Linda McCann, RD, CSR,LD Senior Director of Quality Satellite Healthcare, Inc. Mountain View, CA

1. Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, andTreatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Linda McCann, RD, CSR,LD Senior Director of Quality Satellite Healthcare, Inc. Mountain View, CA

2. 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 • Vascular or other soft tissue calcification • Abnormalities in bone turnover, mineralization, volume, linear growth, or strength Moe et al. Kidney Int 2006;69:1945-1953

3. Classification of Renal Osteodystrophy T M V Mineralization Reflects how well bone collagen becomes calcified Normal-Abnormal Volume Amount of bone per unit volume of tissue, affected by , endocrine disorders, mechanical stimuli, toxicities, neurological function, vascular supply, growth factors and cytokines. High-Normal-Low Turnover Rate of remodelling High-Normal-Low Slide courtesy of Susan Ott

4. Process

5. NOMENCLATURE AND DESCRIPTION FOR RATING GUIDELINE RECOMMENDATIONS

6. Determinants of strength of recommendation Guyatt, et al, BMJ 2008

7. CKD Abnormal levels and bioactivity of laboratory parameters: Laboratory PTH Calcium Phosphorus 25(OH)D 1,25(OH)2D Surrogate Outcomes High High High Normal Normal Normal * Normal * Normal * Low * Low Low Low Low Bone turnover : Osteocalcin , Vessel stiffness : Pulse wave Bone specific alkaline velocity, pulse pressure Vessel and phosphatase , Vessel / valve calcification : Bone Bone and CVD valve C - terminal cross links X - ray, US, CT, EBCT, disease: Surrogate Outcomes disease: Bone mineralization /density : MSCT, IMT abnormal abnormal DXA, qCT , qUS Vessel patency : structure or Bone turnover, Coronary angiogram, Doppler structure or function mineralization Duplex US function & structure : Histology Fractures, Pain, Cardiovascular Decreases in mobility, Disease events strength or growth Clinical Outcomes Disability, Decreased QOL, Hospitalizations, Death Evidence Model for CKD-MBD

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

9. Prevalance of types of bone disease as determined by bone biopsy. These pie charts represent the prevalence of various types of bone disease in CKD. Differences are due to inconsistent classification methods, geographic areas, genetic background, and treatment strategies. One of the most problematic classification differences relates to the bone formation which requires tetracycline labeling, hindered because normal ranges cannot be determined on autopsy or surgical series

10. KDIGO: Diagnosis of CKD-MBDBiochemical Abnormalities Diagnosis of CKD-MBD depends primarily on lab and other measures; interpretation of biochemical and hormonal values requires that there be an understanding of the assay type and precision, interassay variability, blood sample handling, normal postprandial, diurnal, and seasonal variations in the individual parameters.

11. Sources and magnitude of variation in measures of Ca, P, PTH, and D sterols • Underscores need to use trends • Underscores need to use same assays/timing of samples

12. Variations in Measurement • Significant variation in measured serum P values depending on the EXACT machine used to measure P even using the same assay technique. • Using phosphomolybdate UV assay the mean values range from 4.82 to 5.64 between 2 different machines • These lab differences will create HUGE cost differences in care and potentially expose patients to more risk for over or under use of drugs.

13. Diagnosis of CKD-MBD: Biochemical Abnormalities • In CKD stages 3-5D, the suggestionsa are to: • “Might” Measure 25(OH)D (calcidiol) levels • Repeat testing on the basis of: • Baseline values • Therapeutic interventions • In the absence of knowing the optimum levels and the issues related to measurement, the decision on whether, when, how often to measure must be individualized. Consider how the measure will impact management and treatment decisions and the level of resources available • Correct vitamin D deficiency and insufficiency in accordance to treatment strategies recommended for the general population. a. 3.1.3 (2C) KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130

14. How much D?

15. Not all Vitamin D Assays are Equal “We thus believe that in countries where vitamin D2 is prescribed (even in a low proportion of patients, as in France), 25-OH-D assays should measure both 25-OH-D2 and 25-OH-D3 and that the only interesting information to be provided to physicians in clinical practice is the sum of the 25-OH-D2 and 25-OH-D3 concentrations.” Massart and Souberbielle, Clin Chemistr 55 (6): 1247 (2009) Not from KDIGO

16. 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 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) a. 3.1.4 (1C); b. 3.1.5 (2D) KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130

17. Targets • Evidence based • Highest design level research -often unavailable • Observational data • KDOQI – based primarily on observational • KDIGO – based on high level evidence – most topics have little or none • Common sense recommendations Not from KDIGO

18. PTH • PTH synthesis/secretion occurs in response to low calcium, high phos, and low 1,25 vitamin D levels. • Synthesis/secretion are suppressed by high calcium, high calcitriol, and high FGF 23 levels. • PTH is oscillatory but blunted in CKD • Ionized Calcium is the most critical determinent of minute to minute PTH secretion. Not from KDIGO

19. PTH • Secretion happens within minutes • Synthesis happens within hours/days • Diffuse hyperplasia → early nodularity → → single nodule happens over weeks to years Not from KDIGO

20. SHPT • Progressive disease • Increased secretion and synthesis • Hyperplasia • Chronic elevation of PTH • Abnormal calcium, phos and vit D metabolism contribute to development and severity • Associated with adverse clinical outcomes including bone and soft tissue abnormalities Not from KDIGO

21. What is the target? • Problems with sample collection and variability raise significant concerns re setting an absolute level and their strict use as a clinically relevant biomarker • However, to not measure or treat is equally concerning. • Use of trends is critical – absolute or optimal target is questionable • But..

22. Bio vs Intact • Benefit of bio has not been demonstrated • 1-84 creates bone resorption, 7-84 is antagonistic to bone resorption

23. Random action = chaos • Protocols allow us to see the outcomes of our interventions • They allow immediate intervention on MD behalf based on reasonable judgment and Not from KDIGO

24. KDIGO: Diagnosis of CKD-MBDVascular Calcification

25. Calcification • In non-CKD, magnitude of Coronary Artery Calcification (CAC) by (EBCT) or multi-slice computed tomography (MSCT) is a strong predictor of CV event risk. • In the CKD, coronary artery/generalized vascular calcification is exceedingly more prevalent, severe, and accelerated. • Ref standard for detecting CV calcification is CT-based CAC score, but other techniques (lateral abdominal X-ray, pulse wave velocity (PWV), echocardiography may yield good information. • Presence/severity of CV calcification strongly predict CV morbidity and mortality CKD.

26. Calcification • There is limited CKD, RCT evidence that slowing arterial calcification impacts mortality. • A small majority of WG members felt that inconsistencies remained in RCT reports aimed to demonstrate that intervention improved pt level outcomes, thus indiscriminate screening not rec for every CKD-MBD. • Implies that screening is done at discretion of treating MD, especially if knowledge of calcification may impact therapeutic decision making “ Consensus that known vascular/valvular calcification and its magnitude identify patients at high CV risk. Therefore, the presence of vascular/valvular calcification should be considered for individualized tx ofCKD-MBD.”

27. 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) Arterial Media Calcification in ESRD: Impact on All-Cause and Cardiovascular Mortality n=202 ESRD=end-stage renal disease HD=hemodialysis Not from KDIGO *For illustration purposes only London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H. Nephrol Dial Transplant. 2003;18:1731-1740.

28. Diabetes and CKD: Compounded Risk for Vascular Calcification • Diabetes has been identified as an independent risk factor for vascular calcification • Coexistence of diabetes and CKD potentiate vascular calcification dramatically versus either condition alone • In fact, more than 65 percent of people with diabetes die from cardiovascular disease or stroke Multistage probability sample from 2000-2002, pts between 30-65yrs, logistic regression was used to examine the association between stages of CKD and CAC scores (> 10, >100, >400 vs 10 or less in nonCKD. CKD was defined as GFR > 60 for stage 1, 2 and < 60 for stages 3-5 (excluding dialysis). Kramer H, Toto R, Peshock R, Cooper, R, Victor R: Association between chronic kidney disease and coronary artery calcification: the Dallas Heart Study American Diabetes Association. Diabetes: heart disease and stroke. www.diabetes.org.http://www.diabetes.org/diabetes-heart-disease-stroke.jsp. Accessed April 8, 2009. Not from KDIGO

29. Treatment of CKD-MBD: Phosphorus and Calcium

30. Defining Normal “Normal” for healthy individuals.

31. Hyperphosphatemia Despite a lack of RCT evidence, it is reasonable to lower P in CKD patients using phosphate binders. Additional options to lower phosphorus include limiting dietary phosphate intake (while ensuring adequate protein intake) and/or increasing frequency or duration of dialysis (in those who require renal replacement therapy). Insufficient evidence that any specific phosphate binder significantly impacts patient-level outcomes. Thus, the choice of phosphate binder should be individualized, and the guidance offered in this recommendation is based on effects of the available agents on a range of clinical parameters, rather than on phosphorus-lowering alone.

32. Hyperphosphatemia • Associated w/poor outcomes/mortality in CKD Stage 5D; high normal P levels associated with mortality in non-CKD patients/Stage 3 patients. • CKD Stages 4-5D commonly have a high P linked to the development of CKD-MBD, including SHPT, reduced calcitriol levels, abnormal bone remodeling, soft-tissue calcification. • May directly cause or exacerbate other aspects of CKD-MBD, specifically secondary HPT, a reduction in calcitriol levels, bone disease, and arterial calcification. • No evidence that lowering serum P to a specific target range leads to improved clinical outcomes in patients with CKD. • Recommended goals of therapy must therefore be based on observational data.

33. 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)

34. 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 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

35. Treatment of CKD-MBD:Phosphorus 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

36. Treatment of CKD-MBD:Phosphorus 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

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

38. How can we do it?

40. Area of focus: Phosphorus Control • Various binders • Consider Advantages/Disadvantages for individual pt • Individual tolerance • GI side effects seem to be dose related • Try again with lower dose • Use combination

41. PTH Levels

42. Treatment Initiation Ranges

43. 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)

44. 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 suggested a. 4.2.3 (2C); b. 4.2.5 (2B) KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130

45. 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

46. In Summary … KDIGO International Clinical Practice Guidelines PTH Calcium Phosphorus • Calcification represents highest risk • Detect with x-ray or ultrasound • Limit Calcium in • Hypercalcemia • Calcification • Low PTH • ADBD Evaluate PTH in context of alkaline phosphatase, serum P, serum Ca, vitamin D deficiency/ replacement; avoid extreme 2-9x upper norm Marked changes should trigger treatment changes Decrease cinacalcet in event of hypocalcemia Goal = Normal or toward normal Treat the trends: Treat P and Ca to normal, PTH Avoid Extremes KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130