Guidelines and new evidence on CKD - MBD treatment

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2 Guidelines and new evidence on CKD - MBD treatment Goce Spasovski ERBP Advisory Board member University of Skopje, R. Macedonia ERA-EDTA CME course IV Congress of Nephrology of B&H, April 25, 2015, Sarajevo, BiH

3 Session Objectives Mineral and Bone Disorders in CKD patients General issues Guidelines KDIGO guidelines & Controversies conference update Treatment options Adynamic bone disease (ABD) Hyperparathyroid bone disease (HPTH)

4 Defining CKD-MBD The first CKD-MBD Controversies Conference, held in Madrid in 2005, developed the definition of CKD-MBD.

5 Publishing the CKD-MBD Guideline The first KDIGO clinical practice guideline on CKD-MBD was published in August 2009.

6 After the publication

7 After the publication

8 After the publication

Controversies Conferences Controversies Conferences

important Practice Updates Guidelines nephrology topics

the community The KDIGO Controversies Conference may

the development or update of an existing KDIGO Clinical

9 Controversies Conferences Controversies Conferences Revision Controversies & Conferences examine Clinical important Practice Updates Guidelines nephrology topics that result in a published position paper to share with the community The KDIGO Controversies Conference may conclude that there is enough evidence and need to prompt the development or update of an existing KDIGO Clinical Clinical Practice Conferences Practice Guideline Implementation Task Force Research

11 Controversies Conference Objective The goal was to review the evidence accumulated since 2009 and identify which recommendations potentially warrant revisions (or deletions) and what new scope topics or recommendations could be considered in a future systematic review. This conference was NOT intended to draft new guideline statements or reappraise the evidence grade for each guideline statement. These tasks will be reserved for future the Work Group and Evidence Review Team to undertake. ASN Kidney Week November 7, 2013 Atlanta, USA

12 Conference Overview: Participants 74 attendees from 5 continents and 19 countries Represented experts in adult, pediatric and transplant nephrology, endocrinology, cardiology, bone histomorphometry and epidemiology Divided into four Breakout Groups 1. Vascular Calcification 2. Calcium and Phosphorus 3. Bone Quality 4. Vitamin D and PTH ASN Kidney Week November 7, 2013 Atlanta, USA

$abnormalities, Vascular calcifications Soft tissue calcifications CVD, fractures, mortality$

13 Mineral & Bone Disorder (MBD) Systemic Complication in CKD Mineral Hormonal Bone abnormalities, Vascular calcifications Soft tissue calcifications CVD, fractures, mortality General overview

Pathophysiology of CKD - MBD BLOOD VESSEL BONE resorption 200 mg/day Deposition Vascular calcification PARATHYROID GLAND BLOOD 200 mg/day Resorption Ca ++ PO 4 -- Ca ++ -- PO 4 150 mg/day Formation

14 Pathophysiology of CKD - MBD BLOOD VESSEL BONE resorption 200 mg/day Deposition Vascular calcification PARATHYROID GLAND BLOOD 200 mg/day Resorption Ca ++ PO 4 -- Ca PO mg/day Formation PTH 150 mg/day KIDNEY (RENAL FAILURE) Ca reabs. 1 a hydroxylase FOOD 800 mg/day Absorption 1,25(OH) 2 D mg -- Daily food PO 4 abs. 800 mg 400 mg Faecal excretion INTESTINE Spasovski G et al. Semin Dial 2009; 22(4):

15 FGF-23 Regulation of Phosphate Homeostasis FGF-23 Bone Serum Phosphorous Kidney P reabsorption 1,25(OH) 2 D 3 P excretion in urine Adapted from Stubbs J, et al. Semin Dial. 2007;20:

16 Consequences of Elevated Serum Phosphorus Pi Ca ++ Calcitriol PTH resistance Calcitriol resistance PTH Secretion Parathyroid Cell Growth Increased CaxP & risk of metastatic calcifications HPTH Treatment ABD Morbidity & Mortality Spasovski G et al. Semin Dial 2009; 22(4):

17 Bone as primary reservoir of calcium & phosphorus Hydroxyapatite % of total body Ca % of total body PO 4 Bone 99 % 29 % Intracellular Interstitial Plasma 0.9 % % % 70 % (exch.) 0.1 % 0.9 % Spasovski G et al. Semin Dial 2009; 22(4):

19 Bone Histology in ROD Osteitis Fibrosa Mixed lesion Adynamic bone disease Osteomalacia

20 Changing spectrum of renal osteodystrophy Spectrum of Renal Bone Disease in patients with end-stage renal bone disease not yet in dialysis Osteomalacia 12% Hyperpara 9% N = 84 Adynamic bone 23% Mixed lesion 18% Prospective, Non-randomized, Macedonian Population N = 84 patients Histomorphometric criteria according to: Salusky et al., Kidney Int.,33,1988 Parfitt et al., Calcif Tissue Int 42, 1988 Normal bone 38% GB Spasovski et al. Nephrol Dial Transpl 2003; 18:

21 Changing spectrum of renal osteodystrophy Adynamic Bone Disease - bone and beyond Evolution of ROD distribution pattern over time Brandenburg VM & Floege J. NDT plus (2008) 3: Malluche HH, Mawad H, Monier-Faugere MC. Nephrol Dial Transpl 2004; 19 Suppl 1: i9-13

Renal osteodystrophy in the first decade of the new millennium: analysis of 630 bone biopsies in black and white patients. Malluche HH, Mawad H, Monier-Faugere MC.

22 Renal osteodystrophy in the first decade of the new millennium: analysis of 630 bone biopsies in black and white patients. Malluche HH, Mawad H, Monier-Faugere MC. J Bone Miner Res 2011; 26: Prevalence of low, normal, and high bone turnover in black and white CKD stage 5 patients on maintenance dialysis. Significant difference in distribution (chi-square, p <.001).

23 Physiopathology of Adynamic Bone Al + Fe Mg ++ Better Pi control Diabetes Vit.D treatm. VDR polymorphism Relative hypoparathyroidism VDR expression Down regulation of PTH receptor Insufficient PTH levels Osteoblastic dysfunction Diabetes Older age Older age Male gender Malnourishment Ca receptor expression Decreased BFR Uremic toxins Extracellular Ca ++ Growth factors Al + Fe Ca load: Ca based binders HD & CAPD dialysis fluid Ca conc. Vit.D treatment

24 Clinical Relevance and Consequences Association in CKD patients between: MBD (abnormal mineral metabolism & bone health) & Fractures decreased quality of life VC most important cause of morbidity CVD significant mortality Bone health and vascular calcification relationship in chronic kidney disease Spasovski G. Int Urol Nephrol 2007;39:

$CKD - MBD: Bone lose & fracture United States Renal Data System data (300,000 patients) - The relative risk for hip$

25 CKD - MBD: Bone lose & fracture United States Renal Data System data (300,000 patients) - The relative risk for hip fracture in dialysed patients is 4.4 times (men and women) that of age-matched controls. Alem A et al. Kidney Int 2000, 58: 396-9

26 Disordered bone remodelling can induce vascular calcification High bone turnover Phosphate Calcium Precipitation in vessels and soft tissues Low bone turnover Calcification High bone turnover leads to release of Ca + P from bone. Low bone turnover hinders their emplacement in bone. Result is cardiovascular and soft tissue calcification. London et al. J Am Soc Nephrol 2004;15: ; Spasovski G. Int Urol Nephrol 2007;39:

27 Arterial calcification increases mortality risk Probability of survival arteries calcified 1 artery calcified 2 arteries calcified 3 arteries calcified n=110 p< Duration of follow-up (months) 4 arteries calcified Presence and extent of vascular calcifications predict cardiovascular and allcause mortality in dialysis patients. Prospective trial in 110 dialysis patients assessing cardiovascular (CV) calcifications, mean follow up 53 months. Endpoints: All cause and CV mortality using univariate and multivariate survival analysis. Blacher et al. Hypertension 2001;38:

28 Topic #1: Vascular Calcification In patients with CKD stages 3 5D, we suggest that a lateral abdominal radiograph can be used to detect the presence or absence of vascular calcification, and an echocardiogram can be used to detect the presence or absence of valvular calcification, as reasonable alternatives to computed tomography based imaging (2C) We suggest that patients with CKD stages 3 5D with known vascular/valvular calcification be considered at highest cardiovascular risk (2A). It is reasonable to use this information to guide the management of CKD MBD (not graded). Revision Yes No ASN Kidney Week November 7, 2013 Atlanta, USA

29 Types of Phosphate Binders Calcium acetate / carbonate Efficient but associated with vascular - soft tissue calcification Metal-based - (non-calcium) Aluminium efficient but with long-term toxicity shown Lanthanum systemically absorbed; bone deposition (no toxicity) Renagel/Renvela (sevelamer-hcl/co 3 ) (non-calcium) Calcium-metal-free; non-absorbed phosphate binder. No risk of vascular and soft tissue calcification *MCI-196 (non-calcium) cholestilan - cholebine Calcium & metal-free non-absorbed phosphate binder. Efficient and safe treatment, no risk of soft and VC *Calcium acetate/magnesium carbonate Decreased Ca load efficient, Mg increase as a concern bone effect unknown Goodman WG et al. NEJM 2000;342: London GM et al. JASN 2004;15: Malluche HH et al. NDT 2002; 17: Locatelli F et al. Drugs 2003;6: Chertow GM et al. KI 2002;62: Block GA et al. KI 2005;68: Spasovski G et al. NDT 2006;21: *Locatelli F et al. NDT 2010;25: * Francisco A et al. NDT 2010;25:

30 What is Precise P & Ca Management? K-DOQI Guidelines GB Renal Association Guidelines EDTA Guidelines KDIGO Guidelines on CKD-MBD

K/DOQI* guidelines for Bone Metabolism and Disease / Dislipidemia in Chronic Kidney Disease (1.1 1.8 mmol/l) (< 4.4 mmol 2 /l 2 ) (< 2.56 mmol/l) (< 5.

31 K/DOQI* guidelines for Bone Metabolism and Disease / Dislipidemia in Chronic Kidney Disease ( mmol/l) (< 4.4 mmol 2 /l 2 ) (< 2.56 mmol/l) (< 5.12 mmol/l) The K/DOQI guidelines have become widely accepted and are basis of many national treatment guidelines in Eastern Europe National Kidney Foundation K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis 2003;42(Suppl 3):S1-S202. National Kidney Foundation K/DOQI Clinical Practice Guidelines for managing Dyslipidemias in Chronic Kidney Disease. Am J Kidney Dis. 2003;41(suppl 3):S1-91.

32 Relative Hazard of Death (95% CI) Mortality Risk Varies According to Number of Laboratory Targets* Achieved Concurrently 1,8 1,6 Three Targets (Reference) Two Targets One Target No Targets 1,51 1,4 1,39 1,37 1,35 1,2 1,21 1,20 1,15 1,0 1,00 0,8 N = 22,937 All ipth & P ipth & Ca Ca & P Groups Defined by Targets Achieved P ipth Ca None Time-dependent model. *Laboratory targets from National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI ). KDOQI TM is a trademark of the National Kidney Foundation, Inc. Danese MD, et al. Clin J Am Soc Nephrol. 2008;3:

33 K/DOQI* guidelines for Bone Metabolism and Disease in Chronic Kidney Disease (> 1.8 mmol/l) Non Ca based (> 2.7 mmol/l) Non Ca based Sevelamer remains first line treatment option (Lanthanum, MCI 196) Ca based binders contraindicated in low PTH, high Ca, severe calcifications National Kidney Foundation K/DOQI Clinical Practic Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis 2003;42(Suppl 3):S1-S202.

34 KDIGO Guidelines 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 (ABD) 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

35 Type of treatment for hyperphosphataemia and related outcomes

37 Non-CBPB are associated with a decreased risk of all-cause mortality vs. CBPB in patients with CKD All Cause Mortality Favors non-calcium Favors calcium Jamal, et al. Lancet 2013

38 New Studies - P binders in CKD 3-4 CKD stage 3b 4 patients Block, et al. JASN 2012

39 New Studies - P binders in CKD 3-4 Block, et al. JASN 2012

40 VC & Mortality & P binders (in CKD 3-4) Type of binder Patients compliance & tolerance Methodological issues Surrogate outcome (VC) Hard outcome (CVD & mortality) Placebo control - ethics Statistical analysis Baseline matching Sample size Druke & Massy, JASN 2012

41 Topic #2: Calcium + Phosphate In patients with CKD stages 3 5D, we suggest maintaining serum calcium in the normal range (2D). Argument: New evidence to suggest that calcimimetics may alter clinical significance of low calcium Revision Yes No ASN Kidney Week November 7, 2013 Atlanta, USA

42 Topic #2: Calcium + Phosphate In patients 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). Arguments: New data from RCTs, safety data Distinguish pre-dialysis and dialysis Revision Yes No ASN Kidney Week November 7, 2013 Atlanta, USA

43 New Studies Jamal, et al. Lancet 2013

44 Non-CBPB are associated with a decreased risk of all-cause mortality vs. CBPB in patients with CKD All Cause Mortality Favors non-calcium Favors calcium Jamal, et al. Lancet 2013

45 Oral CaCO3 - positive net bone balance but less than overall Ca balance (soft-tissue dep.) CKD stage 3b 4 patients Hill et al, Kidney International 2013

46 Oral CaCO3 - positive net bone balance but less than overall Ca balance (soft-tissue dep.) in CKD 3-4 Hill et al, Kidney International 2013

47 Oral CaCO3 in CKD positive net balance Ca balance in CKD patients (neutral/depleted) Doubled dietary Ca intake (500 vs 1000mg) Neutral balance with 1000mg depletion? No comparison with Non-CBPB (VC) Isotopic based Ca kinetics Extraskeletal deposition is challenged Bone deposition Osteoporosis - avidity for Ca Repetitive data different status Evenepoel & Wolf, JASN 2012

48 THERAPEUTIC APPROACH PREVENTION OF COMPLICATIONS OF THERAPY... OF HYPERPHOSPHATEMIA & MBD & ROD & VC IN CKD PATIENTS

49 Reducing Calcium Load With a Calcium-free Phosphate Binder Total Elemental Calcium Intake (average g/wk) g/wk Phosphate binder: 3-5 g/day (20-30% resorption) 1300 mg/day Dialysate: 1.25 moll/l - net influx mg calcium / HD Diet: intake 600 mg calcium per day Calcium Binder* 4.3 g/wk Calcium-Free, Metal-Free Binder Binder (dose 5 g/day) Dialysate (2.5 meq/l) Diet (600 mg/day) Bleyer AJ et al. Am J Kidney Dis. 1999;33: Data on file, Genzyme Corporation Hsu CH. Am J Kidney Dis. 1997;29:

50 Topic #3: Bone Quality (ABD vs HPTH) In patients with CKD stages 3 5D, it is reasonable to perform a bone biopsy in various settings including, but not limited to: unexplained fractures, persistent bone pain, unexplained hypercalcemia, unexplained hypophosphatemia, possible aluminum toxicity, and prior to therapy with bisphosphonates in patients with CKD MBD (not graded) Argument: Secondary analyses in osteoporosis trials New therapies denosumab and teriparatide Revision Yes No ASN Kidney Week November 7, 2013 Atlanta, USA

51 Effects of Sevelamer Hydrochloride and Calcium Carbonate on ROD in HD Patients Ferreira A, Frazao J et al. J Am Soc Nephrol 2008; 19:

Evolution of renal bone disease of all patients after one year of treatment with either

52 Classification of ROD in LC and CC group (Lanthanum) Patients with either low bone turnover at baseline and those evolving toward low bone turnover at follow-up in both study groups Evolution of renal bone disease of all patients after one year of treatment with either lanthanum or calcium carbonate D'Haese PC, Spasovski GB et al. Kidney Int 2003; 63: Suppl 85:73-78

53 Evolution of bone and plasma concentration of lanthanum in dialysis patients before, during 1 year treatment with lanthanum carbonate and after two years of follow up. Bone lanthanum concentrations of patients receiving lanthanum carbonate (solid circle) and calcium carbonate treatment (open circle) for 12 months, followed by 2 years of treatment with calcium carbonate. There is a slow release of lanthanum from its bone deposits 2 years after the discontinuation of the treatment and no association with aluminium-like bone toxicity. Spasovski G et al. Nephrol Dial Transpl 2006; 21(8):

54 ABD - SAVE THE BONE & THE HEART Reduction of Calcium Load and successful P control Individualized program do not harm!

55 Lowered Dialysate Calcium in PD: Increased PTH and Bone Formation. Haris A et al. Kidney Int 2006; 70(5):931-7 Control Ca Low Ca Before After P-value Before After P-value tca (mm) NS P<0.001 ica (mm) NS P< PO 4 (mm) NS NS Mg (mm) NS NS ALP (U/l) NS NS PTH (pm) NS P< n = 9 n = 14

56 Treatment of ABD with LCD and HCD Improvement of Bone and Mineral Parameters Related to ABD by Diminishing Dialysate Calcium Pre HD param. LCD HCD unit Baseline 3 months 6 months Baseline 3 months 6 months tca Pre HD 2.44 ± ± 0.19 a 2.39 ± ± ± 0.19 a 2.39 ± 0.17 b tca Post HD 2.41 ± ± ± 0.20 b 2.65 ± 0.18 c 2.50 ± 0.17 a,c 2.63 ± 0.19 b,c ica Pre HD 1.10 ± ± 0.12 a 1.07 ± 0.09 b 1.11 ± ± 0.08 c 1.07 ± 0.08 ica Post HD 1.09 ± ± 0.14 a 1.12 ± 0.09 b 1.20 ± 0.08 c 1.16 ± 0.22 c 1.18 ± 0.08 c P 1.50 ± ± ± ± ± 0.46 a 1.58 ± 0.45 a Ca x P ipth pg/ml* TAP U/L* BAP U/L* 3.68 ± ± ± ± ± ± ± ± 43.4 a 78.6 ± 44.7 a 43.5 ± ± ± 29.6 c 59.5 ± ± 26.7 a 84.0 ± 35.4 a 58.0 ± ± ± 25.9 c 23.4 ± ± ± 22.3 a 25.4 ± ± ± 9.7 c Spasovski G et al. Bone 2007; 41:

57 Vitamin K 2 Improves Bone Metabolism in HD pts. with a Low PTH 40 HD pts with low intact PTH levels (<100 pg/ml) randomised into a vitamin K₂ group receiving oral menatetrenone (45 mg/day) for 1 year and a control group without vitamin K₂. Ochiai M, et al. Nephron Clin Pract. 2011; 117(1):c15-9.

New Strategies in Treatment of MBD and Associated Cardiovascular Disease in Patients with CKD - HPTH Spasovski G, Recent Patents on Cardiovascular Drug Discovery, 2008; 3(3):222-8 INDIVIDUALIZED

58 New Strategies in Treatment of MBD and Associated Cardiovascular Disease in Patients with CKD - HPTH Spasovski G, Recent Patents on Cardiovascular Drug Discovery, 2008; 3(3):222-8 INDIVIDUALIZED COMBINATION Dose of Ca carbonate/acetate As much as needed (AMAN) Non Ca-based P binders in pts at risk for VC & CVD Vitamin D (AMAN) Use Low Calcium dialysate - always Use aluminum (small amount, shortly) Vit. D analogs upon indication Calcimimetics upon indication

59 Topic #4: Vitamin D + PTH In patients with CKD stages 3 5 not on dialysis, the optimal PTH level is not known. However, we suggest that patients with levels of intact PTH (ipth) above the upper normal limit of the assay are first evaluated for hyperphosphatemia, hypocalcemia, and vitamin D deficiency (2C). It is reasonable to correct these abnormalities with any or all of the following: reducing dietary phosphate intake and administering phosphate binders, calcium supplements, and/or native vitamin D (not graded). Argument: Concerns with calcium load and balance Stage dependent phosphate binder treatment Revision Yes No ASN Kidney Week November 7, 2013 Atlanta, USA

60 Topic #4: Vitamin D + PTH In patients with CKD stages 3 5 not on dialysis, in whom serum PTH is progressively rising and remains persistently above the upper limit of normal for the assay despite correction of modifiable factors, we suggest treatment with calcitriol or vitamin D analogs (2C) Argument: PTH values > upper normal range may be appropriate. Paricalcitol was not associated with improved CV outcomes in the PRIMO or OPERA studies, vs. hypercalcemia risk. Revision Yes No ASN Kidney Week November 7, 2013 Atlanta, USA

61 New Studies - PRIMO At 48 weeks, the change in left ventricular mass index did not differ between treatment groups. Doppler measures of diastolic function also did not differ. Episodes of hypercalcemia were more frequent in the paricalcitol group compared with the placebo group. Thadhani et al, JAMA 2012

62 Topic #4: Vitamin D + PTH In patients with CKD stage 5D, we suggest maintaining ipth levels in the range of approximately two to nine times the upper normal limit for the assay (2C). We suggest that marked changes in PTH levels in either direction within this range prompt an initiation or change in therapy to avoid progression to levels outside of this range (2C). Revision Yes No ASN Kidney Week November 7, 2013 Atlanta, USA

63 Effect of Cinacalcet on CVD in Pts Undergoing D The EVOLVE Trial Investigators* COST-EFFECTIVENESS OF THE TREATMENT WITH CINACALCET AND VITAMIN D ANALOGS? N Engl J Med. 2012; 367(26):

New Studies: EVOLVE After adjustment for baseline

end point was 0.88 (95% CI, 0.79 to 0.97; P = 0.008).

use of commercially available cinacalcet, relative hazards for

64 New Studies: EVOLVE After adjustment for baseline characteristics, the relative hazard for the primary composite end point was 0.88 (95% CI, 0.79 to 0.97; P = 0.008). When censored after kidney transplantation, parathyroidectomy, or use of commercially available cinacalcet, relative hazards for the primary composite end point was 0.90 (95% CI, 0.82 to 0.99; P = 0.03). Chertow et al, NEJM 2012

Comparison of PTH level at baseline and end of study (median-iqr-range) The median (interquartile range; IQR) PTH at baseline was 985 (674, 1621) pg/ml, and values decreased nominally

65 Comparison of PTH level at baseline and end of study (median-iqr-range) The median (interquartile range; IQR) PTH at baseline was 985 (674, 1621) pg/ml, and values decreased nominally to 480 (268, 798) pg/ml, or by a median (IQR) percnt change of -48.3% (- 68.8%, -26.5%), after treatment with cinacalcet, p<0.001 Behets, Spasovski et al. Kidney Int Apr;87(4):846-56

66 Primary efficacy endpoint: comparison of BFR (median-iqr-range) at baseline and end of study The median (IQR) value for BFR/T.Ar at baseline exceeded the upper limit of the normal reference range ( µm 2 /mm 2 /day), but it decreased from (545.9, ) to (172.2, 641.8) µm 2 /mm 2 /day at end of study, p< Behets, Spasovski et al. Kidney Int Apr;87(4):846-56

67 CKD - MBD management conclusion An aggressive treatment of hyperphosphatemia with Ca based P- binders might lead towards an opposite effect: - hypoparathyroidism, hypercalcemia, calcifications Evidence for use of non Ca-based binders favors survival Vitamin D and PTH Careful treatment with Vitamin D (increased Ca burden) High PTH may be appropriate in particular cases Marked increased in PTH out of the guidelines range may be treated by Calcimimetics & Vit. D analogs in shpth upon indication - no other treatment is effective Bone quality Bone biopsy may be appropriate for diagnosis / follow up purpose

68 Even the best treatment option are not perfect Do no harm and prevent complications

Cinacalcet treatment in advanced CKD - is it justified?

Cinacalcet treatment in advanced CKD - is it justified? Goce Spasovski ERBP Advisory Board member University of Skopje, R. Macedonia TSN Congress October 21, 2017, Antalya Session Objectives From ROD to