kdigo clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of...

KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, andTreatment of Chronic Kidney Disease-Mineral 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.

Moe et al. Kidney Int 2006;69:1945-1953

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

Chronic Kidney Disease – Mineral Bone Disorder(CKD – MBD)

KDIGO CKD-MBD Guidelines Work Group Members

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

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

KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130

Key Categories in KDIGO

Diagnosis/Evaluation

Treatment

Vascular Calcification

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

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: Diagnosis of CKD-MBDBiochemical 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


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-S130a. 3.1.3 (2C)


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)

KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130a. 3.1.4 (1C); b. 3.1.5 (2D)

Evaluation of CKD-MBD: Biochemical Abnormalities


CKD Stage

GFR Range (mL/min/1.73 m2)

KDIGO

3

30–59

Every 6 – 12 months

4

15–29


5

<15 or dialysis


Phosphorus & Calcium

CKD Stage

GFR Range (mL/min/1.73 m2)

KDIGO

3

30–59

Based on baseline level and CKD stage

4

15–29


5

<15 or dialysis


PTH

KDIGO: Diagnosis of CKD-MBDVascular 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

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)n=202

ESRD=end-stage renal diseaseHD=hemodialysis

London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H. Nephrol Dial Transplant. 2003;18:1731-1740.

*For illustration purposes only

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 CKD–MBD

KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130a. 3.3.1 (2C)

Calcification prevalence increases as kidney function decreases

51%

64%

83%

0%

20%

40%

60%

80%

100%

CKD 4* New HD** Prevalent HD***

51%

64%

83%

0%

20%

40%

60%

80%

100%

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

Based on data from Mehrotra R et al. Kidney Int. 2004;66;2022-2031; Russo D et al. Am J Kidney Dis. 2004;44:1024-1030; 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

25%

40%

54% 54%

73%

90% 93%

0%

20%

40%

60%

80%

100%

Patie

nts

(%)

Kramer ‘05 Russo ‘04 Spiegel ‘04 Qunibi ‘05 Spiegel ‘04 Mehrotra Kramer ‘05

Non-Diabetics DiabeticsN 28 85 56 55 73 130 13

GFR Stg 3-5 Stg 2-5 <15 48 <15 47 Stg 3-5

Months

0 6 12 18 24 30 36 42 48 54 60 66

Su

rviv

al D

istr

ibu

tio

n F

un

ctio

n

0.00

0.25

0.50

0.75

1.00

CCS=0

CCS< 400

CCS >= 400

No. at RiskCCS = 0 46 42 42 39 34 18 4CCS < 400 42 41 40 36 32 14 1 CCS >= 400 39 37 35 31 26 15 4

CAC=0CAC 1-400CAC≥400

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. 2007;71(5):438-441.

The degree of calcification in patients new to dialysis has a significant impact on mortality

Treatment of CKD-MBD: Phosphorus and Calcium

Defining Normal

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

“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]

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: Normal for Lab

5D KDIGO: Towards Normal




Treatment Target Ranges


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

KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130a. 4.1.1 (2C); b. 4.1.2 (2D); c. 4.1.4 (not graded)


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


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.


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

KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130a. 4.1.5 (1B); b. 4.1.5 (2C)

51% - 83% 57% 16% - 54%

CalcificationPersistently

Low PTHABDHypercalcemia

1,2,3 2 2,3,4

Patients In Whom it is Recommended Calcium Be Restricted

1Russo D, Corrao S, Miranda I, et al. Am J Neph 2007;27:152-1582Chertow GM, Burke SK, Raggi P, et al. Kidney Int. 2002;62:245-2523Block GA, Spiegel DM, Ehrlich J, et al. Kidney Int. 2005;68:1815-18244Qunibi W, Moustafa M, Muenz LR, et al. AJKD. 20085Andress D.Kid Int. 2008;73:1345-13546KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130

Recommended for Calcium Restriction

5 – 40% CKD 3/46

20 – 50 % HD6

40 – 70% PD5

Phosphate Binding Compounds


PTH Levels

Treatment Initiation Ranges

Stage Treatment Initiation Range iPTH

3 KDIGO: > Upper limit of Normal 4.2.2 (2C)

KDOQI: 35-70 pg/mL


KDOQI: 70-110 pg/mL


KDOQI: 150-300 pg/mL

5D KDIGO: 2 to 9x upper limit of Normal 4.2.3 (2C)

KDOQI: 150-300 pg/mL


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

KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130a. 4.2.1 (2C); b. 4.2.1 (not graded); c. 4.2.2 (2C)

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-S130a. 4.2.3 (2C); b. 4.2.5 (2B)

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

KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130a. 4.2.4 (2B); b. 4.2.4 (2C)

In Summary …

Phosphorus

Goal = Normal

Calcium

Calcification represents highest risk

Detect with x-ray or ultrasound

Restrict Calcium in1. Hypercalcemia2. Calcification3. Low PTH4. ADBD

PTH

Evaluate PTH in context of hyperphosphatemia, hypocalcemia, vitamin D deficiency

Marked changes should trigger treatment changes

Decrease cinacalcet in event of hypocalcemia

KDIGO International Clinical Practice Guidelines

Treat the trends: Treat P and Ca to normal, PTH to Goal


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