What are we missing in CKD-MBD management definitions and diagnosis

WHAT ARE WE MISSING IN
CKD-MBD MANAGEMENT
MAGDY ELSHARKAWY
PROF. OF INT. MED & NEPHROLOGY
AIN-SHAMS UNIVERSITY

Definition of CKD-MBD
A systemic disorder of mineral and bone metabolism due
to CKD manifested by either one or a combination of the
following:
– Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism
– Abnormalities in bone turnover, mineralization, volume, linear growth, or
strength
– Vascular or other soft tissue calcification
• Moe et al Kidney International June 2006

Standardization of Terms
• The term renal osteodystrophy (ROD)
should be used exclusively to define the bone
pathology associated with CKD.
• The clinical, biochemical, and imaging
abnormalities should be defined more broadly
as a clinical entity or syndrome called Chronic
Kidney Disease-Mineral and Bone Disorder
(CKD-MBD).

A Framework for Classification of CKD-MBD
Type*
Laboratory
Abnormalities
Bone Disease
Calcification of
Vascular or Other
Soft Tissue
L + - -
LB + + -
LC + - +
LBC + + +
* L = laboratory abnormalities (of calcium, phosphorus, PTH,
alkaline phosphatase or vitamin D metabolism); B = bone disease
(abnormalities in bone turnover, mineralization, volume, linear
growth, or strength); C = calcification of vascular or other soft
tissue.
•Kidney International June 2006

What are we
missing in this
definitions?

What are we
missing in this
definitions?
Clinical Definitions

Etiology & Management of ROD
• Diagnosis of ROD
• Biochemical Markers
• Radiology
• Histology and Pathology

Biochemical Markers of Renal
Osteodystrophy
• Total Calcium (8.5-10mg/dl)
• Phosphorus ( 3.5-5.2mg/dl).
• PTH assays (150-300pg/dl KDOQI).
• PTH assays (150-700pg/dl KDIGO)
• Alkaline phosphatase (age related).
• Aluminum.

Grahame Elder, JOURNAL OF BONE AND MINERAL RESEARCH, 2002

Evolution of type
of renal
osteodystrophy
after cinacalcet
treatment.
Geert J Behets et al,. KI 2014

Geert J Behets et al,. KI 2014

Changes in types of bone disease (based on qualitative evaluation of bone).
Aníbal Ferreira et al. JASN 2008;19:405-412
©2008 by American Society of Nephrology

The percentage of hyperphosphatemia
was 50% and iPTH > 300 pg/mL was
also 50%.
Elevated iPTH levels showed a
significant association with increased
hyperphosphatemia

What are we
missing in this
diagnosis?

What are we
missing in this
diagnosis?
Lab/ pathology correlations

Biopsy of bone and the microscopic analysis of undercalcified sections after
double tetracycline labeling provide definitive and quantitative diagnosis of
renal bone disease.25 To standardize reports on bone histology, the Kidney
Disease:
Improving Global Outcomes (KDIGO) CKD-MBD work group proposed the
TMV classification, an assessment of turnover (T), mineralization (M), and bone
volume (V).1 Bone mineralization is assessed by the administration of two
different tetracyclines spaced apart (e.g., tetracycline 500 mg three times daily
for 2 days, followed by a 10-day interval, then demeclocycline 300 mg three
times daily for 3 days) and biopsy 4 days later; the quantitation of bone
mineralization rate is achieved by measuring the distance between the two
fluorescent tetracycline bands.

What are we
missing in this
Diagnosis?

What are we
missing in this
Diagnosis?
Bone biopsy

Phosphorus
• Fasting or postprandial
• Organic and non organic
• Ph binders
• Protein and fish phosphorous

Fasting or
postprandial
Fasting and postprandial
measurements of serum
phosphorus (A), fractional
excretion of phosphorus (B), FGF-
23 (C), serum calcium (D),
fractional excretion of calcium (E),
and PTH (F) after meal 1 in healthy
volunteers (○) and patients with
CKD (▪). Time 0 represents the
fasting measurements.
Isakova et al., JASN 2008

Fasting and postprandial
measurements of serum
phosphorus (A), fractional
excretion of phosphorus (B), FGF-
23 (C), serum calcium (D),
fractional excretion of calcium (E),
and PTH (F) after meal 1 in healthy
volunteers (○) and patients with
CKD (▪). Time 0 represents the
fasting measurements.
Isakova et al., JASN 2008

Phosphorus
content of
common
foods

Comparison: 2017 vs 2009
• New 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)
• 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).

What are we
missing in this
phosphorous?

What are we
missing in this
phosphorous?
Clear Guidelines

G5D, we suggest using a
dialysate calcium concentration
between 1.25 and 1.50 mmol/l
(2.5 and 3.0 mEq/l) (2C).
• 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).

What are we
missing in this
Dialysate Ca?
Clear Guidelines

low serum magnesium level is a significant predictor of
mortality in hemodialysis patients.

From: Magnesium and outcomes in patients with chronic kidney disease: focus on vascular calcification,
atherosclerosis and survival
Clin Kidney J. 2012;5(Suppl_1):i52-i61. doi:10.1093/ndtplus/sfr167
Clin Kidney J | © The Author 2012. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For
permissions, please e-mail: journals.permissions@oup.comThis is an Open Access article distributed under the terms of the
Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-

From: Magnesium and outcomes in patients with chronic kidney disease: focus on vascular calcification, atherosclerosis an
survival
Clin Kidney J. 2012;

From: Use of magnesium as a drug in chronic kidney disease
Clin Kidney J. 2012;5(Suppl_1):i62-i70. doi:10.1093/ndtplus/sfr168
Clin Kidney J | © The Author 2012. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For
permissions, please e-mail: journals.permissions@oup.comThis is an Open Access article distributed under the terms of the
Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-
commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-

A growing body of evidence from in vitro investigations, animal models
and both observational as well as interventional clinical studies point to
the possibility that low magnesium levels are associated with vascular
calcification.
Moreover, several observational studies suggest a relationship between
increased serum magnesium concentrations and better survival rates for
patients receiving long-term dialysis treatment.

(A–D) Cumulative mortality curves for (A) all-cause mortality within 6 months, (B) cardiovascular
(CV) mortality within 6 months, (C) all-cause mortality within 4 years, and (D) cardiovascular
mortality within 4 years according to tertiles of bone alkaline ...
Christiane Drechsler et al. CJASN 2011;6:1752-1759
high levels of BAP were
strongly associated with
short-term mortality in
dialysis patients,
suggesting BAP as an
important biomarker of
bone and mineral
disorder in dialysis
patients.

From: Outcome predictability of serum alkaline phosphatase in men with pre-dialysis CKD
Nephrol Dial Transplant. 2010;25(9):3003-3011. doi:10.1093/ndt/gfq144
Nephrol Dial Transplant | Published by Oxford University Press on behalf of ERA-EDTA 2010. All rights reserved. For
Permissions, please e-mail: journals.permissions@oxfordjournals.orgOxford University Press
High levels of BAP were strongly
associated with short-term
mortality in dialysis patients,
suggesting BAP as an important
biomarker of bone and mineral
disorder in dialysis patients.

What are we
missing is
ALP?
AlP/BAP

Table 3. Results of baseline multivariate Cox regression and competing risk regression
analysis for all-cause mortality in Beijing maintenance hemodialysis patients (n = 8530).
Li D, Zhang L, Zuo L, Jin CG, Li WG, et al. (2017) Association of CKD-MBD Markers with All-Cause Mortality in Prevalent
Hemodialysis Patients: A Cohort Study in Beijing. PLOS ONE 12(1): e0168537. https://doi.org/10.1371/journal.pone.0168537
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168537

Fig 1. Kaplan-Meier curves for the five groups categorized by different iPTH level.
Li D, Zhang L, Zuo L, Jin CG, Li WG, et al. (2017) Association of CKD-MBD Markers with All-Cause Mortality in Prevalent
Hemodialysis Patients: A Cohort Study in Beijing. PLOS ONE 12(1): e0168537. https://doi.org/10.1371/journal.pone.0168537
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168537

PTH
• Assays
• Bone remodeling issue

The third-generation bio-
intact parathyroid hormone
(PTH) (1–84) assay was
designed to overcome
problems associated with
the detection of C-terminal
fragments by the second-
generation intact PTH assay

General
concepts of
osteoporosis
and related
consequences
Bover et al., Journal of Nephrology 2017

Bisphosphonates
• CKD–MBD KDIGO guidelines,
• in patients with CKD stages 1–2 with OP and/or high risk of fracture, treatment as for
the general population is suggested (guideline 4.3.1, evidence 1A).
• In patients with CKD stage 3 with PTH in the normal range and OP and/or high risk of
fracture, treatment as for the general population is again suggested (guideline 4.3.2,
evidence 2B).
• On the other hand, in patients with CKD stage 3 with biochemical abnormalities of CKD–
MBD and low BMD and/or fragility fractures, it is suggested that treatment choices
should take into account the magnitude and reversibility of the biochemical
abnormalities and the progression of CKD, with consideration of a bone biopsy
(guideline 4.3.3, evidence 2D).
• Oral bisphosphonates are also indicated in order to reduce bone loss in
glucocorticoid- or transplant-induced OP
• FDA advises against the use of bisphosphonates in patients with a
GFR <30 ml/min/1.73 m2
• The scarce clinical evidence of efficacy and safety of bisphosphonates in stage
4–5 CKD make it difficult to make any definite recommendations.

Anpalahan, et al., Advances in Nephrology, 2014

Denosumab
• DMab also to be effective in reducing fracture risk and increasing
BMD after 36 months of follow-up in subjects receiving DMAb or
placebo.
• However, other studies have shown that DMab may induce significant
hypocalcemia, especially in CKD and hemodialysis patients with
underlying high-turnover bone disease due to secondary
hyperparathyroidism or metastatic bone disease
Nishikawa ,. Et alClinical Interventions in Aging, 2016

Teriparatide
• Compared with placebo, teriparatide was found
to significantly increase lumbar spine and
femoral neck BMD within each renal function
subgroup.
• A recent post-hoc analysis of a postmarketing
surveillance study that included elderly female
Japanese patients with OP who were at high risk
of fracture (82% had a previous fracture) and
stage 4 or 5 CKD and had been receiving
subcutaneous teriparatide 20 μg daily for up to
24 months revealed that teriparatide appeared
to be effective by increasing BMD and
procollagen type 1 N-terminal propeptide
Nishikawa ,. Et alClinical Interventions in Aging, 2016

Romosozumab
• Humanized monoclonal antibody against sclerostin—an inhibitor of
the Wnt and bone morphogenic protein signaling pathways—which
stimulates bone formation.
• Anti-sclerostin antibody treatment was found to be helpful in
improving bone properties in experimental models of progressive
renal osteodystrophy but only when the PTH levels were low
Moe SM, et al. J Bone Miner Res, 2015

Osteoporosis
Nephrologists should probably not ignore any longer fracture risk
assessment, especially in patients with additional risk factors for osteoporosis
if results will impact treatment decisions.
However, although different therapeutic agents have been shown to reduce
the risk of fracture in CKD patients with low BMD, specific prospective
studies, with or without bone biopsies, in CKD are urgently needed.

Thus, although this study is an important addition to the literature, we still need prospective
observational studies to determine whether measurement of BMD by DXA also predicts
fractures in patients with CKD stages 4 and 5, with overt biochemical manifestations of CKD-
MBD.

An algorithm for fracture risk screening and initiation of anti-fracture strategies in patients with
CKD. CKD-MBD, CKD mineral and bone disease; DXA, dual energy x-ray absorptiometry; PTH,
parathyroid hormone.
Pascale Khairallah, and Thomas L. Nickolas CJASN
doi:10.2215/CJN.11031017
February 2018

• CKD-MBD is a systemic disorder that has significant clinical
implications.
• Treatment of CKD-MBD in children requires special consideration in
order to maximize growth, optimize skeletal health, and prevent
cardiovascular disease.

Growth in children
• After correcting all metabolic abnormalities that can worsen growth
status such as metabolic acidosis, anemia, CKD–MBD and
malnutrition in pediatric patients with mild-to-moderate renal
insufficiency.
• The use of supraphysiological doses of recombinant human GH
(rhGH) has been proved to be safe and effective in increasing growth
and final adult height.

Why would we need vit D
 1- to replenish vit D YES
 2- to increase Ca levels
 3- to control PTH
 4- Skeletal effects
 5- other
CVD, Mortality, and morbidly

 4.2.2.
 In adult patients with CKD Stages 3a-5 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 Stages 4-5
with severe and progressive hyperparathyroidism. (Not
Graded)

Dialysis adequacy
• Hi flux
• HDF

Management of clinical presentations of CKD-MBD:
• Bone pains
• Muscle pain and weakness
• Skeletal deformities
• Pseudogout
• Calcefic periartheritis
• Vascular calcification
• Fractures.
• Tendon rupture
• Pruritus
• Calciphelaxis

Conclusion
• We are missing Large RCT establishing solid endpoints
like, Fractures, calcification, mortality, and quality of
life.
• Attention to ALP, MG and difference in PTH assays.
• Clear guidelines regarding all aspects of CKD-MBD
• Biopsy when indicated
• Reconsider using Magnesium salts alone and as
phosphate binder.

• ferric citrate was generally well tolerated and adverse
events were consistent with its known safety profile.
The most commonly reported adverse events in the
Phase 3 study were diarrhea (21%), constipation
(19%), discolored feces (15%), nausea (11%),
abdominal pain (6%), and hyperkalemia (7%)
Keryx Biopharmaceuticals Inc.’s

What are the key considerations in phosphate
binder treatment?

What are the key considerations in phosphate
binder treatment?
• Data from three observational studies (Isakova et al
study, DOPPS, and COSMOS, and Study) have shown a
survival benefit associated with the early
administration of phosphate binders.
Isakova , et al. JASN 2009;20:388-396.
Lopes AA, et al (DOPPS):Am J Kidney Dis 2012
Cannata-Andia JB COSMOS study. 49th ERA-EDTA Congress; 2012.

Stratified HRs for mortality in the unmatched subcohort (n = 8610) comparing patients who
began treatment with phosphorus binders during the first 90 d on hemodialysis versus those
who were not treated during the first 90 d.
Isakova T et al. JASN 2009;20:388-396

Parameter HR 95% CI P
Intention-to-treat analyses
a
no adjustment 0.58 0.52 to 0.66 <0.0001
multivariable-adjusted
b
0.70 0.62 to 0.79 <0.0001
vitamin D–adjusted
c
0.70 0.62 to 0.79 <0.0001
facility-specific SMR–
stratified
d
0.71 0.62 to 0.81 <0.0001
As-treated analyses
e
no adjustment 0.70 0.61 to 0.78 <0.0001
multivariable-adjusted
b
0.82 0.72 to 0.93 0.001
vitamin D–adjusted
c
0.82 0.72 to 0.93 0.002
facility-specific SMR–
stratified
d
0.71 0.63 to 0.81 <0.0001
25% reduction in the risk of death compared with those who did not receive phosphate binders (HR: 0.75;
95% CI: 0.68–0.83); in models adjusted for nutritional factors, a 12% lower risk of death was reported
Lopes AA, et al (DOPPS):Am J Kidney Dis 2012
DOPPS study

• Third study data from 6321 patients on hemodialysis included in the
COSMOS study also indicate that the use of phosphate binders,
either alone or in combination regimens, was associated with a
significantly lower risk of all-cause mortality.
Cannata-Andia JB COSMOS study. 49th ERA-EDTA Congress; 2012.

Ca Vs Sevelamer
• In clinical practice, calcium containing PB, and sevelamer
hydrochloride are currently the two most commonly used phosphate
binders.
• Previous studies comparing them suggested that they are equally
effective.
QUNIBI et al. (CARE Study). Kidney Int 2004

Phosphate Binders in Moderate CKD
Block G et al. J Am Soc Nephrol. 2012;23:1407-1415.
ACTIVE PLACEBO PLACEBOLANTHANUM SEVELAMER CALCIUM

Ca Vs Sevelamer
• CARE study; the only prospective, randomized,
double-blind study comparing the only two FDA-
approved phosphate binders,
• Calcium-based binders have been shown to be more
effective in reducing serum phosphate levels than
sevelamer hydrochloride
•

Care study
QUNIBI and CHARLES R NOLAN ,Kidney International (2004)

Care study
CONCLUSION
• the superiority of calcium acetate over sevelamer
hydrochloride for achieving the target levels of serum
phosphorus and Ca P product recommended by K/DOQI
guidelines.
• Moreover, calcium acetate appears to be the more cost-
effective choice as first-line treatment for hyperphosphatemia
in patients with ESRD on maintenance dialysis.
WAJEHY QUNIBI and CHARLES R NOLAN ,Kidney International (2004)

Ca Vs Sevelamer
• In other study, in a prospective 42-month study
including 1347 haemodialysis patients, those
prescribed sevelamer HCl had a higher mortality risk
compared with those prescribed calcium carbonate
(HR: 1.46; 95% CI: 1.1–1.9).
Jean G, et al., Hemodial Int 2011

Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis
GEOFFREY A BLOCK, et al., Kidney International (2005)
Median coronary artery calcium score.

Ca Vs Sevelamer
• In BLOCK, et al study , CV mortality in the sevelamer group was ten
times lower than that in the calcium carbonate group (P < 0.001).
• A significant reduction in all-cause mortality, though not in non-CV
mortality, was also noted in the sevelamer group.
BLOCK, et al., Kidney International (2005)

Suki WN, et al . Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients.
Kidney Int 2007

Ca Vs Sevelamer
• A Cochrane review and meta-analysis of studies including patients
with CKD stages 3–5D according to KDOQI guidelines indicated that
sevelamer significantly decreases end-of-treatment serum phosphate
levels compared with placebo, although comparisons of reduction in
serum phosphate with calcium-based binders favored the latter
group.
Navaneethan SD, et al., Database Syst Rev 2011

G3a-G5D, decisions about
phosphate-lowering treatment
should be based on
progressively or persistently
elevated serum phosphate (Not
Graded).
• Old 4.1.5: 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).
• 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).

Phosphate Binders and Mortality
All-Cause Mortality Dialysis Inception
Di Iorio B et al. Clin J Am Soc Nephrol 2012;7:487-493

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

What are we missing in CKD-MBD management definitions and diagnosis

What are we missing in CKD-MBD management definitions and diagnosis

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