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Int Urol NephrolDOI 10.1007/s11255-016-1436-3
NEPHROLOGY – REVIEW
A critical appraisal of chronic kidney disease mineral and bone disorders clinical practice guidelines using the AGREE II instrument
Nigar Sekercioglu1 · Reem Al‑Khalifah9 · Joycelyne Efua Ewusie1 · Rosilene M. Elias10 · Lehana Thabane1,5,6,7,8,9 · Jason W. Busse1,3,4 · Noori Akhtar‑Danesh1 · Alfonso Iorio1,2 · Tetsuya Isayama1 · Juan Pablo Díaz Martínez1 · Ivan D. Florez1,11 · Gordon H. Guyatt1,2
Received: 21 May 2016 / Accepted: 11 October 2016 © Springer Science+Business Media Dordrecht 2016
independently and in duplicate, screened titles and abstracts and potentially eligible full text reports to determine eligi-bility and subsequently appraised the guidelines using the Advancing Guideline Development, Reporting and Evalua-tion in Health Care instrument II (AGREE).Results Sixteen CPGs published from 2003 to 2015 addressing the diagnosis and management of CKD-MBD in adult patients (11 English, two Spanish, one Italian, one Portuguese and one Slovak) proved eligible. The National Institute for Health and Care Excellence guideline per-formed best with respect to AGREE II criteria; only three other CPGs warranted high scores on all domains. All other guidelines received scores of under 60% on one or more domains. Major discrepancies in recommendations were not, however, present, and we found no association
Abstract Background Patients with chronic kidney disease min-eral and bone disorders (CKD-MBD) suffer high rates of morbidity and mortality, in particular related to bone and cardiovascular outcomes. The management of CKD-MBD remains challenging. The objective of this systematic sur-vey is to critically appraise clinical practice guidelines (CPGs) addressing CKD-MBD.Methods/design Data sources included MEDLINE, EMBASE, the National Guideline Clearinghouse, Guide-line International Network and Turning Research into Practice up to May 2016. Teams of two reviewers,
Electronic supplementary material The online version of this article (doi:10.1007/s11255-016-1436-3) contains supplementary material, which is available to authorized users.
* Nigar Sekercioglu [email protected]
Reem Al-Khalifah [email protected]
Joycelyne Efua Ewusie [email protected]
Lehana Thabane [email protected]
Jason W. Busse [email protected]
Noori Akhtar-Danesh [email protected]
Alfonso Iorio [email protected]
Ivan D. Florez [email protected]
Gordon H. Guyatt [email protected]
1 Department of Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4K1, Canada
2 Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4K1, Canada
3 The Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, ON, Canada
4 Department of Anesthesia, McMaster University, Hamilton, ON, Canada
5 Department of Pediatrics and Anesthesia, McMaster University, Hamilton, ON, Canada
6 Centre for Evaluation of Medicine, St Joseph’s Healthcare—Hamilton, Hamilton, ON, Canada
7 Biostatistics Unit, Father Sean O’Sullivan Research Centre, St Joseph’s Healthcare, 3rd Floor, Martha Wing, Room H-325, 50 Charlton Avenue East, Hamilton, ON L8N 4A6, Canada
Int Urol Nephrol
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between quality of CPGs which was not associated with resulting recommendations.Conclusions Most guidelines assessing CKD-MBD suffer from serious shortcomings using AGREE criteria although limitations with respect to AGREE criteria do not necessar-ily lead to inappropriate recommendations.
Keywords Chronic kidney disease · Advancing guideline development · Reporting and evaluation in health care instrument · Clinical practice guidelines · Mineral and bone disorder
Background
Chronic kidney disease (CKD) is a growing concern around the world that affects 8–16% of the general population [1]. CKD is associated with high mortality and morbidity, high rates of hospitalization and rehospitalization, reduced qual-ity of life and high healthcare costs related to both CKD itself and associated comorbidity [2–4]. Poorly managed patients suffer worse health outcomes and generate greater healthcare costs [5–7].
Since CKD affects all organ systems, management requires a systematic approach and detailed considerations to prevent progression of CKD and extra-renal complica-tions [8]. The goals of the treatment of CKD include: (1) disease-specific treatment if indicated and (2) management of anemia, acidosis, blood pressure, dialysis dose, dialy-sis volume, proteinuria and disorders of bone and mineral metabolism.
Patients with CKD often suffer from chronic kidney dis-ease mineral and bone disorder (CKD-MBD), a condition that is associated with higher risk of cardiovascular events and bone fractures [9–12]. Both abnormally high or low parathyroid hormone levels and elevated phosphate levels result in disturbances in calcium–phosphate homeostasis and cardiovascular calcifications in the media layers of the arteries that may lead to cardiovascular events [9–12]. The association between CKD-MBD and increased fracture risk results from abnormal bone turnover, architecture and min-eralization [9].
Persistently elevated serum parathyroid hormone con-centration associated with CKD-MBD indicates the pres-ence of renal hyperparathyroidism (HPT). In severe forms of the disease, medical management requires combination therapy: the use of active vitamin D analogs, which works through vitamin D receptors, and calcimimetic agents that work through calcium sensing receptors [13–15]. On the other hand, the management of abnormally low parathyroid hormone levels and the associated adynamic bone disease is often more challenging. An alternative approach to the management of renal HPT is the removal of the parathyroid glands [16].
CKD-MBD also involves disturbances of phosphate metabolism that lead to increased phosphate levels. Through a variety of mechanisms, phosphate binders pre-vent phosphate absorption from the gastrointestinal system [17]. Calcium-based phosphate binders have been associ-ated with an increased risk of all-cause mortality [18–20]. Overall the pathophysiology of CKD-MBD is complex and the management requires close monitoring of clinical and laboratory parameters (i.e., serum phosphate, parathy-roid hormone and calcium) because of potential problems related to safety and tolerability of interventions. CKD-MBD CPGs include recommendations based on evidence and expert opinions. The role of clinical practice guidelines (CPGs) is to summarize the available evidence and provide guidance for healthcare providers. If developed system-atically with adequate rigor, CPGs effectively support the knowledge to action cycle [21]. By closing gaps between evidence and policy that limit the utilization of effective interventions or lead to futile interventions, CPGs can improve patient-important outcomes, patient satisfaction and quality of health care [22]. Another potential positive impact of CPGs is prioritization of future research.
A 2005 systematic review of CPG assessment tools included 24 instruments of which only two had a vali-dated scoring system [23]. The most widely used of these instruments, AGREE (Advancing Guideline Development, Reporting and Evaluation in Health Care) [24], has 23 questions aggregated in six domains [25]. The AGREE II instrument provides an online tutorial for reviewers and, while shorter, is as comprehensive as the other instrument with a validated scoring system [25].
Guidelines are expected to minimize variations in health care and improve health outcomes which can be achieved by well-developed guidelines with valid recommendations. Therefore, it is important to assess the existing guidelines to address their strengths and limitations.
The objective of this study was to critically appraise existing CPGs related to CKD-MBD using the AGREE II instrument. Since the quality of CKD-MBD CPGs have not been examined previously and the condition has a sig-nificant negative impacts on patients’ quality of life and
8 Population Health Research Institute, Hamilton Health Sciences, Hamilton, ON, Canada
9 Division of Pediatric Endocrinology, King Saud University, Riyadh, Saudi Arabia
10 Nephrology Department, University of Sao Paulo School of Medicine, São Paulo, Brazil
11 Department of Pediatrics, University of Antioquia, Medellin, Colombia
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survival, we decided to appraise CPGs on CKD-MBD to address areas for further research and clarification. Our aim also included to explore the direction of CPG recommenda-tions in terms of diagnosis and management.
Methods/design
Eligibility criteria
We included CPGs addressing screening, diagnosis, moni-toring or management of CKD-MBD, including both phar-macological and non-pharmacological interventions. CPGs were excluded if they addressed only a pediatric patient population.
We included CPGs that: (1) were based on systematic evidence synthesis with an explicit research question; (2) employed a grading system to rate the quality of evidence; (3) were published in a peer reviewed journal or in a guide-line database. We excluded position statements or consen-sus statements defined as an organizational policy related to screening, diagnosis or management of CKD-MBD rather than a set of directions and principles developed by a rig-orous methodology. We also excluded commentaries that summarized the evidence from a published CPG and made recommendations according to local factors. We evaluated the most current version of each CPG.
Data sources and search strategy
We conducted electronic literature searches of MEDLINE and EMBASE + EMBASE Classic, from inception of each database to February 8, 2016. Subject and text-word terms were selected for (chronic kidney diseases or hemodialysis) and (demineralization or bone diseases) and (guidelines), without language restrictions. We established search alerts for monthly notification and repeated our search before the final manuscript submission to identify any new relevant CPGs.
We scanned the bibliographies of all eligible CPGs for additional relevant guidelines. We also hand-searched the National Guideline Clearinghouse, Guideline International Network and Turning Research into Practice (see eSearch strategies in the supplement for our full search strategy).
All references were saved in the Covidence online soft-ware program. Teams of two reviewers independently screened each title and abstract from our literature search (NS, RA). If either reviewer identified a citation as poten-tially relevant, we obtained the full text of the article. Two reviewers independently determined the eligibility of all CPGs that underwent full text evaluation (NS, RA). Disagreements were resolved through discussion between reviewers.
Data abstraction
Teams of reviewers (NS, RA, JEE, RME, JPDM, TI, IF) extracted data from all eligible CPGs using a standard-ized, pilot-tested, data collection form accompanied by a detailed instruction manual. Reviewers abstracted the fol-lowing information from each CPG: (1) author, (2) year of publication, (3) main recommendations for the manage-ment of CKD-MBD, (4) target population, (5) outcomes and (6) type of meta-analysis (direct, indirect only or mixed evidence).
Analysis plan
We generated a measure of central tendency and dispersion for each AGREE II domain. We used mean values (SD) for normally distributed and median values (interquartile range; IQR) for non-normally distributed variables. We employed the Shapiro–Wilk normality test to examine dis-tributions of domain scores. We compared performance of English versus non-English CPGs using the t test. Previ-ous CPG appraisal studies on other topics applied language restrictions. We tested the difference in quality between English and non-English CPGs using the scale domain scores for the comparison.
All analyses were performed in Microsoft® Excel and Stata (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP). We made calcu-lation for agreement of full text articles using Kappa with linear weighting (http://vassarstats.net/).
The quality assessment instrument and methods
The AGREE II instrument (www.agreetrust.org) contains 23 items divided into six domains: scope and purpose (ques-tions 1–3); stakeholder involvement (questions 4–6); rigor of development (questions 7–14); clarity of presentation (questions 15–17); applicability (questions 18–21); and edi-torial independence (questions 22–23) (eTable 1 in the sup-plemental file) [24]. A seven point scale is used to answer each question with a range of options from 1 (strongly disa-gree) to 7 (strongly agree) [24]. A standardized score rang-ing from 0 to 100% was then calculated for each domain [24]. eMethods in the supplement present a detailed descrip-tion of the scoring system of the AGREE II instrument.
After assessing all domains, we judged the overall confi-dence in each CPG as follows: “the CPG was strongly rec-ommended” (four of six domains were ≥60%); “the CPG was recommended with alterations” (at least two domain scores were above 60%); and “the CPG is not recom-mended due to very serious problems according to AGREE II criteria” (three of six domains scores were less than 30% or none of the domains was above 60%) [26]. Mean
Int Urol Nephrol
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domain scores are categorized as good (≥80%), acceptable (60–79%), moderate (40–59%) or low (<40%).
All reviewers completed the online tutorial before start-ing quality assessment (http://www.agreetrust.rog/resouce-center/training/). In order to improve reliability of assess-ment, each CPG was assessed by three reviewers. Reviewers first read the CPGs in their entirety and reviewed all relevant information regarding the guideline development process, including supplementary material related to the CPG.
Results
CPG identification
The strategy retrieved a total of 3043 references. Our search yielded 2561 unique citations, of which 101 were retrieved
for full text review; 16 CPGs proved eligible (Fig. 1). We included two additional Canadian CPGs identified from the reference list of a commentary [28]. Weighted Kappa with linear weights was 0.96 for full text eligibility. The Shapiro–Wilk test indicated that domain 2 and 5 did not pass the normality test, and we reported median and inter-quartile ranges (p = 0.04, p = 0.0005, domains 2 and 5, respectively).
Characteristics of CPGs
Table 1 presents characteristics of all eligible CPGs. Year of publication ranged from 2003 to 2015; 11 CPGs were in English [29–40], 2 in Spanish [41, 42], 1 in Italian [43], 1 in Portuguese [44] and 1 in Slovak [45]. The target population was dialysis patients in two CPGs, non-dialy-sis patients in one and kidney transplant patients in three
Fig. 1 PRISMA flow diagram of search results PRISMA 2009 Flow Diagram
Records identified through database searching
(n = 2652)
Scre
enin
gIn
clud
edEl
igib
ility
Iden
tific
atio
n
Additional records identified through other sources
(n =3)
Records after duplicates removed(n = 2561)
Records screened(n = 2561)
Records excluded(n = 433)
Full-text articles assessed for eligibility
(n = 101)
Full-text articles excluded due to following reasons
(n =88):
42 review
14 position statement
1 Wrong outcome
7 Duplication, same study was included before
1 Not found
Studies critical appraised (n = 16)
Studies included in quantitative synthesis
(n = 16)
(three guidelines are added from other sources)
Int Urol Nephrol
1 3
Tabl
e 1
Gen
eral
cha
ract
eris
tics
of e
ligib
le C
PGs
Titl
e of
the
CPG
Cou
ntry
and
yea
r of
pub
licat
ion
Shor
t nam
eO
rgan
izat
ion
Lan
guag
e of
pu
blic
atio
nPu
rpos
es o
f th
e gu
ide-
line
(scr
eeni
ng, d
iagn
o-si
s or
man
agem
ent)
Evi
denc
e su
mm
ary
tabl
es
Qua
lity
tabl
es
K/D
OQ
I cl
inic
al p
ract
ice
guid
elin
es f
or
bone
met
abol
ism
and
dis
ease
in c
hron
ic
kidn
ey d
isea
se [
29]
USA
, 200
3K
/DO
QI
Nat
iona
l Kid
ney
Foun
datio
nE
nglis
hD
iagn
osis
and
man
age-
men
tY
esY
es
KD
IGO
clin
ical
pra
ctic
e gu
idel
ines
for
the
prev
entio
n, d
iagn
osis
, eva
luat
ion,
and
tr
eatm
ent o
f ch
roni
c ki
dney
dis
ease
min
-er
al a
nd b
one
diso
rder
(C
KD
-MB
D)
[30]
USA
, 200
9K
DIG
OK
idne
y D
isea
se O
utco
mes
Q
ualit
y In
itiat
ive
Eng
lish
Dia
gnos
is a
nd m
anag
e-m
ent
Yes
Yes
Nat
iona
l Ins
titut
e fo
r H
ealth
and
Car
e E
xcel
lenc
e [3
1, 3
2]U
K, 2
014
NIC
EN
atio
nal I
nstit
ute
for
Hea
lth
and
Car
e E
xcel
lenc
eE
nglis
hD
iagn
osis
and
man
age-
men
tY
esY
es
Car
ing
for A
ustr
alas
ians
with
Ren
al I
mpa
ir-
men
t, fo
r nu
triti
onal
inte
rven
tions
[33
]A
ustr
alia
, 201
0C
AR
I fo
r nu
triti
onal
in
terv
entio
nsC
arin
g fo
r Aus
tral
asia
ns w
ith
Ren
al I
mpa
irm
ent
Eng
lish
Dia
gnos
is a
nd m
anag
e-m
ent
Yes
Yes
Car
ing
for A
ustr
alas
ians
with
ren
al im
pair
-m
ent m
anag
emen
t of
bone
dis
ease
, cal
-ci
um, p
hosp
hate
and
par
athy
roid
hor
mon
e [3
4]
Aus
tral
ia, 2
006
CA
RI
man
agem
ent o
f bo
ne d
isea
se, c
alci
um,
phos
phat
e an
d pa
ra-
thyr
oid
horm
one
Car
ing
for A
ustr
alas
ians
with
R
enal
Im
pair
men
tE
nglis
hD
iagn
osis
and
man
age-
men
tY
esY
es
Car
ing
for A
ustr
alas
ians
with
Ren
al I
mpa
ir-
men
t bio
chem
ical
targ
ets
[35]
Aus
tral
ia, 2
006
CA
RI
bioc
hem
ical
ta
rget
sC
arin
g fo
r Aus
tral
asia
ns w
ith
Ren
al I
mpa
irm
ent
Eng
lish
Dia
gnos
is a
nd m
anag
e-m
ent
No
No
Eur
opea
n re
nal b
est p
ract
ice
guid
elin
es f
or
rena
l tra
nspl
anta
tion
for
bone
dis
ease
[36
]E
urop
ean
coun
-tr
ies,
200
3E
RB
P fo
r bo
ne d
isea
seE
urop
ean
Ren
al B
est P
ract
ice
Eng
lish
Dia
gnos
is a
nd m
anag
e-m
ent
No
No
Clin
ical
pra
ctic
e gu
idel
ine
and
bone
dis
or-
ders
(C
KD
-MB
D)
[37]
UK
, 201
5N
/AR
enal
Ass
ocia
tion
clin
ical
pr
actic
e gu
idel
ines
Eng
lish
Dia
gnos
is a
nd m
anag
e-m
ent
No
No
Clin
ical
pra
ctic
e gu
idel
ine
for
the
man
age-
men
t of
chro
nic
kidn
ey d
isea
se m
iner
al
and
bone
dis
orde
r [3
8]
Japa
n, 2
013
N/A
Japa
nese
soc
iety
of
Nep
hrol
-og
yE
nglis
hD
iagn
osis
and
man
age-
men
tN
oN
o
Jind
al e
t al.
[39]
Can
ada,
200
6N
/AC
anad
ian
Soci
ety
of N
ephr
ol-
ogy
Eng
lish
Man
agem
ent
No
No
Lev
in e
t al.
[40]
Can
ada,
200
8N
/AC
anad
ian
Soci
ety
of N
ephr
ol-
ogy
Eng
lish
Man
agem
ent
No
No
Gui
delin
es o
n bo
ne m
iner
al d
isor
der
in
chro
nic
kidn
ey d
isea
se [
44]
Bra
zil,
2012
N/A
Bra
zilia
n So
ciet
y of
Nep
hrol
-og
yPo
rtug
uese
Man
agem
ent
No
No
Clin
ical
pra
ctic
e gu
idel
ine
for
chro
nic
kid-
ney
dise
ase
min
eral
and
bon
e di
seas
e [4
2]Sp
ain,
201
1N
/ASp
anis
h D
ialy
sis
and
Tra
ns-
plan
t Soc
iety
Span
ish
Dia
gnos
is a
nd m
anag
e-m
ent
No
No
Rec
omm
enda
tions
of
the
Span
ish
Soci
ety
of N
ephr
olog
y fo
r m
anag
ing
bone
min
eral
m
etab
olic
alte
ratio
ns in
chr
onic
ren
al
dise
ase
[41]
Spai
n, 2
008
SEN
gui
delin
esSp
anis
h So
ciet
y of
Nep
hrol
-og
ySp
anis
hD
iagn
osis
and
man
age-
men
tN
oN
o
Int Urol Nephrol
1 3
CPGs. Ten CPGs made recommendations for both dialysis and non-dialysis patient populations.
Table 2 presents AGREE II quality scores for each CPG [29–31, 33–38, 41–45]. All but three CPGs recommended targets for parathyroid hormone, calcium and phospho-rus serum levels (Table 3) [31–34]. Two CARI guidelines and the NICE guideline made recommendations regarding drugs to ameliorate biochemical abnormalities (Table 1). The NICE guideline also included potential effects of dif-ferent drug choices on biochemical markers, cardiovascular and bone outcomes (Table 1).
The NICE guideline did not provide any specific rec-ommendation about the targets for parathyroid hormone, phosphate or calcium. The main focus was on different treatment options (i.e., phosphate binders) and their effec-tiveness and cost-effectiveness on biochemical abnormali-ties, bone and cardiovascular outcomes as well as on mor-tality. Table 1 includes the summary of main features of the CPGs including whether they focused on thresholds, drugs or both.
Reporting quality of CKD‑MBD CPGs
Domain 1 Scope and purpose
The AGREE II quality scores for domain 1 ranged from 0 to 100% with a mean score of 62% (SD = 33%) (Table 2; eFigure 1). Scores of all CPGs were greater than 60% in the domain 1 with the following exceptions: European Best Practice Guidelines (EBPG) for bone disease guideline [36], Steddon et al. [37], Jindal et al. [39], Carvalho et al. [44], Prados-Garrido et al. [42] and the Slovak Republic CPG [45]. The lack of adequate description of objectives, health questions and study populations resulted in low scores for these CPGs.
Domain 2 Stakeholder involvement
The AGREE II quality scores of domain 2 ranged from 1 to 89% with a median score (IQR) of 21% (12–54%) (Table 2; eFigure 2). K/DOQI [29], KDIGO [30] and NICE [31] CPGs reported stakeholder involvement. The majority of the CPGs did not provide adequate information related to patient preferences or target users and subsequently were assigned low scores. The following CPGs obtained a score higher than 60%: K/DOQI [29], KDIGO [30], NICE [31] and Levin et al. [40].
Domain 3 Rigor of development
The AGREE II quality scores for domain 3 ranged from 1 to 94% with a mean score of 44% (SD = 28%) (Table 2; eFigure 3). Eleven CPGs received less than 60% in this Ta
ble
1 c
ontin
ued
Titl
e of
the
CPG
Cou
ntry
and
yea
r of
pub
licat
ion
Shor
t nam
eO
rgan
izat
ion
Lan
guag
e of
pu
blic
atio
nPu
rpos
es o
f th
e gu
ide-
line
(scr
eeni
ng, d
iagn
o-si
s or
man
agem
ent)
Evi
denc
e su
mm
ary
tabl
es
Qua
lity
tabl
es
Cal
cim
imet
ics,
pho
spha
te b
inde
rs, v
itam
in
D a
nd it
s an
alog
ues
for
trea
ting
seco
ndar
y hy
perp
arat
hyro
idis
m in
chr
onic
kid
ney
dise
ase:
gui
delin
e fr
om th
e It
alia
n So
ciet
y of
Nep
hrol
ogy
[43]
Ital
y, 2
007
N/A
Ital
ian
Soci
ety
of N
ephr
olog
yIt
alia
nM
anag
emen
tY
esN
o
The
Slo
vak
Rep
ublic
CPG
[45
]Sl
ovak
, 200
9N
/ASl
ovak
Slov
akM
anag
emen
tN
oN
o
Int Urol Nephrol
1 3
Tabl
e 2
Qua
lity
of c
linic
al p
ract
ice
guid
elin
es o
n C
KD
-MB
D u
sing
the
AG
RE
E I
I to
ol (
expr
esse
d as
per
cent
age)
Dom
ain
scor
es ≥
80%
: goo
d; 6
0–79
%: a
ccep
tabl
e; 4
0–59
%: m
oder
ate;
<40
% lo
w [
26]
Dom
ain
1, s
cope
and
pur
pose
; D
omai
n 2,
sta
keho
lder
inv
olve
men
t; D
omai
n 3,
rig
or o
f de
velo
pmen
t; D
omai
n 4,
cla
rity
of
pres
enta
tion;
Dom
ain
5, a
pplic
abili
ty;
Dom
ain
6, e
dito
rial
ind
epen
d-en
ce;
over
all
qual
ity o
f C
PG, u
sing
a s
cori
ng s
yste
m (
1 th
roug
h 7)
ove
rall
qual
ity w
as a
sses
sed;
AG
RE
E I
I, A
ppra
isal
of
Gui
delin
es, R
esea
rch
and
Eva
luat
ion
II;
K/D
OQ
I, k
idne
y di
seas
e ou
t-co
mes
qua
lity
initi
ativ
e; K
DIG
O, k
idne
y di
seas
e im
prov
ing
glob
al o
utco
mes
; N
ICE
, Nat
iona
l In
stitu
te f
or H
ealth
and
Clin
ical
Exc
elle
nce;
CA
RI,
car
ing
for
Aus
tral
ian
with
ren
al i
mpa
irm
ent;
EB
PG, E
urop
ean
best
pra
ctic
e gu
idel
ines
for
ren
al tr
ansp
lant
atio
n, s
core
s ra
nges
bet
wee
n 0
and
100%
; SD
, sta
ndar
d de
viat
ion
CPG
ID
, yea
r of
pub
licat
ion
Dom
ain
1D
omai
n 2
Dom
ain
3D
omai
n 4
Dom
ain
5D
omai
n 6
Tota
l AG
RE
E I
I sc
ore;
mea
n (S
D)
The
CPG
rec
omm
ende
d fo
r us
e
1K
/DO
QI
[29]
100
7080
100
4067
76 (
22)
Stro
ngly
rec
omm
ende
d
2K
DIG
O [
30]
100
8094
100
2395
82 (
29)
Stro
ngly
rec
omm
ende
d
3N
ICE
[31
, 32]
100
8988
100
1083
92 (
8)St
rong
ly r
ecom
men
ded
4C
AR
I fo
r nu
triti
onal
inte
rven
-tio
ns [
33]
8017
4070
067
46 (
32)
Rec
omm
ende
d w
ith
alte
ratio
ns
5C
AR
I m
anag
emen
t of
bone
di
seas
e, c
alci
um, p
hosp
hate
and
pa
rath
yroi
d ho
rmon
e [3
4]
7715
3487
1813
41 (
33)
Not
rec
omm
ende
d
6C
AR
I bi
oche
mic
al ta
rget
s [3
5]81
740
8017
1440
(33
)N
ot r
ecom
men
ded
7E
BPG
for
bon
e di
seas
e [3
6]1
14
610
011
(24
)N
ot r
ecom
men
ded
8St
eddo
n et
al.
[37]
2610
4477
2133
35 (
23)
Not
rec
omm
ende
d
9Fu
gaka
wa
et a
l. [3
8]69
3533
877
5047
(28
)R
ecom
men
ded
with
al
tera
tions
10Ji
ndal
et a
l. [3
9]52
4440
8314
3945
(22
)R
ecom
men
ded
with
al
tera
tions
11L
evin
et a
l. [4
0]85
6464
8921
8368
(25
)St
rong
ly r
ecom
men
ded
12C
arva
lho
et a
l. [4
4]33
2017
8727
2535
(26
)N
ot r
ecom
men
ded
13Pr
ados
-Gar
rido
et a
l. [4
2]27
1622
7726
1130
(24
)N
ot r
ecom
men
ded
14To
rreg
rosa
et a
l. [4
1]74
4538
8333
7258
(21
)R
ecom
men
ded
with
al
tera
tions
15M
azza
ferr
o et
al.
[43]
7922
7283
240.
0847
(35
)N
ot r
ecom
men
ded
16T
he S
lova
k R
epub
lic C
PG [
45]
01
166
11
12 (
26)
Not
rec
omm
ende
d
Ove
rall
dom
ain
scor
e; m
ean
(SD
)–
62 (
33)
34 (
29)
44 (
28)
83 (
11)
23 (
23)
33 (
41)
––
Int Urol Nephrol
1 3
Tabl
e 3
Rec
omm
enda
tions
for
the
man
agem
ent o
f C
KD
-MB
D
Con
vers
ion
fact
or [
29]
for
PTH
0.1
06; c
alci
um 0
.249
5; p
hosp
horu
s 0.
3229
CA
RI
Car
ing
for A
ustr
alia
n w
ith r
enal
impa
irm
ent,
CK
D-M
BD
chr
onic
kid
ney
dise
ase
min
eral
and
bon
e di
sord
ers,
CP
G c
linic
al p
ract
ice
guid
elin
es, E
BP
G E
urop
ean
best
pra
ctic
e gu
idel
ines
for
re
nal
tran
spla
ntat
ion,
K/D
OQ
I ki
dney
dis
ease
out
com
es q
ualit
y in
itiat
ive,
KD
IGO
kid
ney
dise
ase
impr
ovin
g gl
obal
out
com
es, N
ICE
Nat
iona
l In
stitu
te f
or H
ealth
and
Clin
ical
Exc
elle
nce,
N/A
no
t ava
ilabl
e
CPG
ID
, yea
r of
pub
licat
ion
Cal
cium
Phos
phat
ePa
rath
yroi
d ho
rmon
eC
alci
um a
nd
phos
phat
e pr
oduc
t
K/D
OQ
I [2
9]C
orre
cted
cal
cium
sho
uld
be
mai
ntai
ned
with
in n
orm
al r
ange
(2
.09–
2.37
mm
ol/L
)
1.13
–1.7
7 m
mol
/L35
–70
pg/m
L f
or s
tage
3 C
KD
; 70–
110
pg/m
L
for
stag
e 4
CK
D; 1
50–3
00 p
g/m
L f
or s
tage
5
CK
D
<55
mg2 /d
L2
KD
IGO
[30
]W
ithin
the
norm
al r
ange
With
in th
e no
rmal
ran
ge2–
9 tim
es u
pper
lim
it of
the
norm
al v
alue
N/A
NIC
E [
31, 3
2]N
/AN
/AN
/AN
/A
CA
RI
for
nutr
ition
al in
terv
entio
ns [
33]
N/A
N/A
N/A
CA
RI
man
agem
ent o
f bo
ne d
isea
se,
calc
ium
, pho
spha
te a
nd p
arat
hyro
id
horm
one
[34]
N/A
N/A
N/A
CA
RI
bioc
hem
ical
targ
ets
[35]
2.1–
2.4
mm
ol/L
0.8–
1.6
mm
ol/L
2–3
times
upp
er li
mit
of th
e no
rmal
val
ue<
4 m
mol
/L
EB
PG f
or b
one
dise
ase
[36]
N/A
N/A
N/A
N/A
Sted
don
et a
l. [3
7]2.
2–2.
5 m
mol
/L1.
1–1.
7 m
mol
/L2–
9 tim
es u
pper
lim
it of
the
norm
al v
alue
Fuga
kaw
a et
al.
[38]
2.09
–2.4
9 m
mol
/L1.
13–1
.93
mm
ol/L
60–2
40 p
g/m
LN
/A
Jind
al e
t al.
[39]
With
in th
e no
rmal
ran
ge c
alci
um
leve
lsW
ithin
the
norm
al p
hosp
hate
leve
l10
0–50
0 pg
/mL
Lev
in e
t al.
[40]
With
in th
e no
rmal
ran
ge c
alci
um
leve
lsW
ithin
the
norm
al p
hosp
hate
leve
lN
/A
Car
valh
o et
al.
[44]
With
in th
e no
rmal
val
ue o
f re
fere
nce
With
in th
e no
rmal
val
ue o
f re
fere
nce
for
eGFR
< 6
0 m
L/m
in/1
.73
[2];
if
on d
ialy
sis:
red
uce
tow
ard
the
norm
al
valu
e
35–7
0 pg
/mL
if e
GFR
< 6
0 m
L/m
in/1
.73
[2];
70
–110
pg/
mL
if e
GFR
15–
29 m
L/m
in/1
.73
[2];
2–9
tim
es h
ighe
r th
an s
uper
ior
limit
of
refe
renc
e fo
r C
KD
5
<55
mg2 /d
L2 f
or
adul
ts
Prad
os-G
arri
do e
t al.
[42]
2.09
–2.3
7 m
mol
/L f
or a
ll st
ages
of
CK
D0.
87–1
.48
mm
ol/L
for
sta
ges
3 an
d 4
CK
DW
ithin
the
norm
al v
alue
of
refe
renc
e fo
r C
KD
3;
2 tim
es th
e up
per
norm
al li
mit
for
CK
D 4
; 2–5
tim
es th
e up
per
norm
al li
mit
for
CK
D 5
N/A
Torr
egro
sa e
t al.
[41]
2–2.
37 m
mol
/L f
or a
ll st
ages
of
CK
D0.
87–1
.48
mm
ol/L
for
sta
ges
1,2,
3 an
d 4
CK
D; 0
.87–
1.61
mm
ol/L
for
sta
ge
5 C
KD
<65
pg/
mL
for
CK
D 2
and
3; <
110
pg/
mL
for
C
KD
4; 1
50–3
00 p
g/m
L f
or C
KD
5N
/A
Maz
zafe
rro
et a
l. [4
3]2.
09–2
.37
mm
ol/L
for
CK
D 5
0.87
–1.4
8 m
mol
/L f
or s
tage
s 3
and
4 C
KD
; 1.1
3–1.
77 m
mol
/L f
or C
KD
st
age
5
35–7
0 pg
/mL
for
CK
D 3
, 70–
100
pg/m
L f
or
CK
D 4
, and
150
–300
pg/
mL
for
CK
D 5
<55
mg2 /d
L2
The
Slo
vak
Rep
ublic
gui
delin
e [4
5]2.
1–2.
4 m
mol
/L f
or a
ll st
ages
of
CK
D0.
9–1.
5 m
mol
/L f
or C
KD
3, 1
.1–
1.8
mm
ol/L
for
CK
D 5
35–7
0 pg
/mL
for
CK
D 3
, 150
–300
pg/
mL
for
C
KD
5
Int Urol Nephrol
1 3
domain. Procedures for update and external review were the most common weaknesses across all included CPGs. The following CPGs received a score higher than 60%: K/DOQI [29], KDIGO [30], NICE [31], Levin et al. [40] and Mazzaferro et al. [43].
Domain 4 Clarity of presentation
The AGREE II quality scores of domain 4 ranged from 61 to 100% with a mean score of 83% (SD = 11%) (Table 2; eFigure 4). This domain was well-addressed in all included CPGs. Recommendations were specific and easily identi-fiable in all CPGs, expect one Canadian guideline [39]. The highest mean score with small variability was in this domain (mean = 83%, SD = 11%).
Domain 5 Applicability
The AGREE II quality scores for domain 5 ranged from 0 to 100% with a median score (IQR) of 21% (10–27%) (Table 2; eFigure 5). The NICE guideline received the highest score, and it was the only CPG received a score above 60%. Most of the CPGs did not mention a knowl-edge translation plan. Barriers, facilitators, monitoring and auditing criteria were not addressed by most of the CPGs. As a result, 15 CPGs received a score below 60%.
Domain 6 Editorial independence
The AGREE II quality scores for domain 6 ranged from 0 to 95% with a mean score of 40% (SD = 33%) (Table 2; eFigure 6). This domain yielded poor scores for many CPGs. Competing interests, including financial and intel-lectual, were poorly addressed in ten guidelines that received a score of less than 60%.
We tested the reporting quality of English-language ver-sus other CPGs. The results indicated that there was not a statistically significant difference in domain scores between English and non-English CPGs (Table 4). Published CPG
appraisal studies applied language restrictions. Therefore, we explored the difference in quality between English and non-English CPGs as an hypothesis generating approach.
Overall the NICE guideline scored the highest domain percentages with the AGREE II instrument. Four out of six-teen CPGs proved acceptable by our criteria; the remainder did not. All of the CPGs relied on pairwise comparisons and did not include multiple treatment comparison (MTC) meta-analysis, except the NICE guideline.
Information on the recommendations
The included CPGs provided consistent recommenda-tions (Table 4). We found no suggestion of an association between adherence to AGREE criteria and the recom-mended management strategies. Of 16 CPGs, four CPGs were strongly recommended and four CPGs were recom-mended with alterations. eTables 2 and 3 in the supplemen-tal file present additional information related to included CPGs. The consistency in recommendations despite vary-ing quality of CPGs may reflect a consensus in the clinical community despite the absence of high quality evidence.
Discussion
Our review identified sixteen CPGs that focused on the man-agement of CKD-MBD, either by making recommendations for target values of parathyroid hormone, calcium and phos-phorus or recommending drugs for patients suffering from hyperphosphatemia or renal HPT. Only four of these guide-lines, including the K/DOQI, KDIGO and NICE guidelines, met most criteria of the AGREE II instrument (supplementary figure 1 through 6), and only the NICE CPG reported an ana-lytical framework and economic modeling with cost-effective-ness analysis. However, guideline recommendations were con-sistent across all 16 CPGs, suggesting that reporting quality does not necessarily result in problematic recommendations.
The domain scores of clarity of presentation were high-est (83%) with the lowest variability (11%). The propor-tion that scored over the threshold of 80% was 68%. The domain related the scope and purpose yielded the second best scores. Applicability scored poorly in the majority of CPGs. This is an expected finding as most of the CPGs did not make a recommendations related to management strat-egies in terms of pharmacological and non-pharmacologi-cal interventions, but management of biochemical targets. In general, more guidance is needed for providers related to management strategies to achieve the proposed targets. The issue was adequately addressed by the NICE guideline which can inform clinical practice in CKD-MBD.
Eleven CPGs applied the Grading of Recommenda-tions, Assessment, Development and Evaluation (GRADE)
Table 4 Performance of English-language versus non-English CPGs (expressed as percentage)
CPG clinical practice guidelines, SD standard deviation
English CPGs; mean domain score (SD)
Non-English CPGs; mean domain score (SD)
Domain 1 70 (31) 43 (33)
Domain 2 39 (31) 21 (15)
Domain 3 51 (27) 30 (24)
Domain 4 85 (12) 79 (8)
Domain 5 24 (27) 22 (12)
Domain 6 49 (32) 22 (29)
Int Urol Nephrol
1 3
approach to evaluate the quality of evidence, which consid-ers the overall risk of bias, precision, consistency, directness and publication bias [46]. Precision requires the assessment of the optimal information size (OIS; the number of patients generated by a conventional sample size calculation for a single trial) and the width of the 95% CIs. With respect to directness, differences in population, intervention, outcomes and settings (primary vs. secondary vs. tertiary care settings) need to be considered. Consistency requires assessment of clinical, methodological and statistical heterogeneity.
After considering these reasons for rating down, the overall quality of evidence in estimates of effect for each outcome is reported as follows: “high” quality of evidence (we are very confident that the true effect lies close to that of the estimate of the effect); “moderate” quality of evi-dence (we are moderately confident in the effect estimate, and the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially differ-ent); “low” quality of evidence (our confidence in the effect estimate is limited, and the true effect may be substantially different from the estimate of the effect); and “very low” quality of evidence (we have very little confidence in the effect estimate, and the true effect is likely to be substan-tially different from the estimate of effect) [47]. A total of eleven CPGs employed the GRADE methodology to assess the quality of evidence.
Two CPGs developed by the Canadian Society of Neph-rology used a grading system from A through D that was developed based on the width of the confidence intervals of effect estimates by the Canadian Hypertension Education Program [39, 40]. The system assesses internal validity, precision (the width of confidence intervals) and external validity [48]. In this system, RCTs begin as grade A, but may be rated down by one or more after being examined for adequate power and applicability of the results [48]. Observational studies begin as Grade C and can be rated down for issues related to applicability and precision [48].
Since decision making in health care is largely decen-tralized, a substantial variation between decisions made by healthcare providers is not surprising in situations when evidence does not show definitive conclusions regarding optimal practice. CPGs facilitate standardized approaches across healthcare providers and healthcare systems using retrieved, appraised and summarized best available evi-dence—but only when evidence is high quality. When evi-dence is not high quality, variable practice may be reason-able, appropriate and inevitable [49].
Clinical practice guidelines are considered as basic units of knowledge translation and require expertise and a teamwork for successful implementation and sustainabil-ity with careful identifications of barriers and facilitators. One should take advantage of facilitators to overcome bar-riers. Clinical pathways provided by well-developed CPGs
based on best current evidence can provide great benefit for patients with CKD-MBD.
Relation to other studies
The AGREE II instrument was employed to appraise CPGs in the past. Several studies defined similar shortcomings in terms of validity of the recommendations and methods of the development process related to CPGs on osteoarthri-tis [50–52]. The assessment of CPGs on peripheral artery disease indicated a positive change in methodological qual-ity after publication of the AGREE II instrument [27]. One study compared AGREE II tool and GRADE methodol-ogy in patients with rheumatoid arthritis and found that the AGREE II tool was not comprehensive enough to accom-modate all GRADE criteria [53].
Strengths and limitations
This is the first study to employ the AGREE II instru-ment for critical appraisal of CPGs related to CKD-MBD. Strengths of our review include explicit eligibility criteria, a comprehensive search (no restrictions in terms of lan-guage and thus are able to present an overview of world-wide guidelines) and independent duplicate assessment of eligibility. We used AGREE II, a rigorously developed and tested instrument, to assess the quality of the CPGs related to CKD-MBD. Lastly, our review was performed by meth-odologists and clinical experts with substantial expertise on quality appraisal and synthesis of evidence.
One limitation of the choice to use AGREE II is that the instrument does not comprehensively address all aspects of a guideline that are important—in particular, some issues high-lighted by the GRADE approach to developing guidelines [52]. In particular, AGREE II does not address whether the evidence summary in the guideline addresses all important issues related to quality of the evidence—risk of bias, pre-cision, consistency, directness and publication bias. Equally important, AGREE II does not assess the extent to which the guideline makes underlying value and preference judgments explicit—a key aspect crucial to the use of the guideline in clinical care. Finally, AGREE II does not explicitly label the issue of the recommendations being consistent with the evi-dence (i.e., that generally moderate or high quality evidence is necessary to justify strong recommendations).
The quality of the guideline (the extent to which the guideline meets AGREE II criteria and other criteria not included in AGREE II) is a separate issue from the cer-tainty (quality, confidence) in the evidence underlying the recommendations the guideline offers. That is, a guide-line may conduct its process optimally, but limitations in the underlying evidence may justify only weak recom-mendations [54, 55]. We did not describe the guidelines’
Int Urol Nephrol
1 3
assessment of the quality of the underlying evidence; when assessed, we did not describe the guidelines’ conclusions about quality of evidence; nor did we make such an assess-ment ourselves.
One could also question our choice of a threshold of 60% for adequate domain scores. One could, for instance, argue that 80% is preferable. One of the limitations of our study is a possible selection bias toward higher quality CPGs.
Implications
We showed there was a wide variation in the quality of CPGs, with most suffering from substantial limitations; these limitations were not, however, associated with dif-fering recommendations. Possible explanations for the consistency in recommendations despite varying guide-line adherence to AGREE II criteria include the evidence being extremely clear and thus, whatever the methodology, conclusions would be evident. This does not appear to be the case, however, because evidence in most instances was not high quality. The consistency of the recommendations appears to reflect a consensus in the clinical community despite the absence of high quality evidence.
Conclusions
Evidence-based management of CKD-MBD requires rig-orously developed CPGs with well-justified valid recom-mendations based on the best available evidence. We found that most CPGs related to CKD-MBD were not satisfactory with major problems with rigor, update and implementa-tion. In this instance, recommendations were consistent and thus unassociated with guideline quality. In other instances, however, this may not be the case, and ensuring trustwor-thiness of guidelines will require adherence to methodo-logical standards.
Compliance with ethical standards
Conflict of interest Authors have no conflict of interest.
Human rights and animal statement This article does not contain any studies with human participants or animals performed by any of the authors.
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