Transcript Slide 1

KDIGO Clinical Practice Guideline for the
Diagnosis, Evaluation, Prevention, and
Treatment of Chronic Kidney DiseaseMineral and Bone Disorder (CKD-MBD)
KDIGO Mission Statement
Improve the care and outcomes of
kidney disease patients worldwide
through promoting coordination,
collaboration and integration of
initiatives to develop and implement
clinical practice guidelines.
Chronic Kidney Disease – Mineral Bone Disorder
(CKD – MBD)
 A systemic disorder of bone
and mineral 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 Int 2006;69:1945-1953
KDIGO CKD-MBD Guidelines
Work Group Members

Tilman Drüeke, MD (Co-chair)

United States
France

Geoffrey Block, MD

Jorge B. Cannata-Andía, MD, PhD

Grahame Elder, MB, BS, PhD

Masafumi Fukagawa, MD, PhD

Vanda Jorgetti, MD, PhD

Markus Ketteler, MD

Craig Langman, MD
United States

José Weisinger, MD
Venezuela
Germany

Angela Yee-Moon Wang, MD, PhD
Hong Kong
Brazil

Susan Ott, MD
United States
Japan

Peter A McCullough, MD, MPH
United States
Australia

Linda McCann, RD, LD, CSR
United States
Spain

Alison MacLeod, MD
United Kingdom
United States

Sharon M. Moe, MD (Co-chair)

David Wheeler, MD
United Kingdom
Adeera Levin, MD,
Canada
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Key Categories in KDIGO
Diagnosis/Evaluation
Vascular Calcification
Treatment
Chronic Kidney Disease (CKD)
 CKD is characterized by the progressive loss of the
kidneys’ ability to remove waste and maintain fluid and
chemical balance in the body
 A CKD diagnosis is made when:
– Kidney damage is present for >3 months, with or without
decreased glomerular filtration rate (GFR), manifested by either
 Pathologic abnormalities, or
 Markers of kidney damage, including abnormalities in blood,
urine or imaging tests
– A GFR level of <60 mL/min/1.73m2 persists for >3 months, with
or without kidney damage
KDIGO Grading of Recommendations
Strength of
Recommendation
Implications
“We recommend …”
Level 1
“Most patients should receive the
recommended course of action.”
Grade for
Quality of
Evidence
Quality of
Evidence
A
High
B
Moderate
C
Low
D
Very Low
“We suggest …”
Level 2
“Different choices will be appropriate
for different patients.”
Not Graded
“The strength of a recommendation is determined not just by the quality of evidence, but also by other, often
complex judgments regarding the size of the net medical benefit, values and preferences, and costs.”
KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130
KDIGO: Diagnosis of CKD-MBD
Biochemical Abnormalities
Diagnosis of CKD-MBD:
Biochemical Abnormalities
 In the initial CKD stagea, the recommendation is to
monitor serum levels of:
– Phosphorus
– Calcium
– PTH
– Alkaline phosphatase
 In CKD stages 3-5Db, frequency of monitoring serum
calcium, phosphorus, and PTH should be based:
– On the presence and magnitude of abnormalities
– The rate of progression of CKD
 In childrenc, the suggestion is to begin monitoring in
CKD stage 2
a. 3.1.1 (1C); b. 3.1.2 (not graded); c. 3.1.1 (2D)
KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130
Diagnosis of CKD-MBD:
Biochemical Abnormalities
 In patients with CKD stages 3-5D, the suggestionsa are
to:
– Measure 25(OH)D (calcidiol) levels
– Repeat testing on the basis of:
 Baseline values
 Therapeutic interventions
– Correct vitamin D deficiency and insufficiency in accordance to
treatment strategies recommended for the general population
a. 3.1.3 (2C)
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Diagnosis of CKD-MBD:
Biochemical Abnormalities
 In patients with CKD stages 3-5D,
– The recommendationa is that therapeutic decisions should be
based on:
 Trends versus a single laboratory value
 All available CKD–MBD assessments
– The suggestionb is that medical practice should be guided by:
 The evaluation of individual values of serum calcium and
phosphorus together
 Rather than the calcium–phosphorus product (Ca x P)
a. 3.1.4 (1C); b. 3.1.5 (2D)
KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130
Evaluation of CKD-MBD:
Biochemical Abnormalities
Phosphorus & Calcium
CKD Stage
KDIGO
GFR Range
(mL/min/1.73 m2)
Every 6 – 12 months
3
30–59
Every 3 – 6 months
4
15–29
Every 1 – 3 months
5
<15 or dialysis
PTH
CKD Stage
KDIGO
GFR Range
(mL/min/1.73 m2)
3
Based on baseline level and CKD stage
30–59
4
Every 6 – 12 months
15–29
5
Every 3 – 6 months
<15 or dialysis
a. 3.1.4 (1C); b. 3.1.5 (2D)
KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130
KDIGO: Diagnosis of CKD-MBD
Vascular Calcification
Arterial Media Calcification in ESRD: Impact
on All-Cause and Cardiovascular Mortality
Arterial Intimal
Calcification*
 usually observed in…
− older patients with a clinical
history of atherosclerosis
before starting HD
− those with typical risk factors
associated with
atherosclerotic disease
n=202
ESRD=end-stage renal disease
HD=hemodialysis
Arterial Medial
Calcification*
 usually observed in…
− young and middle-aged patients
without conventional
atherosclerotic risk factors
− associated with
− duration of HD
− calcium-phosphate
disorders
− oral dose of elemental
calcium prescribed as a
phosphate binder (CaCO3)
*For illustration purposes only
London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H. Nephrol Dial Transplant. 2003;18:1731-1740.
Diagnosis of CKD-MBD:
Vascular Calcification
 In CKD stages 3-5D, the suggestionsa indicate that:
– It is reasonable to use alternatives to computed tomographybased imaging to detect the presence or absence of vascular
calcification, including:
 Lateral abdominal radiograph
 Echocardiogram
– Patients with known vascular/valvular calcification can be
considered at highest cardiovascular risk
– It is reasonable to use this information to guide the management
of CKD–MBD
a. 3.3.1 (2C)
KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130
Calcification prevalence increases as
kidney function decreases
100%
‡
83%
80%
64%
60%
†
51% *
40%
20%
0%
CKD 4*
New HD**
Prevalent HD***
 Chart represents data across three studies of different CKD populations
*Russo D, Corrao S, Miranda I, et al. Progression of coronary artery calcification in predialysis patients. Am J Nephrol. 2007;27:152-158.
†Spiegel
DM, Raggi P, Mehta R, et al. Coronary and aortic calcifications in patients new to dialysis. Hemodialysis Int. 2004;8:265-272.
‡Chertow
GM, Burke SK, Raggi P; for Treat to Goal Working Group. Sevelamer attenuates the progression of coronary and aortic
calcification in hemodialysis patients. Kidney Int. 2002;62:245-252.
Prevalence of Coronary Artery Calcification
in Non-Dialyzed CKD Patients: Meta-Analysis
90%
100%
73%
Patients (%)
80%
54%
60%
40%
93%
54%
40%
25%
20%
0%
Kramer ‘05 Russo ‘04 Spiegel ‘04 Qunibi ‘05 Spiegel ‘04 Mehrotra Kramer ‘05
Diabetics
Non-Diabetics
N
28
GFR Stg 3-5
85
56
55
73
130
13
Stg 2-5
<15
48
<15
47
Stg 3-5
Based on data from Mehrotra R et al. Kidney Int. 2004;66;2022-2031; Russo D et al. Am J Kidney Dis. 2004;44:10241030; Kramer H et al. J Am Soc Nephrol. 2005;16:507-513; Quinibi WY et al. Kidney Int. 2005;68:271-277; Spiegel
DM et al. 2004;2004:265-272
Mehrotra R. J Renal Nutrition. 2006;16:100-118
The degree of calcification in patients new to
dialysis has a significant impact on mortality
Survival Distribution Function
1.00
0.75
0.50
CAC=0
CAC 1-400
CCS< 400
CAC≥400
P = 0.002
CCS=0
0.25
CCS >= 400
0.00
0
6
12
18
24
30
36
42
48
54
60
66
Months
No. at Risk
CCS = 0
CCS < 400
CCS >= 400
46
42
39
42
41
37
42
40
35
39
36
31
34
32
26
18
14
15
4
1
4
Block GA, Raggi P, Bellasi A, Kooienga L, Spiegel DM. Mortality effect of coronary calcification and phosphate binder choice in
incident hemodialysis patients. Kidney Int. 2007;71(5):438-441.
Treatment of CKD-MBD: Phosphorus and
Calcium
Defining Normal
“Normal” Phosphorus
2.5 mg/dl – 4.5 mg/dl
“Normal” Calcium
8.5 mg/dl – 10mg/dl or 10.5
mg/dl
“Normal” iPTH
10 pg/ml - 65 pg/ml
(varies with the assay used)
[Centers for Disease Control recommendations]
“Normal” means within the above ranges. These are normal ranges for healthy individuals.
Treatment Target Ranges
Stage
3
4-5
5D
Target PO4
Target Ca
KDIGO: Maintain Normal
KDIGO: Maintain Normal
KDOQI: 2.7-4.6 mg/dL
KDOQI: Normal for Lab
KDIGO: Maintain Normal
KDIGO: Maintain Normal
KDOQI: 2.7-4.6 mg/dL
KDOQI: Normal for Lab
KDIGO: Towards Normal
KDIGO: Maintain Normal
KDOQI: 3.5-5.5 mg/dL
KDOQI: 8.4-9.5 mg/dL
KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130
K/DOQI clinical practice guidelines for bone metabolism and disease in
chronic kidney disease. Am J Kidney Dis. 2003(suppl 3)
Treatment of CKD-MBD:
Phosphorus and Calcium
 In patients with CKD stages 3-5, the suggestions are to:
– Maintain serum phosphorus in the normal rangea
– Maintain serum calcium in the normal rangeb
 Phosphate binders are suggested in the treatment of
hyperphosphatemiac
 For choice of phosphate binder, it is reasonable to take
into accountc:
– CKD stage
– Presence of other components of CKD-MBD
– Concomitant therapies
– Side-effect profile
a. 4.1.1 (2C); b. 4.1.2 (2D); c. 4.1.4 (not graded)
KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130
Treatment of CKD-MBD:
Phosphorus and Calcium
 In patients with CKD stages 5D, the suggestion is to:
– Lower elevated phosphorus levels toward normal rangea
– Use a dialysate calcium concentration between 1.25 and 1.5
mmol/l (2.5 and 3.0 meq/L)b
a. 4.1.3 (2C); b. 4.1.2 (2D)
KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130
Increased serum phosphorus negatively impacts
the mortality of CKD patients not on dialysis.

The association between higher phosphate levels and mortality risk was present
among patients with absolute serum phosphate levels in the high-normal range

There was no observed increase in mortality risk among patients with lower serum
phosphorus levels
Kestenbaum B, Sampson JN, Rudser KD, et al. Serum phosphate levels and mortality risk
among people with chronic kidney disease. J Am Soc Nephrol. 2005;16:520-528.
Consistent control of phosphorus and other MBD markers
within KDOQI targets is associated with a greater chance
of survival in CKD patients on dialysis.

Simultaneous control of calcium, parathyroid hormone, and phosphorus is associated with improved survival

Sustained achievement of each target over time is associated with improved survival

Patients with phosphorus in target for ≤1 quarter had a 62% higher risk of death than the reference group
(those in target for all 4 quarters)
Danese MD, Belozeroff V, Smirnakis K, Rothman KJ. Consistent control of mineral and bone
disorder in incident hemodialysis patients. Clin J Am Soc Nephrol. 2008;3:1423-1429.
Treatment with phosphate binders is
independently associated with improved survival
among CKD patients on dialysis

Prospective cohort study of 10,044 incident hemodialysis patients comparing 1-year all-cause mortality among
patients who were or were not treated with phosphate binders

The phosphate binder–treated group had a significantly lower mortality rate than the untreated group (P<0.0001)

The 1,434 patients who began treatment with phosphorus binders before dialysis demonstrated a significant
survival advantage compared with 5,055 patients who were treated in the first 90 days (P=0.0008)
Isakova T, Gutiérrez OM, Chang Y, et al. Phosphorus binders and survival on
hemodialysis. J Am Soc Nephrol. 2009;20:388-396.
Treatment of CKD-MBD:
Phosphorus and Calcium
 In patients with CKD stages 3-5D and
hyperphosphatemia, the recommendationa is to:
– Restrict calcium based phosphate binders in the presence of:
 Arterial calcification
 Adynamic bone disease
 Persistently low serum PTH levels
– Restrict the dose of calcium based phosphate binders and/or
restrict the dose of calcitriol or vitamin D analog are suggestedb,
in the presence of:
 Persistent or recurrent hypercalcemia
a. 4.1.5 (1B); b. 4.1.5 (2C)
KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130
Patients In Whom it is Recommended
Calcium Be Restricted
Calcification
1,2,3
51% - 83%
Persistently
Low PTH
57%
2
Recommended
for Calcium Restriction
Hypercalcemia
ABD
2,3,4
16% - 54%
1Russo
5 – 40% CKD 3/46
20 – 50 % HD6
40 – 70% PD5
D, Corrao S, Miranda I, et al. Am J Neph 2007;27:152-158
GM, Burke SK, Raggi P, et al. Kidney Int. 2002;62:245-252
3Block GA, Spiegel DM, Ehrlich J, et al. Kidney Int. 2005;68:1815-1824
4Qunibi W, Moustafa M, Muenz LR, et al. AJKD. 2008
5Andress D.Kid Int. 2008;73:1345-1354
6KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130
2Chertow
Phosphate Binding Compounds
KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130
PTH Levels
Treatment Initiation Ranges
Stage
3
Treatment Initiation Range iPTH
KDIGO: > Upper limit of Normal
4.2.2 (2C)
KDOQI: 35-70 pg/mL
4
KDIGO: > Upper limit of Normal
4.2.2 (2C)
KDOQI: 70-110 pg/mL
5
KDIGO: > Upper limit of Normal
4.2.2 (2C)
KDOQI: 150-300 pg/mL
5D
KDIGO: 2 to 9x upper limit of Normal
4.2.3 (2C)
KDOQI: 150-300 pg/mL
KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130
K/DOQI clinical practice guidelines for bone metabolism and disease in
chronic kidney disease. Am J Kidney Dis. 2003(suppl 3)
Treatment of Abnormal
PTH levels in CKD-MBD
 In patients with CKD stages 3-5 not on dialysis, the optimal PTH
level is unknown
 In patients with levels of intact PTH (iPTH) above the upper normal
limit of the assay, the suggestiona is to, first evaluate for:
–
Hyperphosphatemia
–
Hypocalcemia
–
Vitamin D deficiency
 It is reasonable to correct these abnormalities with any or all of the
followingb:
–
Reducing dietary phosphate intake and administering phosphate
binders, calcium supplements, and/or native vitamin D
 The suggestionc is to treat with calcitriol or vitamin D analogs if:
–
Serum PTH is progressively rising and remains persistently above the
upper limit of normal for the assay despite correction of modifiable
factors
a. 4.2.1 (2C); b. 4.2.1 (not graded); c. 4.2.2 (2C)
KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130
Treatment of Abnormal
PTH levels in CKD-MBD
 In patients with CKD stage 5D, the suggestiona is to:
– Maintain iPTH levels in the range of approximately two to nine
times the upper normal limit for the assay
 To lower PTH, when it is elevated or rising, the
suggestiona is to use:
– Calcitriol
– Or vitamin D analogs
– Or calcimimetics
– Or a combination of calcimimetics and calcitriol or vitamin D
analogs
 In patients with severe hyperparathyroidism who fail to
respond to medical/pharmacological therapy
parathyreidectomy is suggestedb
a. 4.2.3 (2C); b. 4.2.5 (2B)
KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130
Treatment of Abnormal
PTH Levels In CKD-MBD
 In patients with hypocalcemia, the suggestiona is to
reduce or stop:
– calcimimetics depending on severity, concomitant medications,
and clinical signs and symptoms
 If intact PTH levels fall below two times the upper limit
of normal for the assay, the suggestionb is to reduce or
stop:
 Calcitriol
 Vitamin D analogs
 And/or calcimimetics
a. 4.2.4 (2B); b. 4.2.4 (2C)
KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130
In Summary …
KDIGO International Clinical Practice Guidelines
Phosphorus
Calcium
Calcification represents
highest risk
Detect with x-ray or
ultrasound
Goal = Normal
Restrict Calcium in
1.
Hypercalcemia
2.
Calcification
3.
Low PTH
4.
ADBD
PTH
Evaluate PTH in context
of hyperphosphatemia,
hypocalcemia, vitamin D
deficiency
Marked changes should
trigger treatment changes
Decrease cinacalcet in
event of hypocalcemia
Treat the trends: Treat P and Ca to normal, PTH to Goal
KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130