APPLYING KDIGO GUIDELINES TO

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1 Knowledge Exchange 2016 APPLYING KDIGO GUIDELINES TO CLINICAL PRACTICE MARKUS KETTELER, MD, FELLOW OF THE EUROPEAN RENAL ASSOCIATION DIVISION OF NEPHROLOGY, KLINIKUM COBURG COBURG, GERMANY Date of preparalon: Nov 2016 Item code: INTSP/C- ANPROM/FOS/16/0025b

2 DECLARATION OF TRANSPARENCY Honoraria: Amgen, Bristol- Myers Squibb, Medice, Pfizer, Sanofi, Shire and Vifor Fresenius Medical Care Renal Pharma The content of this presentalon does not necessarily reflect the opinion of Shire

3 KDIGO CONTROVERSIES CONFERENCE ON CKD- MBD (MADRID, OCTOBER 2013) 74 aaendees from 19 countries across 5 conlnents Represented experts in adult, pediatric and transplant nephrology, endocrinology, cardiology, bone histomorphometry and epidemiology Divided into 4 Breakout Groups Vascular CalcificaLon Bone Quality Calcium and Phosphorus Vitamin D and PTH CKD- MBD: Chronic Kidney Disease- Mineral and Bone Disorder PTH: Parathyroid hormone Keaeler M, et al. Kidney Int. 2015;87:502-28

4 KDIGO CONTROVERSIES CONFERENCE ON CKD- MBD (MADRID, OCTOBER 2013) Living guideline SelecLve update Full review Keeping up- to- date Refresh Adapted from Keaeler M, et al. Kidney Int. 2015;87:502-8

5 Conference recommendations Overview of recommended changes SelecLve Update in Red Minor AdaptaLon in Grey No changes leh uncolored KDIGO CKD- MBD Work Group. Kidney Int 2009; 76(S113): S1 130

6 2015 InternaLonal Society of Nephrology Revisi5ng KDIGO clinical guideline on chronic kidney disease- mineral and bone disorder: a commentary from a Kidney Disease: Improving Global Outcomes controversies conference Markus Keaeler, Grahame J. Elder, Pieter Evenepoel, Joach H. Ix, Sophie A. Jamal, Marie- Hélène Lafage- Proust, Rukshana Shroff, Ravi I. Thadhani, Marcello A. Tonelli, Bertram L. Kasiske, David C. Wheeler and Mary B. Leonard Keaeler M, et al. Kidney Int. 2015;87:502-8

7 CKD- MBD GUIDELINE UPDATE 2016 Guideline Chairs Markus Keaeler (Germany) Mary B Leonard (USA) Work Group Geoffrey Block (USA) Pieter Evenepoel (Belgium) Masafumi Fukagawa (Japan) Charles A. Herzog (USA) Linda McCann (USA) Sharon M. Moe (USA) Rukshana Shroff (UK) Marcello A. Tonelli (Canada) Nigel D. Toussaint (Australia) Marc G. Vervloet (The Netherlands) Supported by an Evidence Review Team led by Karen A. Robinson Johns Hopkins University, BalLmore (USA)

8 EXAMPLES FROM CHAPTER 4.1 TREATMENT OF CKD MBD: LOWERING HIGH SERUM PHOSPHORUS AND MAINTAINING CALCIUM DISCLAIMER: The following slides contain informalon from: KDIGO 2016 clinical prac5ce guideline update on diagnosis, evalua5on, preven5on and treatment of CKD- MBD. hap://kdigo.org/home/guidelines/ckdmbdupdate/ Which is open to Public Review and may be subject to modificalon KDIGO 2016 clinical praclce guideline update on diagnosis, evalualon, prevenlon and treatment of CKD- MBD. Public Review Drah hap://kdigo.org/home/guidelines/ckdmbdupdate/. Accessed on

9 ASSESSMENT OF PHOSPHORUS AND CALCIUM 4.1.1: In palents with CKD Stages 3a- 5D, treatments of CKD- MBD should be based on serial assessments of phosphorus, calcium and PTH levels, considered together. (Not Graded) 2009: No comparable statement KDIGO 2016 clinical praclce guideline update on diagnosis, evalualon, prevenlon and treatment of CKD- MBD. Public Review Drah hap://kdigo.org/home/guidelines/ckdmbdupdate/. Accessed on

10 RATIONALE This new recommendalon was provided in order to emphasize the complexity and interaclon of CKD- MBD laboratory parameters. Serum phosphorus, calcium and PTH concentralons are all roulnely measured and clinical decisions are ohen made based on these values. Clinical decision making should not be based on a single result, but rather on the trends. Recent post- hoc analyses of large dialysis cohorts suggest that the prognoslc implicalons of individual biochemical components of CKD- MBD largely depend on their context with regard to constellalons of the full array of MBD biomarkers. KDIGO 2016 clinical praclce guideline update on diagnosis, evalualon, prevenlon and treatment of CKD- MBD. Public Review Drah hap://kdigo.org/home/guidelines/ckdmbdupdate/. Accessed on

11 CKD- MBD PHENOTYPE AND ADJUSTED RISK OF DEATH OR CV HOSPITALIZATION Block et al ObservaLonal study using combined data set of 26,221 dialysis palents PaLents were followed for 16 months 2- stage modelling approach to determine the probability of death or cardiovascular hospitalizalon and to assign palents to 1 of 36 phenotypes based on parathyroid hormone (PTH), calcium (Ca), phosphorus (P) levels Adapted from Block G, et al. Clin J Am Soc Nephrol. 2013;12:

12 High PTH High Calcium and Phosphate Target Calcium and Phosphate..and then there are trends Block et al ObservaLonal study using combined data set of 26,221 dialysis palents PaLents were followed for 16 months 2- stage modelling approach to determine the probability of death or cardiovascular hospitalizalon and to assign palents to 1 of 36 phenotypes based on parathyroid hormone (PTH), calcium (Ca), phosphorus (P) levels Adapted from Block G, et al. Clin J Am Soc Nephrol. 2013;12:

13 RATIONALE Furthermore, therapeulc maneuvers aimed at improving one parameter ohen have unintenlonal effects on other parameters. Therefore, the Work Group considered it reasonable to take the context of therapeulc intervenlons into account when assessing values of phosphorus, calcium and PTH, and felt that it was important to emphasize the interdependency of these biochemical parameters for clinical therapeulc decision making. KDIGO 2016 clinical praclce guideline update on diagnosis, evalualon, prevenlon and treatment of CKD- MBD. Public Review Drah hap://kdigo.org/home/guidelines/ckdmbdupdate/. Accessed on

14 ASSESSMENT OF PHOSPHORUS AND CALCIUM 4.1.3: In adult palents with CKD Stages 3a- 5D, we suggest avoiding hypercalcemia (2C). In children with CKD Stages 3a- 5D, we suggest maintaining serum calcium in the age- appropriate normal range. (2C) 2009: In pabents with CKD stages 3 5D, we suggest maintaining serum calcium in the normal range (2D). KDIGO CKD- MBD Work Group. Kidney Int 2009; 76(S113): S1 130 KDIGO 2016 clinical praclce guideline update on diagnosis, evalualon, prevenlon and treatment of CKD- MBD. Public Review Drah hap://kdigo.org/home/guidelines/ckdmbdupdate/. Accessed on

15 EVOLVE TRIAL: LONGITUDINAL LAB VALUES ipth (pmol/l) P (mmol/l) Median intact PTH Median Serum Phosphorus Placebo Cinacalcet Time (months) Time (months) Ca (mmol/l) Ca x P (mmol 2/ L 2 ) 2.73 Median Serum Calcium Time (months) Median Ca x P Product Time (months) Chertow et al Randomised, placebo- controlled trial 3,883 palents with moderate to severe hyperparathyroidism undergoing hemodialysis PaLents were randomly assigned to cinacalcet or placebo (n=1,935) PaLents were followed for up to 64 months Adapted from Chertow et al. N Engl J Med. 2012;367: (Sup. Appendix)

16 RATIONALE The Work Group emphasizes an individualized approach to the treatment of hypocalcemia rather than recommending the correclon of hypocalcemia for all palents. Mild and asymptomalc hypocalcemia (e.g. in the context of calcimimelc treatment) can be tolerated in order to avoid inappropriate calcium loading in adults. KDIGO 2016 clinical praclce guideline update on diagnosis, evalualon, prevenlon and treatment of CKD- MBD. Public Review Drah hap://kdigo.org/home/guidelines/ckdmbdupdate/. Accessed on

17 TREATMENT 4.1.5: In palents with CKD Stages 3a- 5D, decisions about phosphate- lowering treatment should be based on progressively or persistently elevated serum phosphorus. (Not Graded) 2009: In pabents with CKD stages 3 5 (2D) and 5D (2B), we suggest using phosphate- binding agents in the treatment of hyperphosphatemia. It is reasonable that the choice of phosphate binder takes into account CKD stage, presence of other components of CKD MBD, concomitant therapies, and side- effect profile (not graded). KDIGO CKD- MBD Work Group. Kidney Int 2009; 76(S113): S1 130 KDIGO 2016 clinical praclce guideline update on diagnosis, evalualon, prevenlon and treatment of CKD- MBD. Public Review Drah hap://kdigo.org/home/guidelines/ckdmbdupdate/. Accessed on

18 RATIONALE The 2009 KDIGO Guideline commented that available phosphate binders are all effeclve in the treatment of hyperphosphatemia, and that there is evidence that calcium- free binders may favor hallng progression of vascular calcificalons vs. calcium- containing binders. But concerns about calcium balance, uncertainles about phosphate lowering in CKD palents not on dialysis, addilonal hard endpoint RCTs and a systemalc review (effects on mortality comparing calcium- free vs. calcium containing phosphate binders) prompted the decision to re- evaluate this recommendalon. RCTs: Randomized clinical trials KDIGO 2016 clinical praclce guideline update on diagnosis, evalualon, prevenlon and treatment of CKD- MBD. Public Review Drah hap://kdigo.org/home/guidelines/ckdmbdupdate/. Accessed on

19 RATIONALE FGF23 PHOSPHATE ACTIVE PLACEBO Block et al CORONARY CALCIFICATION Randomized, double- blind placebo controlled trial palents with moderate to asdsjdadvanced CKD PaLents were randomly assigned to calcium acetate (n=30), lanthanum carbonate (n=30), sevelamer carbonate (n=30) or placebo (n=58) PaLents were followed up for a maximum of 9 months Adapted from Block G et al. J Am Soc Nephrol. 2012;23: Suppl.

20 RATIONALE Block et al. studied subjects with essenlally normal phosphorus at baseline and as such, normophosphatemia may not be an indicalon to start phosphate- lowering treatments. This suggests that early prevenlve treatment of hyperphosphatemia is currently not supported by data (see Rec 4.1.2). The Work Group felt that the updated guideline should clarify that phosphate- lowering therapies may only be indicated in case of progressive or persistent hyperphosphatemia. Block G et al. J Am Soc Nephrol. 2012;23: KDIGO 2016 clinical praclce guideline update on diagnosis, evalualon, prevenlon and treatment of CKD- MBD. Public Review Drah hap://kdigo.org/home/guidelines/ckdmbdupdate/. Accessed on

21 RATIONALE The broader term phosphate- lowering therapies is preferred over the term phosphate- binding agents introduced in the 2009 Guideline because it appears likely that all possible approaches (i.e. binders, diet, dialysis) can be effeclve. KDIGO 2016 clinical praclce guideline update on diagnosis, evalualon, prevenlon and treatment of CKD- MBD. Public Review Drah hap://kdigo.org/home/guidelines/ckdmbdupdate/. Accessed on

22 TREATMENT 4.1.6: In adult palents with CKD Stages 3a- 5D receiving phosphate- lowering treatment, we suggest restriclng the dose of calcium- based phosphate binders. (2B) In children with CKD Stages 3a- 5D, it is reasonable to base the choice of phosphate- lowering treatment on serum calcium levels. (Not Graded). 2009: In pabents with CKD stages 3 5D and hyperphosphatemia, we recommend restricbng the dose of calcium- based phosphate binders..in the presence of persistent or recurrent hypercalcemia (1B). In pabents with CKD stages 3 5D and hyperphosphatemia, we suggest restricbng the dose of calcium- based phosphate binders in the presence of arterial calcificabon (2C) and/or adynamic bone disease (2C) and/or if serum PTH levels are persistently low (2C). KDIGO CKD- MBD Work Group. Kidney Int 2009; 76(S113): S1 130 KDIGO 2016 clinical praclce guideline update on diagnosis, evalualon, prevenlon and treatment of CKD- MBD. Public Review Drah hap://kdigo.org/home/guidelines/ckdmbdupdate/. Accessed on

23 RATIONALE New evidence from three RCTs supports a more general recommendalon to restrict calcium- based phosphate binders in hyperphosphatemic palents of all stages of CKD. RCTs: Randomized clinical trials KDIGO 2016 clinical praclce guideline update on diagnosis, evalualon, prevenlon and treatment of CKD- MBD. Public Review Drah hap://kdigo.org/home/guidelines/ckdmbdupdate/. Accessed on

24 PHOSPHATE BINDERS IN MODERATE TO ADVANCED CKD Change in Serum Phosphorus (mg/dl) Coronary Artery Calcification Volume Change Block et al Randomized, double- blind placebo controlled trial palents with moderate to asdsjdadvanced CKD PaLents were randomly assigned to calcium acetate (n=30), lanthanum carbonate (n=30), sevelamer carbonate (n=30) or placebo (n=58) PaLents were followed up for a maximum of 9 months Adapted from Block G et al. J Am Soc Nephrol. 2012;23: Suppl.

25 PHOSPHATE BINDERS AND MORTALITY (PREDIALYIS) Survival Probability Dialysis Free Probability Di Iorio et al MulLcentre, prospeclve, randomized non- blinded study 212 non- dialysis dependent CKD palents randomized to sevelamer (n=107) or calcium carbonate (n=105) for 3 years Adapted from Di Iorio B et al. Clin J Am Soc Nephrol. 2012;7:487-93

26 SEVELAMER VS. CALCIUM (DIALYSIS) CV mortality due to cardiac arrythmias All-cause CV mortality Di Iorio et al MulLcentre, prospeclve, randomized open- label study 466 adult CKD stage 5 palents new to dialysis PaLents were randomly assigned to calcium carbonate (n=234) or sevelamer (n=232) PaLents were followed up for 3 years CV: cardiovascular Adapted from Di Iorio B et al. Am J Kidney Dis. 2013;62:771-8

27 CLINICAL KEY MESSAGES It is important to emphasize the interdependency of serum Ca, P, and PTH for clinical therapeulc decision- making. Phosphate- lowering therapies may only be indicated in the case of progressive or persistent hyperphosphatemia. New evidence suggests that excess exposure to exogenous calcium in adults may be harmful in all stages of CKD, regardless of whether other risk markers are present (e.g. hypercalcemia, arterial calcificalon, adynamic bone disease or low PTH levels).