of CKD-MBD should be
based on serial assessments of phosphate, calcium and PTH levels,
considered together (Not Graded).
• 4.1.2: In patients with CKD G3a-G5D, we suggest lowering elevated
phosphate levels toward the normal range (2C).
• 4.1.3: In adult patients with CKD G3a-G5D, we suggest avoiding
hypercalcemia (2C).
• In children with CKD G3a-G5D, we suggest maintaining serum calcium in
the age-appropriate normal range (2C).

• New 4.1.1: In patients with CKD G3a-G5D,
treatments of CKD-MBD should be based on
serial assessments of phosphate, calcium, and
PTH levels, considered together (Not Graded).
• New 4.1.2: In patients with CKD G3a-G5D, we
suggest lowering elevated phosphate levels
toward the normal range (2C).
• New 4.1.3: In patients with CKD G3a-G5D, we
suggest avoiding hypercalcemia (2C).
• In children with CKD G3a-5D, we suggest
maintaining serum calcium in the age-
appropriate normal range (2C).
• Old 4.1.1: In patients with CKD G3a–G5D, we
suggest maintaining serum phosphate in the
normal range (2C). In patients with CKD G5D,
we suggest lowering elevated phosphate
levels toward the normal range (2C).
• Old 4.1.2: In patients with CKD G3a–G5D, we
suggest maintaining serum calcium in the
normal range (2D).

• The results of these tests are influenced by food intake, adherence to and the
timing of drug intake and dietary modifications, differences in assay methods and
by the interval from the last dialysis session
• Due to interdependency of these parameters, therapeutic maneuvers aimed at
improving one often have unintentional effects on other parameters
• Accordingly, the decision should be based not on a single result, but rather on the
trends of serial result

• The trials demonstrating that treatments lowering serum phosphate will improve
patient-centered outcomes are still lacking
• 3 recent historical cohort analyses from DOPPS, ArMORR, and COSMOS suggested
that dialysis patients on phosphate-binder therapy showed improved survival
• In COSMOS study cohort of HD patients, the best patient survival was observed
with serum phosphate close to 4.4 mg/dl
• Both NHANES and MDRD cohorts that examined the general population and
advanced CKD, respectively, dietary intake or intervention to reduce dietary
phosphate intake as assessed by either urinary excretion or dietary recall had
only minimal effects on serum phosphate

• Mild and asymptomatic hypocalcemia can be tolerated in order to avoid
inappropriate calcium loading in adults
• In EVOLVE trial, no negative signals were associated with the persistently low
serum calcium levels in the cinacalcet arm of the trial
• An individualized approach to the treatment of hypocalcemia rather than
recommending the correction of hypocalcemia for all patients is emphasized
• However, significant or symptomatic hypocalcemia should still be addressed

• Childhood and adolescence are critical periods for bone mass accrual.
• A prospective pediatric cohort study showed lower serum calcium levels
were independently associated with lower cortical volumetric BMD Z-
scores, which predicted future fractures
• The Work Group suggests that serum calcium levels are maintained in the
age-appropriate normal range
 Denburg MR, Tsampalieros AK, de Boer IH, et al. Mineral metabolism and cortical volumetric bone mineral
density in childhood chronic kidney disease. J Clin Endocrinol Metab. 2013;98:1930–1938.

Phosphate and Calcium
• 4.1.4: In patients with CKD G5D, we suggest using a dialysate calcium
concentration between 1.25 and 1.50 mmol/l (2.5 and 3.0 mEq/l) (2C).
• 4.1.5: In patients with CKD G3a-G5D, decisions about phosphate-lowering
treatment should be based on progressively or persistently elevated serum
phosphate (Not Graded).
• 4.1.6: In adult patients with CKD G3a-5D receiving phosphate-lowering
treatment, we suggest restricting the dose of calcium-based phosphate binders
(2B).
• In children with CKD G3a-G5D, it is reasonable to base the choice of phosphate-
lowering treatment on serum calcium levels (Not Graded).
• 4.1.7: In patients with CKD G3a–G5D, we recommend avoiding the long-term use
of aluminum-containing phosphate binders, and in patients with CKD G5D,
avoiding dialysate aluminum contamination to prevent aluminum intoxication
(1C).

• New 4.1.4: In patients with CKD G5D, we
suggest using a dialysate calcium
concentration between 1.25 and 1.50
mmol/l (2.5 and 3.0 mEq/l) (2C).
decisions about phosphate-lowering
treatment should be based on
progressively or persistently elevated
serum phosphate (Not Graded).
• Old 4.1.3: In patients with CKD G5D, we
suggest using a dialysate calcium
concentration between 1.25 and 1.50
mmol/l (2.5 and 3.0 mEq/l) (2D).
• Old 4.1.4: In patients with CKD G3a–G5
(2D) and G5D (2B), we suggest using
phosphate-binding agents in the
treatment of hyperphosphatemia.
• It is reasonable that the choice of
phosphate binder takes into account CKD
stage, presence of other components of
CKD-MBD, concomitant therapies, and
side effect profile (Not Graded).

• New 4.1.6: In adult patients with CKD
G3a-G5D receiving phosphate-lowering
treatment, we suggest restricting the
dose of calcium-based phosphate binders
(2B).
• In children with CKD G3a-G5D, it is
reasonable to base the choice of
phosphate-lowering treatment on serum
calcium levels (Not Graded).
• Old 4.1.5: In patients with CKD G3a–G5D
and hyperphosphatemia, we recommend
restricting the dose of calcium-based
phosphate binders and/or the dose of
calcitriol or vitamin D analog in the
presence of persistent or recurrent
hypercalcemia (1B).
• In patients with CKD G3a–G5D and
hyperphosphatemia, we suggest
restricting the dose of calcium-based
phosphate binders in the presence of
arterial calcification (2C) and/or adynamic
bone disease (2C) and/or if serum PTH
levels are persistently low (2C).

Rationale for Update 4.1.4:
• Spasovski et al. found in patients with adynamic bone disease, that the lower
dialysate calcium of 1.25 mmol/l [2.5 mEq/l] improves bone and mineral
parameters compared with the higher concentration of 1.75mmol/l (3.5 mEq/l)
• Ok et al. randomized 425 patients with iPTH levels <300 pg/ml to dialysate
calcium of either 1.25 mmol/l (2.5 mEq/l) or 1.75 mmol/l (3.5 mEq/l). Lowering
dialysate calcium slowed the progression of CAC and improved biopsy-proven
bone turnover

• 4.1.5: Emphasizes the perception that early “preventive” treatment of
hyperphosphatemia is currently not supported by data
• 4.1.6: New evidence from three randomized control trials (RCTs) supports a
more general recommendation to restrict calcium-based phosphate
binders in hyperphosphatemic patients of all severities of CKD
 Block GA, Wheeler DC, Persky MS, et al. Effects of phosphate binders in moderate CKD. J Am Soc Nephrol.
2012;23:1407–1415.
 Hill KM, Martin BR, Wastney ME, et al. Oral calcium carbonate affects calcium but not phosphorus balance
in stage 3-4 chronic kidney disease. Kidney Int. 2013;83:959–966.
 Di Iorio B, Molony D, Bell C, et al. Sevelamer versus calcium carbonate in incident hemodialysis patients:
results of an open-label 24-monthrandomized clinical trial. Am J Kidney Dis. 2013;62:771–778.

Phosphate Binders in Moderate CKD
Block G et al. J Am Soc Nephrol. 2012;23:1407-1415.
• Predialysis patients (CKD G3b–G4) with mean baseline serum phosphate concentrations of 4.2 mg/dl were exposed to 3
different phosphate binders (sevelamer, lanthanum, or calcium acetate) versus matching placebos
• There was a small decrease in serum phosphate concentrations (for those allocated to active treatment) and a 22%
decrease in urinary phosphate excretion (suggesting adherence to therapy)
• The progression of coronary and aortic calcification was observed with active phosphate-binder treatment, while there
was no progression in the placebo arm

Phosphate Binders and Mortality
All-Cause Mortality Dialysis Inception
Di Iorio B et al. Clin J Am Soc Nephrol 2012;7:487-493
In both predialysis and dialysis patients showing significant survival benefits over a 3-year interval for
patients treated with sevelamer versus calcium-containing binders

Sevelamer vs. Calcium
Di Iorio B et al. Am J Kidney Dis. 2013;62:771-778
Arrythmias Cardiovascular Mortality

• Concerns regarding the adverse effects of exogenous calcium may not be
generalizable to children
• Serum calcium levels were positively associated with increases in BMD, was
observed in children with CKD
• This association was significantly more pronounced with greater linear
growth velocity, illustrates the unique needs of the growing skeleton

Phosphate
• 4.1.8: In patients with CKD G3a-G5D, we suggest limiting dietary phosphate
intake in the treatment of hyperphosphatemia alone or in combination
with other treatments (2D).
• It is reasonable to consider phosphate source (e.g., animal, vegetable,
additives) in making dietary recommendations (Not Graded).
• 4.1.9: In patients with CKD G5D, we suggest increasing dialytic phosphate
removal in the treatment of persistent hyperphosphatemia (2C).

we suggest limiting dietary phosphate
intake in the treatment of
hyperphosphatemia alone or in
combination with other treatments. (2D)
• It is reasonable to consider phosphate
source (e.g., animal, vegetable, additives)
in making dietary recommendations. (Not
Graded)
• Old 4.1.7: In patients with CKD G3a–G5D,
we suggest limiting dietary phosphate
intake in the treatment of
hyperphosphatemia alone or in
combination with other treatments (2D).

• The sources of phosphorus include: natural phosphorus (as cellular and protein
constituents) contained in raw or unprocessed foods; phosphorus added to foods
during processing; and phosphorus in dietary supplements or medications
• About 40-60% of animal-based phosphate is absorbed, depending on the GI
vitamin D receptor activations
• Plant phosphate, mostly associated with phytates, is less absorbable (generally
20-50%)
• Inorganic phosphate is more readily absorbed, and its presence in additive-laden
processed, preserved, or enhanced foods or soft drinks is likely to be
underreported in nutrient databases

“Hidden” Phosphate
Sherman RA et al. Clin J Am Soc Nephrol. 2009;4:1370-1373

CHAPTER 4.2:
TREATMENT OF ABNORMAL PTH
LEVELS IN CKD-MBD

Assessment of PTH
• 4.2.1: In patients with CKD G3a-G5 not on dialysis, the optimal PTH level is
not known. However, we suggest that patients with levels of intact PTH
progressively rising or persistently above the upper normal limit for the
assay be evaluated for modifiable factors, including hyperphosphatemia,
hypocalcemia, high phosphate intake, and vitamin D deficiency (2C).

• New 4.2.1: In patients with CKD G3a-G5
not on dialysis, the optimal PTH level is
not known. However, we suggest that
patients with levels of intact PTH
progressively rising or persistently above
the upper normal limit for the assay be
evaluated for modifiable factors, including
hyperphosphatemia, hypocalcemia, high
phosphate intake, and vitamin D
deficiency (2C).
not on dialysis, the optimal PTH level is
not known. However, we suggest that
patients with levels of intact PTH above
the upper normal limit of the assay are
first evaluated for hyperphosphatemia,
hypocalcemia, and vitamin D deficiency
(2C).
• It is reasonable to correct these
abnormalities with any or all of the
following: reducing dietary phosphate
intake and administering phosphate
binders, calcium supplements, and/or
native vitamin D (Not Graded).

• Modest increases in PTH may represent an appropriate adaptive response to declining
kidney function
• The statement revised to include “persistently” above the upper normal PTH level as well
as “progressively rising” PTH levels, rather than “above the upper normal limit”
• That is, treatment should not be based on a single elevated value.
• Although the optimal PTH is not known, rising PTH levels warrant examination of
modifiable factors:
o Vitamin D insufficiency/deficiency
o Hypocalcemia
o Hyperphosphatemia
o High phosphate intake

Calcitriol and Vitamin D
• 4.2.2: In adult patients with CKD G3a-G5 not on dialysis, we suggest
calcitriol and vitamin D analogs not be routinely used (2C). It is reasonable
to reserve the use of calcitriol and vitamin D analogs for patients with CKD
G4-G5 with severe and progressive hyperparathyroidism (Not Graded).
• In children, calcitriol and vitamin D analogs may be considered to maintain
serum calcium levels in the age-appropriate normal range (Not Graded).

• New 4.2.2: In adult patients with CKD
G3a-G5 not on dialysis, we suggest
calcitriol and vitamin D analogs not be
routinely used (2C). It is reasonable to
reserve the use of calcitriol and vitamin D
analogs for patients with CKD G4-G5 with
severe and progressive hyper-
parathyroidism (Not Graded).
• In children, calcitriol and vitamin D
analogs may be considered to maintain
serum calcium levels in the age-
appropriate normal range (Not Graded).
not on dialysis, in whom serum PTH is
progressively rising and remains
persistently above the upper limit of
normal for the assay despite correction of
modifiable factors, we suggest treatment
with calcitriol or vitamin D analogs (2C).

• Multiple RCTs cited in the 2009 guidelines reported benefits of calcitriol or
vitamin D analogs in treating SHPT
• However, adverse effects of hypercalcemia were also noted to be of
concern in the 2009 guidelines
• Two trials, PRIMO and OPERA, demonstrated significantly increased risk of
hypercalcemia with paricalcitol, compared to placebo, in the absence of
beneficial effects on surrogate cardiac endpoints

The PRIMO Trial
• At 48 weeks, the change in left
ventricular mass index and diastolic
function did not differ between
treatment groups
• Episodes of hypercalcemia were more
frequent in the paricalcitol group
compared with the placebo group
• However, paricalcitol treatment reduced
PTH levels within 4 weeks and
maintained levels within the normal
range throughout the study duration

The OPERA Trial
• Change in LVMI did not differ significantly
between groups, nor did secondary outcomes
such as measures of systolic and diastolic
function
• Hypercalcemia occurred in 43.3% and 3.3% of
participants in the paricalcitol and placebo
arms, respectively
• However, paricalcitol treatment significantly
reduced iPTH and ALP levels as well as the
cardiovascular-related hospitalizations, when
compared with placebo

• This review included 18 studies (576 children)
• Bone disease, as assessed by changes in PTH levels, was improved by all
vitamin D preparations regardless of route or frequency of administration

Maintaining/Lowering PTH
• 4.2.3: In patients with CKD G5D, we suggest maintaining intact PTH levels
in the range of approximately 2 to 9 times the upper normal limit for the
assay (2C).
• We suggest that marked changes in PTH levels in either direction within
this range prompt an initiation or change in therapy to avoid progression to
levels outside of this range (2C).
• 4.2.4: In patients with CKD G5D requiring PTH-lowering therapy, we
suggest calcimimetics, calcitriol, or vitamin D analogs, or a combination of
calcimimetics with calcitriol or vitamin D analogs (2B).

• New 4.2.4: In patients with CKD G5D
requiring PTH-lowering therapy, we
suggest calcimimetics, calcitriol, or
vitamin D analogs, or a combination of
calcimimetics with calcitriol or vitamin D
analogs (2B).
• Old 4.2.4: In patients with CKD G5D and
elevated or rising PTH, we suggest calcitriol,
or vitamin D analogs, or calcimimetics, or a
combination of calcimimetics and calcitriol or
vitamin D analogs be used to lower PTH (2B).
• It is reasonable that the initial drug selection
for the treatment of elevated PTH be based
on serum calcium and phosphorus levels and
other aspects of CKD-MBD (Not Graded).
• It is reasonable that calcium or non-calcium-
based phosphate binder dosage be adjusted
so that treatments to control PTH do not
compromise levels of phosphorus and
calcium (Not Graded).

• Old 4.2.4 (cont’d)
• We recommend that, in patients with
hypercalcemia, calcitriol or another vitamin D
sterol be reduced or stopped (1B).
• We suggest that, in patients with
hyperphosphatemia, calcitriol or another
vitamin D sterol be reduced or stopped (2D).
• We suggest that, in patients with
hypocalcemia, calcimimetics be reduced or
stopped depending on severity, concomitant
medications, and clinical signs and symptoms
(2D).
• We suggest that, if the intact PTH levels fall
below two times the upper limit of normal
for the assay, calcitriol, vitamin D analogs,
and/or calcimimetics be reduced or stopped
(2C).

Chertow GM, et al. N Engl J Med. 2012;367:2482-2494
• EVOLVE evaluated the effect of cinacalcet
versus placebo in 3883 HD patients
• All patients were eligible to receive
conventional therapy, including phosphate
binders, vitamin D sterols, or both
• The primary composite end point was the
time until death, myocardial infarction,
hospitalization for unstable angina, heart
failure, or a peripheral vascular event.
Cinacalcet did not significantly reduce the risk
of death or major cardiovascular events

• EVOLVE did not meet its primary endpoint that cinacalcet reduces the risk
of death or clinically important vascular events in CKD G5D patients
• However, the results of secondary analyses suggest that cinacalcet may be
beneficial in this population or a subset
• The higher cost of cinacalcet was also a relevant consideration given its un-
certain clinical benefits
• No consensus was reached to recommend cinacalcet as first-line therapy
• Calcimimetics, calcitriol and vitamin D analogs are all acceptable first-line
options in CKD G5D patients

• The PARADIGM trial compared a cinacalcet-based treatment strategy with
an active vitamin D based strategy in 312 HD patients and demonstrated
similar reductions in PTH in both treatment arms
• The BONAFIDE trial evaluated bone histomorphometry in 77 paired bone
biopsy samples in cinacalcet-treated subjects with proven high-turnover
bone disease and demonstrated reductions in bone formation rates and
substantial increase in the number of subjects with normal bone histology
 Behets GJ, Spasovski G, Sterling LR, et al. Bone histomorphometry before and after long-term treatment with cinacalcet in dialysis patients
with secondary hyperparathyroidism. Kidney Int. 2015;87:846856.
 Block GA, Bushinsky DA, Cheng S, et al. Effect of etelcalcetide vs cinacalcet on serum parathyroid hormone in patients receiving
hemodialysis with secondary hyperparathyroidism: a randomized clinical trial.JAMA.2017;317:156–164.

• Studies of cinacalcet in children are limited to case reports, case series, a
single-center experience (with 4 to 28 patients), and an open label study of
a single dose in 12 children on dialysis
• In recognition of the unique calcium demands of the growing skeleton,
PTH-lowering therapies should be used with caution in children to avoid
hypocalcemia
• Future studies are needed in children before issuing pediatric-specific
recommendations

Severe Hyperparathyroidism
4.2.5:
• In patients with CKD G3a–G5D with severe hyperparathyroidism (HPT) who
fail to respond to medical or pharmacological therapy, we suggest
parathyroidectomy (2B).
Owing to a lack of RCTs of medical vs surgical therapy of HPT, these management
strategies are difficult to compare

CHAPTER 4.3:
TREATMENT OF BONE WITH
BISPHOSPHONATES, OTHER
OSTEOPOROSIS MEDICATIONS, AND
GROWTH HORMONE

Treatment Options
• 4.3.1: In patients with CKD G1–G2 with osteoporosis and/or high risk of
fracture, as identified by World Health Organization criteria, we
recommend management as for the general population (1A).
• 4.3.2: In patients with CKD G3a–G3b with PTH in the normal range and
osteoporosis and/or high risk of fracture, as identified by World Health
Organization criteria, we suggest treatment as for the general population
(2B).

Treatment Options
• 4.3.3: In patients with CKD G3a-G5D with biochemical abnormalities of
CKD-MBD and low BMD and/or fragility fractures, we suggest that
treatment choices take into account the magnitude and reversibility of the
biochemical abnormalities and the progression of CKD, with consideration
of a bone biopsy (2D).
• 4.3.4: In children and adolescents with CKD G2–G5D and related height
deficits, we recommend treatment with recombinant human growth
hormone when additional growth is desired, after first addressing
malnutrition and biochemical abnormalities of CKD-MBD (1A).

• New 4.3.3: In patients with CKD G3a-G5D
with biochemical abnormalities of CKD-MBD
and low BMD and/or fragility fractures, we
suggest that treatment choices take into
account the magnitude and reversibility of
the biochemical abnormalities and the
progression of CKD, with consideration of a
bone biopsy (2D).
• Old 4.3.3: In patients with CKD G3a–G3b with
biochemical abnormalities of CKD-MBD and
low BMD and/or fragility fractures, we
suggest that treatment choices take into
account the magnitude and reversibility of
the biochemical abnormalities and the
progression of CKD, with consideration of a
bone biopsy (2D).
• Old 4.3.4: In patients with CKD G4–G5D
having biochemical abnormalities of CKD-
MBD, and low BMD and/or fragility fractures,
we suggest additional investigation with
bone biopsy prior to therapy with
antiresorptive agents (2C).

• Rec. 3.2.2 now addresses the indications for a bone biopsy prior to
antiresorptive and other osteoporosis therapies
• Therefore, the old Rec. 4.3.4 was removed, and Rec. 4.3.3 was
broadened from CKD G3a-G3b to CKD G3a-G5D.

Management of Osteoporosis in CKD
• Shigematsu et al. in a post hoc analysis of three Japanese trials observed a significant
improvement in lumbar spine BMD, which did not differ in eGFR ≥30 to <60, ≥60 to <90,
and ≥90 ml/min per 1.73 m2. Risendronate did not result in a significant change in eGFR
over the 48 weeks of follow-up.
• Toussaint et al. reported that 18 months of alendronate versus placebo resulted in an
increase in lumbar spine T score by 0.3 in patients with CKD stages 3 and 4
 Shigematsu T, Muraoka R, Sugimoto T, Nishizawa Y: Risedronate therapy in patients with mild-to-moderate chronic kidney disease with
osteoporosis: Post-hoc analysis of data from the risedronate phase III clinical trials. BMC Nephrol 18: 66, 2017
 ToussaintND, LauKK, StraussBJ, Polkinghorne KR, Kerr PG: Effect of alendronate on vascular calcification in CKD stages 3 and 4: A pilot
randomized controlled trial. Am J Kidney Dis56: 57–68, 2010

Management of Osteoporosis in CKD
• A post hoc analysis of FREEDOM Trial showed that Denosumab increased BMD at the
spine and hip and resulted in a 68% lower odds of vertebral fracture in subjects with
eGFR of 30–59 ml/min. There was no interaction between treatment effect and kidney
function, and adverse events did not differ by creatinine clearance.
• Miller et al. in a post hoc analysis of the Fracture Prevention Trial in post-menopausal
women with osteoporosis found that Teriparatide increased BMD at the spine and
femoral neck; and had similar efficacy in preventing vertebral and nonvertebral fracture
in patients with creatinine clearance <80 ml/min compared with >80 ml/min.
 Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J,
Libanati C, Siddhanti S, Christiansen C; FREEDOM Trial: Denosumab for prevention of fractures in postmenopausal women with
osteoporosis. N Engl J Med361: 756–765, 2009
 Miller PD, Schwartz EN, Chen P, Misurski DA, Krege JH: Teriparatide in postmenopausal women with osteoporosis and mild or moderate
renal impairment. Osteoporos Int18:59–68,2007

Pediatric perspective
• Linear height deficit is one of the cardinal features of progressive CKD in
pediatric patients
• The studies with rhGH showed an improvement in height s.d. score, height
velocity, and height velocity s.d. score
• There are limited bone biopsy data in children treated with rhGH
• rhGH has been licensed by the FDA since 1988 for the treatment of linear
growth failure

• The Cochrane article reviewed 15 RCTs (629 children) that compared rhGH therapy with
placebo
• Depending on the study, the effects were evaluated at 6, 12 or 24 months, with positive
results at all time points
Authors' conclusions
• One year of 28 IU/m²/wk rhGH in children with CKD resulted in a 3.88 cm increase in
height velocity above that of untreated patients

CHAPTER 5:
EVALUATION AND TREATMENT OF
KIDNEY TRANSPLANT BONE DISEASE

Background: Biochemical abnormalities

Background: Osteoporosis and Fracture
• The prevalence of osteoporosis in post-transplants is estimated to be 30%
• An estimated 22.5% will experience a fracture within the first 5 years
following transplantation
• When compared to ESRD patients, the relative risk of a hip fracture is 34%
higher during the first 6 months following transplantation, and then
decreases subsequently
• There is an estimated 60% increase risk of death associated with a hip
fracture in post-renal transplants when compared to general population

Assessment
• 5.1: In patients in the immediate post–kidney transplant period, we
recommend measuring serum calcium and phosphate at least weekly, until
stable (1B).
• 5.2: In patients after the immediate post–kidney transplant period, it is
reasonable to base the frequency of monitoring serum calcium, phosphate,
and PTH on the presence and magnitude of abnormalities, and the rate of
progression of CKD (Not Graded).

Assessment
5.2 (cont’d.):
• Reasonable monitoring intervals would be:
• In CKD patients receiving treatments for CKD-MBD, or in whom biochemical
abnormalities are identified, it is reasonable to increase the frequency of
measurements to monitor for efficacy and side effects (Not Graded).
• It is reasonable to manage these abnormalities as for patients with CKD G3a–G5
(see Chapters 4.1 and 4.2) (Not Graded).

Assessment/Treatment
• 5.3: In patients with CKD G1T–G5T, we suggest that 25(OH)D (calcidiol)
levels might be measured, and repeated testing determined by baseline
values and interventions (2C).
• 5.4: In patients with CKD G1T–G5T, we suggest that vitamin D deficiency
and insufficiency be corrected using treatment strategies recommended for
the general population (2C).

Assessment
• 5.5: In patients with CKD G1T-G5T with risk factors for osteoporosis, we
suggest that BMD testing be used to assess fracture risk if results will alter
therapy (2C).

• New 5.5: In patients with CKD G1T-G5T
with risk factors for osteoporosis, we
suggest that BMD testing be used to
assess fracture risk if results will alter
therapy (2C).
• Old 5.5: In patients with an estimated
glomerular filtration rate greater than
approximately 30 ml/min per 1.73 m2, we
suggest measuring BMD in the first 3 months
after kidney transplant if they receive
corticosteroids, or have risk factors for
osteoporosis as in the general population
(2D).
• Old 5.7: In patients with CKD G4T–5T, we
suggest that BMD testing not be performed
routinely, because BMD does not predict
fracture risk as it does in the general
population and BMD does not predict the
type of kidney transplant bone disease (2B).

• 2009 Rec. 5.5 (addressing CKD transplant patients with eGFR > 30
ml/min/1.73 m2) and Rec. 5.7 (addressing CKD G4T-G5T) were combined to
yield 2017 Rec. 5.5
• There is growing evidence that DXA BMD predicts fractures in patients with
CKD across the spectrum of CKD data

Treatment
• 5.6: In patients in the first 12 months after kidney transplant with an
estimated glomerular filtration rate greater than approximately 30 ml/min
per 1.73 m2 and low BMD, we suggest that treatment with vitamin D,
calcitriol/alfacalcidol, and/or antiresorptive agents be considered (2D).
• We suggest that treatment choices be influenced by the presence of CKD-
MBD, as indicated by abnormal levels of calcium, phosphate, PTH, alkaline
phosphatases, and 25(OH)D (2C).
• It is reasonable to consider a bone biopsy to guide treatment (Not Graded).
• There are insufficient data to guide treatment after the first 12 months.

• New 5.6: In patients in the first 12 months
after kidney transplant with an estimated
approximately 30 ml/min per 1.73 m2 and low
BMD, we suggest that treatment with vitamin
D, calcitriol/alfacalcidol, and/or antiresorptive
agents be considered (2D).
• We suggest that treatment choices be influenced by
the presence of CKD-MBD, as indicated by abnormal
levels of calcium, phosphate, PTH, alkaline
phosphatases, and 25(OH)D (2C).
• It is reasonable to consider a bone biopsy to guide
treatment (Not Graded).
• There are insufficient data to guide treatment
after the first 12 months.
• Old 5.6: In patients in the first 12 months
after kidney transplant with an estimated
approximately 30 ml/min per 1.73 m2 and low
BMD, we suggest that treatment with vitamin
D, calcitriol/alfacalcidol, or bisphosphonates
be considered (2D).
• We suggest that treatment choices be influenced by
the presence of CKD–MBD, as indicated by
abnormal levels of calcium, phosphorus, PTH,
alkaline phosphatases, and 25(OH)D (2C).
• It is reasonable to consider a bone biopsy to guide
treatment, specifically before the use of
bisphosphonates due to the high incidence of
adynamic bone disease (Not Graded).
• There are insufficient data to guide treatment
after the first 12 months.

• The second bullet is revised, consistent with the new bone biopsy
recommendation (i.e., 2017 Rec. 3.2.2).

Treatment
• 5.7: In patients with CKD G4T–G5T with known low BMD, we suggest
management as for patients with CKD G4–G5 not on dialysis, as
detailed in Chapters 4.1 and 4.2 (2C).

Key Messages
Prospective studies evaluating BMD testing represents a substantial advance since the original
guideline, making a reasonable case for BMD testing if the results will impact future treatment.
It is important to emphasize the interdependency of serum calcium, phosphate, and PTH for clinical
therapeutic decision-making.
Phosphate-lowering therapies may only be indicated in the case of “progressive or persistent
hyperphosphatemia”.
New evidence suggests that excess exposure to exogenous calcium in adults may be harmful in all
severities of CKD, regardless of other risk markers.

Key Messages
It is reasonable to limit dietary phosphate intake, when considering all sources of dietary
phosphate (including “hidden” sources).
The PRIMO and OPERA studies failed to demonstrate improvements in clinically relevant outcomes
but did demonstrate increased risk of hypercalcemia. Accordingly, routine use of calcitriol or its
analogs in CKD G3a-G5 is no longer routinely recommended.
No consensus was reached to recommend cinacalcet as first-line therapy for lowering PTH in all
patients with SHPT and CKD G5D.

Diagnosis, Evaluation, Prevention and Treatment of CKD-MBD

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