Chronic Kidney Disease-Related Mineral and Bone Disorder:

Public Health Problem

Kerry Willis PhD

National Kidney Foundation

0

5

10

15

20

25

30

35

1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996

Year of ESRD Incidence or Transplantation

21.5

19.8

4.1

2.0

1999 annual report of the US Renal Data System

Dea

ths/

100

pat

ien

t-ye

ars

Dialysis All ESRD Cadaveric Transplant Living Related Transplant

Adjusted 1st Year Patient Death Rates by Treatment Modality and Year of Incidence, 1986-96

0.01

100

10

1

0.1

An

nu

al m

ort

alit

y (%

)

25–34 45–54 65–74 8535–44 55–64 75–84

Age (years)

Cardiovascular Mortality in the General Population and in Dialysis Patients

General populationMale Female

BlackWhite

Dialysis populationMale Female

BlackWhite

NKF’s Clinical Practice Guidelines

• Evidence Based Review• Publication and Dissemination• Implementation • Reassess Impact• Update

DOQI KDIGOK/DOQI

DialysisAnemiaAccess

Nutrition (00)Dialysis (’01)*Anemia (’01)*Access(‘01)*CKD class. (’02)Bone/Mineral (’03) Lipids (’03)Htn (’04)CV (’05)Diabetes (’07)

Hep C (’08)Bone/Mineral (’08)

1997 2005

*updates

http://www.kidney.org/professionals/kdoqi

1999

http://www.kdigo.org/welcome.htm

NKF-K/DOQI Definition of CKD

Structural or functional abnormalities of the kidneys for >3 months, as manifested by either:

1. Kidney damage, with or without decreased GFR, as defined by

• pathologic abnormalities• markers of kidney damage

– urinary abnormalities (proteinuria)– blood abnormalities (renal tubular syndromes)– imaging abnormalities

• kidney transplantation2. GFR <60 ml/min/1.73 m2, with or without kidney

damage

Stage Description GFR (ml/min/1.73 m2)

1 Kidney damage with normal or GFR

90

2 Kidney damage with mild GFR 60-89

3 Moderate GFR 30-59

4 Severe GFR 15-29

5 Kidney failure < 15 (or dialysis)

KDOQI: CKD Staging

CKD is a Public Health Problem

• CKD is common

• CKD is harmful

• We have treatment

CKDCKDdeathdeathCKDCKDdeathdeath

ComplicationsComplicationsComplicationsComplications

Screening for CKD

risk factors:diabetes

hypertensionage >60

family historyUS ethnic minorities

CKD riskreduction;

Screening forCKD

Diagnosis& treatment;

Treat comorbid

conditions;Slow

progression

Estimateprogression;

Treatcomplications;

Prepare forreplacement

Replacementby dialysis

& transplant

NormalNormalNormalNormal IncreasedIncreasedriskrisk

IncreasedIncreasedriskrisk

KidneyKidneyfailurefailureKidneyKidneyfailurefailureDamageDamageDamageDamage GFRGFR GFRGFR

11.3 m11.3 m5.6%5.6%

7.7 m7.7 m7.7 m7.7 m3.8%3.8%

0.3 m0.3 m0.2%0.2%

Conceptual Model for CKD

KI (2007) 71, 31-38. Levin et. al.

Prevalence of Abnormal Mineral Metabolism in CKD

>4.6

K/DOQI Clinical Practice Guidelineson Bone Metabolism and Disease

in Chronic Kidney Disease

Published October 2003

KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease

Chair: Vice-Chair:Shaul G. Massry, MD Jack W. Coburn, MDKECK School of Medicine VA Greater Los Angeles Work Group Members:Glenn M. Chertow, MD, MPH James T. McCarthy, MDUniversity of California, San Francisco Mayo Clinic

Keith Hruska, MD Sharon Moe, MDBarnes Jewish Hospital Indiana University

Craig Langman, MD Isidro B. Salusky, MDChildren’s Memorial Hospital UCLA School of Medicine

Hartmut Malluche, MD Donald J. Sherrard, MDUniversity of Kentucky VA Puget Sound

Kevin Martin, MD, BCh Miroslaw Smogorzewski, MDSt. Louis University University of Southern California

Linda M. McCann, RD, CSR, LD Kline Bolton, MDSatellite Dialysis Centers RPA Liaison

K/DOQI™ Clinical Practice Guidelineson Bone Metabolism Target Levels

CKD Stage 3

CKD Stage 4

CKD Stage 5

(on dialysis)

P(mg/dL)

2.7 - 4.6 2.7 - 4.6 3.5 - 5.5*

Ca(mg/dL)

“Normal” “Normal”

8.4 - 9.5; Hypercalcemia =

>10.2

Intact PTH

(pg/mL)35 - 70 70 - 110

150 - 300*

*Evidence

Treatment Recommendations(Stages 3 & 4)

• Decrease total body phosphorus burden by dietary restriction and phosphorus binder therapy- 2.7- 4.6 mg/dL; begin when EITHER elevated serum phosphorus OR elevated serum PTH

• Treat elevated PTH with active oral vitamin D sterol to target of 35-70 (CKD 3) or 70-110 (CKD 4) pg/mL by intact assay

• Normalize serum calcium

• Normalize serum phosphorus by diet and phosphorus binder therapy- 3.5-5.5 mg/dL (1.13 -1.78 mmol/L); limit elemental calcium intake from binders to 1500 mg/day

• Treat elevated PTH with active vitamin D sterol to target of 150-300 pg/mL (16-32 pmol/L) by intact assay

• Normalize serum calcium- ideally 8.4 -9.5 mg/dL (2.10-2.38 mmol/L), and always < 10.2 mg/dL (2.55 mmol/L); Ca X P < 55 mg2/dL2

Treatment RecommendationsStage 5 (dialysis)

Abnormal boneAbnormal bone

AgeAge

Oxidation (OxLDL)Oxidation (OxLDL)

DiabetesDiabetes

HTNHTN

Advanced glycationAdvanced glycation end-productsend-products

SmokingSmoking

GeneticsGenetics

DyslipidemiaDyslipidemiaCarbonyl stressCarbonyl stress

Low fetuin-ALow fetuin-A

Traditional Risk Factors Non-traditional Risk Factors

Elevated IL-1, Il-6, TNFElevated IL-1, Il-6, TNF

HomocysteineHomocysteine

Abnormal mineral metabolismAbnormal mineral metabolism

FracturesFracturesCardiovascular Cardiovascular disease in CKDdisease in CKD

Classification Issues in Bone and Mineral Disorders

• The term renal osteodystrophy is used to describe different entities

• The predominant use is to describe a disorder of bone remodeling. However this does not take into account new data that there is increased morbidity/mortality of abnormal serum biochemistries (i.e. phosphorus), nor increased awareness of vascular disease related to bone and mineral disorders in CKD patients.

Definition, Evaluation and Classification of Renal Osteodystrophy:

A position statement from Kidney Disease Improving Global Outcomes (KDIGO)

April, 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).

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

A Framework for Classification of CKD-MBD

Type*Laboratory

AbnormalitiesBone 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

www.kdigo.org

Summary1. CKD is defined using eGFR and classified into 5

stages2. This classification can help predict clinical outcomes3. Early detection and treatment can improve patient

outcomes4. There is a link between CVD and bone and mineral

disease in CKD5. New CKD-MBD classification will form the basis for

updated, international clinical practice guidelines

Population Attributable Risk of All Cause Mortality in CKD 5D

• 17.5% Mineral metabolism abnormalities (Phosphorus > 5.0 mg/dl, Calcium >

10 mg/dl, intact PTH > 600 pg/ml)• 11.3% Anemia (hgb < 11 g/dl)• 5.1% Inefficient Dialysis (URR < 65%)

Corollary: We should be able to significantly improve mortality of CKD patients by improving control of mineral metabolism

Block et al JASN 2004Block et al JASN 2004