1. KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment 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. 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)

4. 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

5. Key Categories in KDIGO Diagnosis/Evaluation Treatment Vascular Calcification

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 >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 3 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 AHigh BModerate CLow DVery Low Not Graded KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130 “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.”

8. KDIGO: Diagnosis of CKD-MBD Biochemical Abnormalities

9. Diagnosis of CKD-MBD: Biochemical Abnormalities In the initial CKD stage a, the recommendation is to monitor serum levels of: –Phosphorus –Calcium –PTH –Alkaline phosphatase In CKD stages 3-5D b, 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 children c, 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 suggestions a 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 recommendation a is that therapeutic decisions should be based on:  Trends versus a single laboratory value  All available CKD–MBD assessments –The suggestion b 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-S130 a. 3.1.4 (1C); b. 3.1.5 (2D)

12. Evaluation of CKD-MBD: Biochemical Abnormalities KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130 a. 3.1.4 (1C); b. 3.1.5 (2D) CKD Stage GFR Range (mL/min/1.73 m2) KDIGO 3 30–59 Every 6 – 12 months 4 15–29 Every 3 – 6 months 5 <15 or dialysis Every 1 – 3 months 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 Every 6 – 12 months 5 <15 or dialysis Every 3 – 6 months PTH

13. KDIGO: Diagnosis of CKD-MBD Vascular Calcification

14. 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 disease HD=hemodialysis London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H. Nephrol Dial Transplant. 2003;18:1731-1740. *For illustration purposes only

15. Diagnosis of CKD-MBD: Vascular Calcification In CKD stages 3-5D, the suggestions a 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-S130 a. 3.3.1 (2C)

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. 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.

17. 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% 73% 90% 93% 0% 20% 40% 60% 80% 100% Patients (%) Kramer ‘05Russo ‘04Spiegel ‘04Qunibi ‘05Spiegel ‘04MehrotraKramer ‘05 Non-Diabetics Diabetics N 28 85 56 55 73 130 13 GFR Stg 3-5 Stg 2-5 <15 48 <15 47 Stg 3-5

18. CAC=0 CAC 1-400 CAC≥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

19. Treatment of CKD-MBD: Phosphorus and Calcium

20. Defining Normal “Normal” means within the above ranges. These are normal ranges for healthy individuals. “Normal” Phosphorus2.5 mg/dl – 4.5 mg/dl “Normal” Calcium8.5 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]

21. StageTarget PO 4 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 Treatment Target Ranges 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-MBD: Phosphorus and Calcium In patients with CKD stages 3-5, the suggestions are to: –Maintain serum phosphorus in the normal range a –Maintain serum calcium in the normal range b Phosphate binders are suggested in the treatment of hyperphosphatemia c For choice of phosphate binder, it is reasonable to take into account c : –CKD stage –Presence of other components of CKD-MBD –Concomitant therapies –Side-effect profile KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130 a. 4.1.1 (2C); b. 4.1.2 (2D); c. 4.1.4 (not graded)

23. Treatment of CKD-MBD: Phosphorus and Calcium In patients with CKD stages 5D, the suggestion is to: –Lower elevated phosphorus levels toward normal range a –Use a dialysate calcium concentration between 1.25 and 1.5 mmol/l (2.5 and 3.0 meq/L) b KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130 a. 4.1.3 (2C); b. 4.1.2 (2D)

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. 2005;16:520-528.

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. 2008;3:1423-1429.

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 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.

27. Treatment of CKD-MBD: Phosphorus and Calcium In patients with CKD stages 3-5D and hyperphosphatemia, the recommendation a 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 suggested b, in the presence of:  Persistent or recurrent hypercalcemia KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130 a. 4.1.5 (1B); b. 4.1.5 (2C)

28. 51% - 83% 57%16% - 54% Calcification Persistently Low PTH ABDHypercalcemia 1,2,322,3,4 Patients In Whom it is Recommended Calcium Be Restricted 1 Russo D, Corrao S, Miranda I, et al. Am J Neph 2007;27:152-158 2 Chertow GM, Burke SK, Raggi P, et al. Kidney Int. 2002;62:245-252 3 Block GA, Spiegel DM, Ehrlich J, et al. Kidney Int. 2005;68:1815-1824 4 Qunibi W, Moustafa M, Muenz LR, et al. AJKD. 2008 5Andress D.Kid Int. 2008;73:1345-1354 6 KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130 Recommended for Calcium Restriction 5 – 40% CKD 3/4 6 20 – 50 % HD 6 40 – 70% PD 5

29. Phosphate Binding Compounds KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130

30. PTH Levels

31. Treatment Initiation Ranges StageTreatment Initiation Range iPTH 3 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

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 suggestion a is to, first evaluate for: –Hyperphosphatemia –Hypocalcemia –Vitamin D deficiency It is reasonable to correct these abnormalities with any or all of the following b : –Reducing dietary phosphate intake and administering phosphate binders, calcium supplements, and/or native vitamin D The suggestion c 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 suggestion a 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 suggestion a 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 suggestion a 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 suggestion b is to reduce or stop:  Calcitriol  Vitamin D analogs  And/or calcimimetics KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130 a. 4.2.4 (2B); b. 4.2.4 (2C)

35. In Summary … Phosphorus Goal = Normal Calcium Calcification represents highest risk Detect with x-ray or ultrasound 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 KDIGO International Clinical Practice Guidelines Treat the trends: Treat P and Ca to normal, PTH to Goal KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130