1. Chronic Kidney Disease-Related Mineral and Bone Disorder: Public Health Problem Kerry Willis PhD National Kidney Foundation

2. Year of ESRD Incidence or Transplantation 21.5 19.8 4.1 2.0 1999 annual report of the US Renal Data System Deaths/100 patient-years DialysisAll ESRDCadaveric TransplantLiving Related Transplant Adjusted 1st Year Patient Death Rates by Treatment Modality and Year of Incidence, 1986-96

3. 0.01 100 10 1 0.1 Annual mortality (%) 25–3445–5465–74  85 35–4455–6475–84 Age (years) Cardiovascular Mortality in the General Population and in Dialysis Patients General population Male Female Black White Dialysis population Male Female Black White

4. NKF’s Clinical Practice Guidelines Evidence Based Review Publication and Dissemination Implementation Reassess Impact Update

5. DOQIKDIGOK/DOQI Dialysis Anemia Access 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) 19972005 *updates http://www.kidney.org/professionals/kdoqi 1999 http://www.kdigo.org/welcome.htm

6. 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 transplantation 2. GFR <60 ml/min/1.73 m 2, with or without kidney damage

7. StageDescriptionGFR (ml/min/1.73 m 2 ) 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

8. CKD is a Public Health Problem CKD is common CKD is harmful We have treatment

9. CKD death ComplicationsComplications Screening for CKD risk factors: diabetes hypertension age >60 family history US ethnic minorities CKD risk reduction; Screening for CKD Diagnosis & treatment; Treat comorbid conditions; Slow progression Estimate progression; Treat complications; Prepare for replacement Replacement by dialysis & transplant NormalNormal Increased risk Kidney failure DamageDamage  GFR 11.3 m 5.6% 7.7 m 3.8% 0.3 m 0.2% Conceptual Model for CKD

10. >4.6

11. K/DOQI Clinical Practice Guidelines on Bone Metabolism and Disease in Chronic Kidney Disease Published October 2003

12. KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease Chair:Vice-Chair: Shaul G. Massry, MDJack W. Coburn, MD KECK School of MedicineVA Greater Los Angeles Work Group Members: Glenn M. Chertow, MD, MPHJames T. McCarthy, MD University of California, San FranciscoMayo Clinic Keith Hruska, MDSharon Moe, MD Barnes Jewish HospitalIndiana University Craig Langman, MDIsidro B. Salusky, MD Children’s Memorial HospitalUCLA School of Medicine Hartmut Malluche, MDDonald J. Sherrard, MD University of KentuckyVA Puget Sound Kevin Martin, MD, BChMiroslaw Smogorzewski, MD St. Louis UniversityUniversity of Southern California Linda M. McCann, RD, CSR, LDKline Bolton, MD Satellite Dialysis CentersRPA Liaison

13. K/DOQI™ Clinical Practice Guidelines on Bone Metabolism Target Levels CKD Stage 3 CKD Stage 4 CKD Stage 5 (on dialysis) P (mg/dL) 2.7 - 4.6 3.5 - 5.5* Ca (mg/dL) “Normal” 8.4 - 9.5; Hypercalcemia = >10.2 Intact PTH (pg/mL) 35 - 7070 - 110 150 - 300* *Evidence

14. 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

15. 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 mg 2 /dL 2 Treatment Recommendations Stage 5 (dialysis)

16. Abnormal bone Age Oxidation (OxLDL) Diabetes HTN Advanced glycation end-products end-products Smoking Genetics Dyslipidemia Carbonyl stress Low fetuin-A Traditional Risk FactorsNon-traditional Risk Factors Elevated IL-1, Il-6, TNF  Homocysteine Abnormal mineral metabolism Fractures Cardiovascular disease in CKD

17. 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.

18. Definition, Evaluation and Classification of Renal Osteodystrophy: A position statement from Kidney Disease Improving Global Outcomes (KDIGO) April, 2006

19. 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).

20. 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

21. A Framework for Classification of CKD-MBD Type* Laboratory Abnormalities Bone 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

22. www.kdigo.org

23. Summary 1.CKD is defined using eGFR and classified into 5 stages 2.This classification can help predict clinical outcomes 3.Early detection and treatment can improve patient outcomes 4.There is a link between CVD and bone and mineral disease in CKD 5.New CKD-MBD classification will form the basis for updated, international clinical practice guidelines

24. 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 2004