KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)

1
KDIGO Clinical Practice Guideline for the
Diagnosis, Evaluation, Prevention, andTreatment
of Chronic Kidney Disease-Mineral and Bone
Disorder (CKD-MBD)
2
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.

3
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 2006691945-1953
4
KDIGO CKD-MBD Guidelines Work Group Members

• Sharon M. Moe, MD (Co-chair)
• United States
• Alison MacLeod, MD
• United Kingdom
• Linda McCann, RD, LD, CSR
• United States
• Peter A McCullough, MD, MPH
• United States
• Susan Ott, MD
• United States
• Angela Yee-Moon Wang, MD, PhD
• Hong Kong
• José Weisinger, MD
• Venezuela
• David Wheeler, MD
• United Kingdom

• Tilman Drüeke, MD (Co-chair)
• France
• Geoffrey Block, MD
• United States
• Jorge B. Cannata-Andía, MD, PhD
• Spain
• Grahame Elder, MB, BS, PhD
• Australia
• Masafumi Fukagawa, MD, PhD
• Japan
• Vanda Jorgetti, MD, PhD
• Brazil
• Markus Ketteler, MD
• Germany
• Craig Langman, MD
• United States
• Adeera Levin, MD,
• Canada

KDIGO. Kid Int. 2009 76 (Suppl 113)S1-S130
5
Key Categories in KDIGO
Diagnosis/Evaluation
Vascular Calcification
Treatment
6
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 gt3 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 lt60 mL/min/1.73m2 persists for gt3
  months, with or without kidney damage

7
KDIGO Grading of Recommendations
Strength of Recommendation Implications
Level 1 We recommend Most patients should receive the recommended course of action.
Level 2 We suggest Different choices will be appropriate for different patients.
Grade for Quality of Evidence Quality of Evidence
A High
B Moderate
C Low
D Very Low
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
8
KDIGO Diagnosis of CKD-MBDBiochemical
Abnormalities
9
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
10
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

KDIGO. Kid Int. 2009 76 (Suppl 113)S1-S130
a. 3.1.3 (2C)
11
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 CKDMBD 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 calciumphosphorus product (Ca x
  P)

KDIGO. Kid Int. 2009 76 (Suppl 113)S1-S130
a. 3.1.4 (1C) b. 3.1.5 (2D)
12
Evaluation of CKD-MBD Biochemical Abnormalities
Phosphorus Calcium
CKD Stage GFR Range (mL/min/1.73 m2) KDIGO
3 3059 Every 6 12 months
4 1529 Every 3 6 months
5 lt15 or dialysis Every 1 3 months
PTH
CKD Stage GFR Range (mL/min/1.73 m2) KDIGO
3 3059 Based on baseline level and CKD stage
4 1529 Every 6 12 months
5 lt15 or dialysis Every 3 6 months
a. 3.1.4 (1C) b. 3.1.5 (2D)
KDIGO. Kid Int. 2009 76 (Suppl 113)S1-S130
13
KDIGO Diagnosis of CKD-MBDVascular
Calcification
14
Arterial Media Calcification in ESRD Impact on
All-Cause and Cardiovascular Mortality

• 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)

• 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

n202 ESRDend-stage renal disease HDhemodialysi
s
For illustration purposes only
London GM, Guerin AP, Marchais SJ, Metivier F,
Pannier B, Adda H. Nephrol Dial Transplant.
2003181731-1740.
15
Diagnosis of CKD-MBD Vascular Calcification

• In CKD stages 3-5D, the suggestionsa indicate
  that
• It is reasonable to use alternatives to computed
  tomography-based 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 CKDMBD

a. 3.3.1 (2C)
KDIGO. Kid Int. 2009 76 (Suppl 113)S1-S130
16
Calcification prevalence increases as kidney
function decreases

• 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. 200727152-158. Spiegel
DM, Raggi P, Mehta R, et al. Coronary and aortic
calcifications in patients new to dialysis.
Hemodialysis Int. 20048265-272. 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.
200262245-252.
17
Prevalence of Coronary Artery Calcification in
Non-Dialyzed CKD Patients Meta-Analysis
Based on data from Mehrotra R et al. Kidney Int.
2004662022-2031 Russo D et al. Am J Kidney
Dis. 2004441024-1030 Kramer H et al. J Am Soc
Nephrol. 200516507-513 Quinibi WY et al.
Kidney Int. 200568271-277 Spiegel DM et al.
20042004265-272 Mehrotra R. J Renal Nutrition.
200616100-118
18
The degree of calcification in patients new to
dialysis has a significant impact on mortality
P 0.002
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.
200771(5)438-441.
19
Treatment of CKD-MBD Phosphorus and Calcium
20
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 (varies with the assay used) 10 pg/ml - 65 pg/ml Centers for Disease Control recommendations

• Normal means within the above ranges. These are
  normal ranges for healthy individuals.

21
Treatment Target Ranges
Stage Target PO4 Target Ca
3 KDIGO Maintain Normal KDOQI 2.7-4.6 mg/dL KDIGO Maintain Normal KDOQI Normal for Lab
4-5 KDIGO Maintain Normal KDOQI 2.7-4.6 mg/dL KDIGO Maintain Normal KDOQI Normal for Lab
5D KDIGO Towards Normal KDOQI 3.5-5.5 mg/dL KDIGO Maintain Normal 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)
22
Treatment of CKD-MBDPhosphorus 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
23
Treatment of CKD-MBDPhosphorus 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
24
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.
200516520-528.
25
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. 200831423-1429.
26
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 bindertreated group had a
  significantly lower mortality rate than the
  untreated group (Plt0.0001)
• 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 (P0.0008)

Isakova T, Gutiérrez OM, Chang Y, et al.
Phosphorus binders and survival on hemodialysis.
J Am Soc Nephrol. 200920388-396.
27
Treatment of CKD-MBDPhosphorus 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
28
Patients In Whom it is Recommended Calcium Be
Restricted
Calcification
Persistently Low PTH
ABD
Hypercalcemia
1,2,3
2
2,3,4
51 - 83
57
16 - 54
5 40 CKD 3/46 20 50 HD6 40 70 PD5
Recommended for Calcium Restriction
1Russo D, Corrao S, Miranda I, et al. Am J Neph
200727152-158 2Chertow GM, Burke SK, Raggi P,
et al. Kidney Int. 200262245-252 3Block GA,
Spiegel DM, Ehrlich J, et al. Kidney Int.
2005681815-1824 4Qunibi W, Moustafa M, Muenz
LR, et al. AJKD. 2008 5Andress D.Kid Int.
2008731345-1354 6KDIGO. Kid Int. 2009 76
(Suppl 113)S1-S130
29
Phosphate Binding Compounds
KDIGO. Kid Int. 2009 76 (Suppl 113)S1-S130
30
PTH Levels
31
Treatment Initiation Ranges
Stage Treatment Initiation Range iPTH
3 KDIGO gt Upper limit of Normal 4.2.2 (2C) KDOQI 35-70 pg/mL
4 KDIGO gt Upper limit of Normal 4.2.2 (2C) KDOQI 70-110 pg/mL
5 KDIGO gt 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
32
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

KDIGO. Kid Int. 2009 76 (Suppl 113)S1-S130
a. 4.2.1 (2C) b. 4.2.1 (not graded) c. 4.2.2
(2C)
33
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

KDIGO. Kid Int. 2009 76 (Suppl 113)S1-S130
a. 4.2.3 (2C) b. 4.2.5 (2B)
34
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
35
In Summary
KDIGO International Clinical Practice Guidelines
Phosphorus
Calcium
PTH
Goal Normal

• Calcification represents highest risk
• Detect with x-ray or ultrasound
• Restrict Calcium in
• Hypercalcemia
• Calcification
• Low PTH
• ADBD

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