CKD-MBD: Can we do better in improving outcomes?

Transcription

1 CKD-MBD: Can we do better in improving outcomes? 13 th Congress of the Balkan cities Association of Nephrology, Dialysis, and Artificial Organs Transplantation Sarajevo, 06. October 2017.

2 Vascu ar ca cificatio s c i ica importa ce Prof.dr. Sa ji Rački, C i ica Hospita Ce tre Rijeka, CRO CKD-MBD: New insights in selection of phosphate binders Prof.dr. Alma Idrizi, University Medical Centre of Tirana Mother Teresa, ALB Overview of KDIGO guideline update and local implementation Prof.dr. Halima Resić, Clinical Centre University of Sarajevo, BiH

3 Vascular calcifications clinical importance Sa ji Rački University Hospital Center Rijeka, Croatia 13 th Congress of the Balkan cities Association of Nephrology, Dialysis, and Artificial Organs Transplantation Sarajevo, 06. October SABA.SEC (10/17)

4 This presentation is sponsored by Sanofi. This information is provided for medical and scientific purpose only. Sanofi does not approve usage of its products outside the approved SmPC.

5 Objectives Describe calcium as an essential body mineral and identify its essential functions. Identify calcium as a risk factor for mortality in CKD-MBD. Identify consequences of excess calcium load in CKD-MBD. Describe causes of hypercalcemia, as well as treatment options in CKD-MBD. Discuss how calcium contributes to calcium x phosphorus product.

6 Calcium Most abundant mineral in body 1 99% located in hard tissues, bone and teeth 1 Functions Build and maintain bones and teeth 1 Activation of enzymes for metabolic functions 1 Blood coagulation 1 Permeability of cell membrane 1 Transmission of nerve impulses 1 Contraction of skeletal, cardiac, and smooth muscle fiber 1 Corrected serum calcium Adjusted for low serum albumin to prevent over administration or under administration of calcium supplements 1 Recommended intake for HD and PD patients: < 2000 mg/day (diet, medications, and dialysate used) 1 Healthy adults (dependent upon age and gender): mg/day 1 1. Counts CS. Core Curriculum for Nephrology Nursing. Fifth ed. Pitman, NJ: American Nephrology Nurses Association; 2008:557.

7 Calcium The K/DOQI guidelines note that serum levels of calcium should be maintained as follows: CKD Stage 3 & 4 Maintain serum calcium within the normal range(evidence) 1 CKD Stage 5 Between mmol/l (OPINION) 1 The KDIGO guidelines note that serum levels of calcium should be maintained as follows: CKD stages 3-5D Maintain serum calcium in the normal range (2D) 2 1. National Kidney Foundation. KDOQI Avoid clinical practice hypercalcemia guidelines for bone metabolism and (KDIGO disease in chronic 2017 kidney disease. update) Am J Kidney Dis. 2003; 42 Suppl 3: KDIGO Clinical Practice Guideline for CKD-MBD Kidney International Supplements (2017) 7,

8 Relative Risk of Death Mortality Risk by Serum Ca Levels in Patients on Hemodialysis N = 40, 538 N = 58,058 Fresenius (Block et al) DaVita (Kalantar-Zadeh et al) < >11.0 Serum Ca (mg/dl) multivariate adjusted case-mix and MICS data Adapted from Block GA, Klassen PS, Lazarus JM, et al. Mineral Metabolism, Mortality, and Morbidity in Maintenance Hemodialysis. J Am Soc Nephrol. 2004;15: Adapted from Kalantar-Zadeh K, Kuwae N, Regidor DL et al. Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients. Kidney Int. 2006; 70:

9 Goodman: Coronary Artery Calcification Scores in Young Dialysis Patients Calcification Score * A Clinical Study of Calcification in 39 Young Dialysis Patients 10,000 Calcification scores nearly doubled in 10 out of patients with positive initial scan when rescanned at months Age (years) * Determined by electron beam computed tomography (EBCT). Adapted with permission from Goodman WG et al. N Engl J Med. 2000;342(20):

10 Guérin: Factors Associated With Increased Arterial Calcification Patient Characteristics and Values (Mean) by Calcification Score in 120 Stable Nondiabetic Patients With ESRD Undergoing Dialysis Characteristics Ca cificatio Score ANOVA Age (y) Dia ysis (mo) Fibri oge (g/l) Serum calcium (mg/dl) Serum phosphorus (mg/dl) NS Ca x P product (mg 2 /dl 2) NS CaCO 3 (g/day e eme ta ) Cholesterol (mg/dl) NS Hyperca cemia (%) Bo d type = statistically significant differences between groups. (n=120) Patie ts ith a mea dai y e eme ta ca cium i take from a phosphate bi der of 1.5 g/day had a mea ca cificatio score of 2. ANOVA=analysis of variance; NS=not significant. Adapted from Guérin AP et al. Nephrol Dial Transplant. 2000;15(7)

11 Median CACS* RIND Study: Coronary Artery Calcification in Patients New to Hemodialysis A randomized, open-label study in 129 patients new to hemodialysis Sevelamer HCl 1 Calcium N=54 N=55 N=51 N=53 N=45 N=47 N=40 N=45 Baseline 6 month 12 month 18 month Note: The clinical significance of the attenuation of calcification is unknown 2. *CACS = Coronary Artery Calcification Score. 1. Adapted with permission from Block GA et al. Kidney Int. 2005;68(4): Kidney Disease Improving Global Outcomes (KDIGO). Clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int. 2009;76(suppl 113):S1-S130.

12 Median % Change Median % Change Treat-to-Goal Study: Coronary Artery and Aortic Calcification in Hemodialysis Patients A 52-week open-label randomized clinical trial in 200 hemodialysis patients. Calcification was measured in by EBT in 186 hemodialysis patients. n= % Coronary Artery 14% a Sevelamer HCl 6% 25% a Week 26 Week 52 Note: In patients with calcification scores >= 30 at baseline. te: The clinical significance of the attenuation of calcification is unknown 2. a Within treatment P< % Calcium Aorta 24% a 28% a 5% Week 26 Week Adapted with permission from Chertow GM, et al. Treat to Goal Working Group. Kidney Int. 2002;62(1): Kidney Disease Improving Global Outcomes (KDIGO). Clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int. 2009;76(suppl 113):S1-S130.

13 Diagnosis of Vascular Calcification KDOQI Guide i e 16.2: If arterial calcification is identified at by plain radiography in any of the following sites (abdominal aorta, carotid arteries, ileofemoral axis or femoropopliteal axis), identification of calcification at another site should be sought. 1 If vascular calcification is present in two or more sites, prescription of a noncalcium-containing phosphate binder should be considered. 1 KDIGO Guide i e 3.3, in CKD stages 3-5D 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) 2 Patients with known vascular/valvular calcification should be considered at highest cardiovascular risk (2A). 2 It is reasonable to use this information to guide the management of CKD-MBD (not graded) 2 1. National Kidney Foundation. KDOQI clinical practice guidelines for cardiovacular disease in dialysis patients Am J Kidney Dis. 2005; 45 Suppl 3: KDIGO clinical practice guidelines for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorders (CKD-MBD). Kidney International 2009; 76 Suppl 113: S44.

14 The patient s medical chart can be useful in providing evidence of cardiovascular & other soft tissue calcification. Check the following sections of the medical chart to uncover possible cardiovascular and/or other soft tissue calcification. Diagnostic Tests EBCT 1 MSCT 1 Echocardiogram 1 X-rays 1 Dialysis Flow Sheet All dialysis patients should have a pulse pressure (PP) determined monthly before dialysis 3 Evidence of Calcification Checklist Past Medical History Diabetes 2 Inflammation 2 Dyslipidemia and/or increased oxidized LDL 2 Hypertension 2 Smoking 2 Warfarin therapy 2 Calcium overload 2 Low PTH/adynamic bone 2 High PTH 2 Hyperphosphatemia 2 For PP > 60 mm Hg and systolic BP > 135 mm Hg, KDOQI recommends reducing PP by achieving ideal body wieght and using antihypertensive medication. 3 Pulse Pressure = systolic BP diastolic BP 3 Degree of large artery calcification can be indirectly inferred by increases in pulse pressure and pulse wave velocity Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. Kidney Int. 2009;76(suppl 113):S1-S Olgaard K, ed. KDIGO Clinical Guide to Bone and Mineral Metabolism in CKD. National Kidney Foundation; National Kidney Foundation. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis 2005;45(4)(suppl 3):S16-S138.

15 KDIGO Guidelines: Calcium In chronic kidney disease patients on dialysis with hyperphosphatemia, KDIGO suggests restriction of the dose of calciumbased phosphate binders in the presence of: Persistent or recurrent hypercalcemia (1B) Arterial calcification (2C) Adynamic bone disease (2C) Persistently low PTH level (2C) 1B = A KDIGO recommendation with moderate quality of supportive evidence 2C = A KDIGO suggestion with low quality of supportive evidence

16 Hypercalcemia Serum calcium >2.55 mmol/l 1 May lead to soft tissue calcification in CKD Stage Causes decreased neuromuscular activity 2, that can lead: Cardiac arrhythmias 2 Decreased memory 3 Confusion 3 Disorientation 2 Fatigue 2 Muscle weakness 2 Lethargy 2 Anorexia 2 Nausea 2 Constipation 2 Calcium deposits in soft tissues 2 resulting in: Irritation and inflammation 2 Kidney stones 2 1. 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: Yucha C, Guthrie D. Renal homeostasis of calcium. Nephrol Nursing J. 2003; 30: 6: Lewis SM, Heitkemper MM, Dirksen SR, et al. Medical Surgical Nursing: Assessment and Management of Clinical Problems. Sixth ed. St. Louis, MO: Elsevier; 2004:346.

17 Why patients may be hypercalcemic Increased intake 1 Diet and Phosphate binders Low bone turnover (adynamic bone disease) Increased absorption 1 Low phosphorus levels 1 Vitamin D overdose 1 Dialysate calcium 2 Increased mobilization of calcium from bone 1 Hyperparathyroidism 1 High bone turnover Malignancy 1 Multiple fractures 1 Prolonged immobilization 1 Acidosis 1 1. Counts CS. Core Curriculum for Nephrology Nursing. Fifth ed. Pitman, NJ: American Nephrology Nurses Association; 2008: Gupta A, Wang j, Norris K. Serum Calcium and total calcium load in kidney disease. Nephrol News & Issues. 2003; Nov:

18 Calcium Balance Overall calcium balance is insufficient because it does not consider redistribution of calcium that occurs in patients with CKD, especially those on dialysis. 1 Redistribution of calcium is often in the form of soft tissue and/or vascular calcification. 1 Patients with extraosseous calcification may be in a positive, neutral, or negative total calcium balance. 1 In dialysis patients, total body calcium is often maldistributed Bushinsky, DA. Contribution of intestine, bone, kidney, and dialysis to extracellular fluid calcium content. Clinical Journal of American Society of Nephrology. 2010; 5: S12-S22.

19 Serum Calcium May Not Reflect Total Body Calcium Load Distribution of Calcium in the Body Bone calcium 99% of total body Ca (990 g) Intracellular calcium 0.9% of total body Ca (9 g) Interstitial calcium 0.075% of total body Ca (0.75 g) Total body calcium = 1000 g Plasma calcium 0.025% of total body Ca (0.25 g) Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney diseasemineral and bone disorder (CKD-MBD) Kidney Int. 2009;76(suppl 113):50, S1-S130.

20 Serum Calcium B ood ca cium eve is ot a gauge of ho much ca cium is i the body. 1 Blood calcium concentration is not informative as to whether calcium is moving into or out of the extracellular fluid (ECF). 1 The level of blood calcium is set by a variety of hormones and other factors to provide optimal cellular function. 1 Co ti ua moveme t of ca cium i to ECF from i testi e a d/or bo e i i crease b ood ca cium co ce tratio o y he it exceeds the rate of ca cium depositio at other ECF sites Bushinsky, DA. Contribution of intestine, bone, kidney, and dialysis to extracellular fluid calcium content. Clinical Journal of American Society of Nephrology. 2010; 5: S12-S22.

21 An analysis has shown that CKD patients on dialysis are almost always in positive calcium balance Bushinsky DA. Clin J Am Soc Nephrol. 2010;5(suppl 1):S12-S22. Dietary intake of 37.5 mmol (1.5 g) elemental Ca/d will likely result in positive ECF Ca At almost all dietary Ca intakes, use of activated 1,25(OH) 2 D 3 is likely to result in positive ECF Ca Amount of Ca retained is substantial and could amount to as much as 4% of normal bone Ca mass

22 Despite being in positive calcium balance, the majority of CKD patients have serum calcium levels in the normal range. Only one-third of CKD stage 5 patients have hypercalcemia. Craver L et al. Nephrol Dial Transplantation. 2007;22: Serum calcium levels remain adequate for the majority of CKD patients and do not accurately predict total body calcium load

23 Calcification is a common, progressive consequence of CKD across all patient populations and is not associated with serum calcium a Percent based on CAC score > zero. b Subjects evaluated using electron beam computed tomography. c Corrected calcium. d Subset analysis represents patients 20 to 30 years old (total N=39). e Value reflects mean serum calcium of 14 patients with calcification. 1. Russo D et al. Am J Nephrol. 2007;27: Block GA et al. Kidney Int. 2005;68: Chertow GM et al. Kidney Int. 2002;62: Goodman WG et al. N Engl J Med. 2000;342: Separate clinical studies have shown evidence of vascular calcification in CKD patients who are on dialysis and not on dialysis, while baseline serum calcium levels fell within the normal range Serum calcium does not accurately reflect or predict overall body calcium load

24 Calcium is out of range what do I do? Calcium is below target In CKD Stage 5D patients with elevated or rising PTH, assess calcimimetic therapy; consider reducing dose or discontinuing 1 Patients should receive therapy to increase if serum calcium < 2.1 mmol/l: Clinical symptoms of hypocalcemia exist (paresthesia, Chvostek s and Trouseau s signs, bronchospasm, lanryngospasm, tetany, or seizures) 2 ipth level is above target range for CKD Stage 2 Therapy should include: Calcium supplement or calcium-based binder (not to exceed 1500 mg/d) 2 Oral Vitamin D sterols 2 Corrected Calcium is above target (>2.55 mmol/l), in CKD Stage 5 Evaluate dietary calcium intake 2 Reduce or replace calcium-based phosphate binders with noncalcium-, nonaluminum-, nonmagnesium-containing phosphate binders 2 Consider reducing or holding D hormone until levels return to target range 2 If hypercalcemia (cca > 2.55 mmol/l) persists despite modification of theray with vitamin D and/or discontinuation of calcium-based phosphate binders, dialysis using low dialysate calcium ( mmol/l) may be used for 3-4 weeks 2 1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD) Kidney Int. 2009;76(suppl 113):50, S1-S 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-S201.

25 Ca cium x Phosphorus Product.

26 Ca X P Product The K/DOQI guidelines note calciumphosphorus product should be maintained as follows: CKD Stage 3-5 Maintain serum calcium-phosphorus product at < 4.5 mmol 2 /L 2 (EVIDENCE) 1 Best achieved by co tro i g serum eve s of phosphorus ithi the target ra ge (OPINION) 1 The KDIGO 2017 guidelines note: CKD Stage 3-5D Individual values of serum calcium and phosphorus, evaluated together, should be used to guide clinical practice rather than calcium-phosphorus product (Ca x P)(2D) 2 1. National Kidney Foundation. KDOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003; 42 Suppl 3: KDIGO Clinical Practice Guideline for CKD-MBD Kidney International Supplements (2017) 7, 1 59.

27 Calcification of the Lung Periarticular Calcification Noncalcified Slide courtesy of E. Slatopolsky; used with permission Calcified Slide courtesy of D. Sherrard; used with permission

28 Slide courtesy of H. Malluche; used with permission. Slide Courtesy of R. Biesecker; used with permission Cutaneous/Subcutaneous Calcification Ocular Calcification.

29 Mechanism of Action: non metal, non calcium binder Sevelamer is a nonabsorbed binder with no evidence of accumulation For illustrative purposes only. Not intended as actual representation or scale. Renvela SmPC

30 Summary Calcium is the most abundant mineral in the body with essential functions. 1 In CKD, elevated serum calcium has been shown to increase relative risk of mortality 2,3 Elevated total body calcium may not be reflected by increased serum calcium levels 4 Increased intake of calcium-based binders has been shown to be associated with calcification 5 and increased coronary artery calcification score 6 Treatment for hypercalcemia (>2.55 mg/dl) in CKD Stage 5, may include reduction of calcium load from: Diet 7 Calcium-based phosphate binders 7 Vitamin D hormone replacement therapy 7 Dialysate concentration, if hypercalcemia persists despite modification to Vitamin D and phosphate binder therapy 7 KDIGO guidelines suggest utilizing individual serum calcium and phosphorus levels, rather than the calcium-phosphorus product.(2d) 8

31 Failed SHPT treatment in dialysis patient Case presentation.

32 Case report 60-years old man on maintenance hemodialysis (started at 2005) has been referred to our center for kidney transplant waiting list evaluation. Underlying renal disease glomerulonephritis Concomitant diseases: arterial hypertension with LVH prostatic adenoma

33 Case report Height 185 cm, weight 75 kg, BMI 21,9 kg/m 2 RRF diuresis 200 ml/day Smoker, non-alcocholic Blood pressure 140/80 mmhg ECG: sinus rhytm 75/min, LVH Cardiac ultrasound: no valvular disease, no contractility defects, LVH, EF 50%, diastolic dysfunction

34 Case report Chest x-ray normal Abdominal ultrasound reduced kidney parenchyme, otherwise normal EGDS, colonoscopy, hemocult normal Urology: PSA normal, prostatic adenoma, no RU Virology, bacteriology normal ORL, stomatology, neulogy, ophtalmology findings normal Doppler ultrasound iliac arteries no significant stenosis

35 MSCT angiography Diffuse calcifications of aorta and iliac arteries

36 Baseline laboratory data Variab e Predia ysis BUN Predia ysis creati i e Hemog obi Epo dose (average mo th y C.E.R.A.) C-reactive protei Measured tota ca cium Serum phosphorus 26.8 mmo /L 886 µmo /L 112 g/l 145 mcg 8 mg/l 2.45 mmo /L 2.31 mmo /L Ca cium x phosphorus product 5.7 I tact PTH Serum A bumi 63 pmo /L (573 pg/ml) 41 g/l

37 SHPT and other treatment Low phosphate diet prescribed patient was not compliant Calcitriol 0,25 mcg Sevelamer hydrochloride 3x800 mg Concomitant medication: Folic acid 5 mg Lercanidipin 10 mg Venofer 100 mg 1x week Mircera 150 mcg monthly Esomeprasole 40 mg Losartan 50 mg.

38 SHPT switch to paricalcitol and sevelamer Ca (mmol/l) P (mmol/l) ipth (pg/ml) parikalcitol (µg) Sevelamer HCl 10 (3xWk) 10 (2xWk) 10 (1xWk) 5 (1xWk) 3x1600 mg 3x1600 3x800 2x800 Other treatment changes 1. Switch to high-volume hemodiafiltration 2. Lower dialysate calcium content 1,25 mmol/l.

39 Pre-Tx examination 2 years after Blood pressure 135/75 mmhg ECG: sinus rhytm 75/min, LVH Cardiac ultrasound: no valvular disease, no contractility defects, decreased LVH, EF 55%, diastolic dysfunction still present Abdominal ultrasound reduced kidney parenchyme, otherwise normal Urology: PSA normal, prostatic adenoma, no RU.

40 Laboratory data Variab e Predia ysis BUN Predia ysis creati i e Hemog obi, o epo Epo dose (average mo th y C.E.R.A.) C-reactive protei Measured tota ca cium Serum phosphorus 24.6 mmo /L 850 µmo /L 114 g/l 126 mcg 6 mg/l 2.23 mmo /L 1.61 mmo /L Ca cium x phosphorus product 3.57 I tact PTH Serum A bumi 22 pmo /L (200 pg/ml) 42 g/l

41 Pre-Tx examination 2 years after MSCT angiography 12/2011 MSCT angiography 2010

42 Pre-Tx examination 2 years after Still severe iliac calcifications Splenic artery Left renal artery.

43 Pre-Tx examination 2 years after Patient was finaly accepted for waiting list Orthotopic kidney transplantation was chooses as an option One month later he was transplanted ( )

44 Transplanted kidney, orthotopic position, after left nephrectomy Arterial anastomosis

45 Arterial anastomosis power doppler Intrarenal vascularisation resistive index RI.

46 Kidney graft function, 30 days post Tx 15 months later egfr 55 ml/min egfr 49,7 ml/min

47 Conclusion Failure of severe SHPT treatment could not only be harmful for cardiovascular morbidity and mortality due to excessive vascular calcification, but can also reject them to be successfully transplanted. This could be major influence to quality of life among patients on renal replacement therapy. Successful control of SHPT could improve the patient chance for life.

48 Vascular calcifications clinical importance Prof.dr. Sanjin Rački, Clinical Hospital Centre Rijeka, CRO CKD-MBD: Ne i sights i se ectio of phosphate bi ders Prof.dr. Alma Idrizi, University Medical Centre of Tirana Mother Teresa, ALB Overview of KDIGO guideline update and local implementation Prof.dr. Halima Resić, Clinical Centre University of Sarajevo, BiH

49 CKD-MBD: New insights in selection of phosphate binders A ma Idrizi Clinic of Nephrology, UHC Mother Teresa, Tirana, Albania 13 th Congress of the Balkan cities Association of Nephrology, Dialysis, and Artificial Organs Transplantation Sarajevo, 06. October SABA.SEC (10/17)

50 This presentation is sponsored by Sanofi. This information is provided for medical and scientific purpose only. Sanofi does not approve usage of its products outside the approved SmPC.

51 Iron-based binders

52 From small studies to metaanalysis focus on Effect on ca cificatio Morta ity Bo e histo ogy Effects on biochemica parameters Effect on hospita izatio s Effect on qua ity of ife Effect on adverse eve ts Cost

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54 RIND study: Effects of sevelamer and calcium on coronary artery calcification In Patients New to Hemodialysis N=54 N=55 N=51 N=53 N=45 N=47 N=40 N=45 Block, GA, Kidney Int; Vol 68(4): , 2005

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56 Change in coronary artery and aortic calcification in Treat-to-Goal (TTG) study Paolo Raggi et al. CJASN 2010;5:S31-S40.

57 Cumu ative I cide ce of A -Cause Morta ity DCOR: Dialysis Clinical Outcomes Revisited Sevelamer vs. Calcium salts All-Cause Mortality Patie ts treated ith seve amer for 2 years experienced a statistica y sig ifica t reductio i the re ative risk for a -cause morta ity [RR 0.66 (0.48, 0.94)] % p = 0.02 No. at Risk Calcium Sevelamer Ca cium Seve amer Time o Study (Years)

58 Cumulative survivals Phosphate Binders and All-Cause Mortality Mortality Consecutive outpatients (n=212; stage 3 4 CKD) were randomized to: - seve amer ( =107) - ca cium carbo ate ( =105) Dialysis Inception Di Iorio Am J Kidney Dis by the National Kidney Foundation, Inc.

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60 Bo e formatio rate sig ifica t y i creased from base i e i the seve amer group but ot i the ca cium group.

61 Treatment with sevelamer carbonate powder improves serum bicarbonate in chronic kidney disease patients on haemodialysis Delmez J. Clin Nephrol. 2007; 68: )

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65 Sevelamer carbonate on AGEs products and antioxidant/pro-oxidant status in patients with diabetic kidney disease Sevelamer carbonate: reduced circulating and cellular AGEs increased antioxidants decreased pro-oxidants did not change HbA1c or the albumin/creatinine ratio overall in patients with T2DM Yubero-Serrano EM et al. Clin J Am Soc Nephrol May 7;10(5):759-66

66 Matteo Ruggeri a Filippo Cipriani b Antonio Bellasi c, d Domenico Russo e Biagio Di Iorio f Blood Purif 2014;37: DOI: / Received: June 17, 2014 Accepted: July 6, 2014 a Faculty Table 1. Baseline of Economics, characteristics Università and 3-year Cattolica clinical outcomes del Sacro for Cuore, the base Rome case CEA, b Market Access and Corporate Affairs, Genzyme, Published online: August 2, 2014 Modena, c Division of Nephrology, Sant Anna Hospital, Como, d Department of Health Sciences, University of Milan, Milan, e Department of Nephrology, School Sevelamer of Medicine, Calcium Federico carbonate II University, Difference Naples and f Division of Nephrology, p value 1 A. Landolfi Hospital, Solofra, Italy (n = 107) (n = 105) (95% CI) Baseline characteristics Age, years 57.4± ± Male 65 (61%) 64 (61%) 0.55 Diabetes 29 (27%) 30 (29%) 0.16 Coronary artery calcification 67 (62.6%) 50 (47.6%) 0.02 r Three-year Is Cost-Saving outcomes vs. Calcium Carbonate Survival Key All-cause Words deaths 12 (11.2%) 22 (21.0%) 9.7% ( ) LYs per patient 2.89± ± ( ) 0.23 alysis-dependent Chronic Hospitalizations kidney disease Hyperphosphatemia CKD Patients Sevelamer in Italy: Calcium Patients carbonate admitted Cost-effectiveness 33 (31.0%) 72 (69.0%) 37.7% ( 58.4 to 45.8) <0.001 Total hospitalizations ( to 88.6) <0.001 Nephrology ( 87.7 to 41.8) <0.001 Level Cardiology Cost-Effectiveness 10 Analysis 33 of 23 the ( 42.4 to 7.8) <0.001 ICU ( 12.5 to 5.6) <0.001 Abstract Hospitalizations per patient treated 0.67± ± ( 2.35 to 0.5) <0.05 Objectives: Dialysis To conduct a cost-effectiveness analysis of ENT Patients initiating Study dialysis 31 (29.0%) 42 (40%) 11.0% ( 15 to 8) sevelamer Total dialysis versus sessions calcium carbonate 4,804 in patients with 6,957 non-dialysis-dependent Dialysis sessions per patient CKD (NDD-CKD) 44.90±78.93 from the Italian 66.26±90.38 NHS per ( to 17.16) 2,153 ( 4.3 to 0.12) spective using patient-level data from the INDEPENDENT-CKD curve. A subgroup analysis of patients dialysis during the INDEPENDENT-CKD ducted. Results: Sevelamer was associa tional LYs (95% CI 0.04 to 0.16) and 5,615 (95% CI 10,066 to 1,164) per pa calcium carbonate. On the basis of the sevelamer was dominant compared to c 87.1% of 10,000 bootstrap replicates. Sim served in the subgroup analysis. Results nificant reduction in all-cause mortality a er hospitalizations in the sevelamer gro 1 Statistical significance between treatment groups was determined using t test and Fisher exact test for continuous and discrete variables, study. respectively; Methods: significance Patient-level was set 5% for all data tests. on all-cause mortality, di-

67 costs and effects involves cost savings for sevelamer versus calcium carbonate. al e o t res ol (EUR) Matteo Ruggeri a Filippo Cipriani b Antonio Bellasi c, d Domenico Russo e Biagio Di Iorio f Blood Purif 2014;37: DOI: / a Faculty of Economics, Università Cattolica del Sacro Cuore, Rome, b Market Access and Corporate Affairs, Genzyme, Table 3. Summary of clinical outcomes and costs over 36 months for the CEA on the subgroup of patients Published who did online: not initiate August dialysis Modena, c Division of Nephrology, Sant Anna Hospital, Como, d Department of Health Sciences, University of 2 Milan,, 2014 Milan Outcome, e Department of Nephrology, Sevelamer School of Medicine, Calcium Federico carbonate II University, Difference Naples (95% and CI) f Division of Nephrology, p value A. Landolfi Hospital, Solofra, Italy (n = 76) (n = 63) Survival All-cause deaths 8 (10.5%) 16 (25.4%) 14.9% ( 27.6 to 2.1) LYs per patient 2.87± ± ( 0.01 to 0.22) Hospitalizations Patients admitted 13 (17.1%) 38 (60.3%) 43.2% ( 45.8 to 25.2) < Total hospitalizations ( 92 to 60) < Key Words Nephrology ( 74 to 40) < Cardiology ( 21 to 5) < Chronic ICUkidney disease Hyperphosphatemia 1 Sevelamer 10 9 ( 15 to 2) < Received: June 17, 2014 Accepted: July 6, 2014 curve. A subgroup analysis of patients dialysis during the INDEPENDENT-CKD ducted. Results: Sevelamer was associa tional LYs (95% CI 0.04 to 0.16) and 5,615 (95% CI 10,066 to 1,164) per pa calcium carbonate. On the basis of the Hospitalizations per patient treated 0.42± ± ( 2.25 to 1.54) <0.014 Costs Phosphate binder costs per patient 2,396.71± ± , (1,854 2,921) < Hospitalization costs per patient Nephrology 1,232.24±3, ,756.83±5, , ( 10,122 to 4,400) < Cardiology ±1, ±2, ( 3,054 to 257) < ICU 49.08± ±1, ( 470 to 2,256) < Total 1,572.95±3, ,345.68±6, , ( 12,864 to 1,562) < Total costs per patient 3,969.66±3, ,441.90±6, , (3,996 to 948) < r Is Cost-Saving vs. Calcium Carbonate alysis-dependent CKD Patients in Italy: Calcium carbonate Cost-effectiveness Level Cost-Effectiveness Analysis of the Abstract Objectives: To conduct a cost-effectiveness analysis of ENT sevelamer Study versus calcium carbonate in patients with non-dialysis-dependent CKD (NDD-CKD) from the Italian NHS perspective using patient-level data from the INDEPENDENT-CKD study. Methods: Patient-level data on all-cause mortality, di- sevelamer was dominant compared to c 87.1% of 10,000 bootstrap replicates. Sim served in the subgroup analysis. Results nificant reduction in all-cause mortality a er hospitalizations in the sevelamer gro

68 Meta-analysis from Jamal to Jamal, Significantly lower all cause mortality with non-cbbs than CBBs and ca ed for research to compare morta ity amo g o - CBBs Sekercioglu, Study compared effects of available phosphate binders on important outcomes in patients with CKD-MBD Patel Palmer, Study compared and ranked many phosphatebinder strategies for CKD Patel, Compariso n of o y seve amer versus CBB in CKD patients

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70 All-cause mortality for each of phosphate binder, according to type of trial according to dialysis status Author s co s usio s Patients who were taking o -ca cium-based phosphate bi ders had about a 20% reductio in overall morta ity compared to patients who were taking ca cium-based bi ders. The other interesting was irrespective of serum phosphate, so both the calcium-based and noncalcium-based binder groups experienced a reduction in serum phosphate. Total RR=0.87; Ci in favor of non-calcium based binders Jamal SA et al., Lancet: 2013;382:

71 Compared ith CBBs, seve amer ca decrease i the preva e ce of hyperca cemia, a d be efits vascu ar ca cificatio i the o g-term. Seve amer improves c i ica y re eva t outcomes i ESRD patie ts o dia ysis.

72 Objective: To compare the effects of avai ab e phosphate bi ders o patie t-importa t outcomes i patie ts ith CKD-MBD Patients with CKD-MBD, randomized to receive: ca cium-based phosphate bi ders (CCB): including: calcium acetate, calcium citrate or calcium carbonate o -ca cium-based phosphate bi ders ( o -CBB): sevelamer hydrochloride, sevelamer carbonate, lanthanum carbonate, sucroferric oxy-hydroxide and ferric citrate), phosphorus restricted diet placebo or no treatment

73 Conventional meta-analysis for all cause mortality, CV mortality, hospitalizations A cause morta ity Higher morta ity ith ca cium versus o -ca cium based bi ders RR, 1.76 [95% CI,1.21 to 2.56] These results raise questions about CV morta ity Sig ifica hether t admi istratio of ca cium as i crease a i terve tio Hospitalization for CKD-MBD remai s ethica 73 Non significan Non significan t increase Sekercioglu N et al. (2016), PLoS ONE

74

75 Flow diagram of search results and selection of included studies Palmer S. et al. AJKD, 2016.

76 Treatment Outcomes all cause mortality Sevelamer appeared to reduce all-cause mortality compared to calcium (OR, 0.39; 95% CI, ) and was ranked best for this outcome. Palmer S. et al. AJKD, 2016.

77 No evide ce that a y phosphate bi der o ered morta ity comapred to p acebo Comapred to ca cium, sevelamer reduced all cause mortality Treatment effects of lanthaum, iron, and colestilan were not significant Lanthaum caused ausea Sevelamer posed the highest risk for co stipatio Iron caused diarrhea Palmer S. et al. AJKD, 2016.

78 Sevelamer Versus Calcium-Based Binders for Treatment of Hyperphosphatemia in CKD: A Meta-A a ysis of Ra domized Co tro ed Tria s Patel L.,* Bernard L; Clin J Am Soc Nephrol 11: , 2016

79 RCT comparing sevelamer with CBBs 25 studies Included Only RCTs and quasi-rcts >8 weeks in duration enrolling adults with CKD stages 3 5 and on dialysis (egfr#59 ml/min per 1.73 m2 or on dialysis In RCTs, the first phase was included where possible 4770 participants (88% on hemodialysis) Excluded Post-transplantation studies single-arm or observational studies abstracts Patel L.,* Bernard L; Clin J Am Soc Nephrol 11: , 2016

80 Mai study resu ts Compared with CBBs, sevelamer sig ifica t y o ered a -cause morta ity in patients with CKD stages 3 5 and on dialysis. 46% reduction in all cause mortality risk for sevelamer No sig ifica t differe ce i CV morta ity between sevelamer and CBBs. Hospita izatio parameters did ot differ between sevelamer and CBBs. Patel L.,* Bernard L; Clin J Am Soc Nephrol 11: , 2016

81 Format: Abstract matched to the newly treated patients on the basis of their risk of death. Author information Abstract Clin J J Am Am Soc Soc Nephrol. Nephrol Sep ;12(9): Sep 7;12(9): doi: /CJN Epub 2017 Jul 19. BACKGROUND AND OBJECTIVES: Prior studies have shown that sevelamer attenuates RESULTS: Of 12,564 patients, 2606 were subsequently treated with sevelamer hydrochloride or progression sevelamer Initiation of carbonate. arterial of Sevelamer calcification After beginning and and may sevelamer Mortality reduce the therapy, risk among of of death mean Hemodialysis compared serum phosphorus with calciumbased phosphate binders. In clinical practice, however, sevelamer is is used not only as as an levels decreased Patients by 0.3 Treated mg/dl in the with first Calcium-Based 4 months and gradually Phosphate decreased thereafter. Binders. We matched alternative but also as an add-on therapy in in patients already being treated with calcium-based 1, Komaba treated H patients, Wang M with, Taniguchi at least M one, Yamamoto as-yet-untreated S, Nomura patient. T, Schaubel Patients DE, Smith treated AR with, Zee sevelame J, phosphate binders. We analyzed the Dialysis Outcomes and Practice Patterns Study (DOPPS) Karaboyas A 3, Bieber B 3, Fukagawa M 8, Tentori F 3,9 1, data to test the hypothesis that the initiation of of sevelamer is is associated with improved survival in in patients Author on hemodialysis information 3 treated 3 with calcium-based 8 phosphate 3,9 binders. had a 14% lower risk for mortality compared with as-yet-untreated patients (hazard ratio, 0.86; 95% confidence interval, 0.76 to 0.97). Similar results were observed in the sensitivity analyses DESIGN, Abstract SETTING, PARTICIPANTS, & MEASUREMENTS: We included 12,564 patients from Author information DOPPS BACKGROUND phase 3 and AND phase OBJECTIVES: 4 ( ) Prior who studies were prescribed have shown calcium-based that sevelamer phosphate attenuates binders progression at baseline of arterial or before calcification sevelamer and treatment. may reduce Mortality the risk risk of death was assessed compared using with acalcium- sequential based phosphate stratification binders. method In to clinical to identify practice, as-yet-untreated however, sevelamer patients who is used were not appropriately only as an matched alternative to the but newly also treated as an add-on patients therapy on the in basis patients of of their already risk of of being death. treated with The use of sevelamer as an add-on or alternative therapy to calcium-based phosphate binders. We analyzed the Dialysis Outcomes and Practice Patterns Study (DOPPS) RESULTS: Of 12,564 patients, 2606 were subsequently treated with sevelamer hydrochloride data to test the hypothesis that the initiation of sevelamer is associated with improved survival in or sevelamer carbonate. After beginning sevelamer therapy, mean serum phosphorus levels patients on hemodialysis treated with calcium-based phosphate binders. decreased by 0.3 mg/dl in in the first 4 months and gradually decreased thereafter. We matched 2501 DESIGN, treated SETTING, patients with PARTICIPANTS, at at least one as-yet-untreated & MEASUREMENTS: patient. We Patients included treated 12,564 with patients sevelamer from had DOPPS a 14% phase lower risk 3 and for phase mortality 4 ( ) compared with who as-yet-untreated were prescribed patients calcium-based (hazard phosphate ratio, 0.86; 95% binders confidence at baseline interval, or before 0.76 to to sevelamer 0.97). Similar treatment. results were Mortality observed risk was in in the assessed sensitivity using analysesa when sequential changing stratification the matching method calipers to identify or or the treated as-yet-untreated and as-yet-untreated patients who ratios, were and appropriately by by using when changing the matching calipers or the treated and as-yet-untreated ratios, and by using propensity score matching. CONCLUSIONS: phosphate binders is associated with improved survival in patients on maintenance hemodialysis. Copyright 2017 by the American Society of Nephrology.

82 Sevelamer was associated with a nonsignificant reduction in mortality and significantly lower hospitalization rates and hypercalcemia compared with calcium-based binders. Lanthanum and iron-based binders did not show superiority for any

83 Conclusions Non-calcium based phosphate binders cause less vascular calcification compared with other calcium-based binders. Non-calcium based phosphate binders improve biochemical parameters, quality of life, rate of hospitalization.

84 continued Meta-analysis concluded that sevelamer treatment was associated with improved survival and all-cause of mortality compared with calcium-based binders and placebo. Further research is needed to explore the effects of different types of phosphate binders, including novel agents such as iron, on quality and quantity of life.

85 Vascular calcifications clinical importance Prof.dr. Sanjin Rački, Clinical Hospital Centre Rijeka, CRO CKD-MBD: New insights in selection of phosphate binders Prof.dr. Alma Idrizi, University Medical Centre of Tirana Mother Teresa, ALB Overvie of KDIGO guide i e update a d oca imp eme tatio Prof.dr. Ha ima Resić, C i ica Ce tre U iversity of Sarajevo, BiH

86 2017 KDIGO Guidelines Update Ha ima Resic Clinic for Hemodialysis Clinical Center University of Sarajevo 13 th Congress of the Balkan cities Association of Nephrology, Dialysis, and Artificial Organs Transplantation Sarajevo, 06. October 2017.

87 This presentation is sponsored by Sanofi. This information is provided for medical and scientific purpose only. Sanofi does not approve usage of its products outside the approved SmPC.

88 What is on the agenda? 1. The KDIGO guidelines Development process Overview Background Contents and Grading 2. Serum phosphate and calcium targets and treatment 3. Abnormal PTH levels in CKD-MBD and treatment 4. Conclusions

89 KDIGO Kidney Disease: Improving Global Outcomes (KDIGO) is a global organization that aims to improve care and outcomes of kidney disease patients worldwide through the development and implementation of nephrology clinical practice guidelines (CPGs). KDIGO has produced 9 comprehensive guidelines since 2008 that cover major areas of kidney disease care.

90 Modern therapy guidelines are needed for quality scientific and therapeutic progress KDIGO Guideline for Chronic Kidney Disease -Mineral and Bone Disorder (CKD- MBD) Kidney Int 2009 KDIGO Guideline for Chronic Kidney Disease -Mineral and Bone Disorder (CKD- MBD) Update Kidney Int Suppl CKD-MBD Chro ic Kid ey Disease-Mi era a d Bo e Disorder KDIGO Clinical Practice Guideline for CKD-MBD Kidney International Supplements (2017) 7, 1 59.

91 Guideline development process Consensus conference was in September 2005 in Spain Authors: International work group with 19 experts from North- and South America, Europe, Australia, and Asia Evidence review team: Epidemiologists from Tufts University, Boston, grading the quality of originally studies Public review in July/August 2008 with 180 experts participating First Publication was in August 2009

92 KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention,and Treatment of CKD MBD based on best information available as of July Cited from the guidelines: It is designed to provide information and assist decision-making. It is not intended to define a standard of care, and should not be construed as one, nor should it be interpreted as prescribing an exclusive course of management. KDIGO Clinical Practice Guideline for CKD-MBD Kidney International Supplements (2017) 7, 1 59.

93 Overview of KDIGO 2017 Guidelines Update This KDIGO update represents selective update of the prior CKD-MBD Guideline published in Emphasis has been on the rationale for the changes made to the original guideline document. This update, along with the 2009 publication, is intended to assist the practitioner caring for adults and children with chronic kidney disease (CKD), those on chronic dialysis therapy, or individuals with a kidney transplant. 1 1 Markus Ketteler, Executive summary of the 2017 KDIGO Chronic Kidney Disease Mineral and Bone Disorder (CKD-MBD) Guideline Update: what s changed and why it matters, Kidney International (4/2017).

94 Background of KDIGO 2017 Guidelines Update Over the years after first Guidelines in 2009 multiple randomized controlled trials (RCTs) and prospective cohort studies emerged, which promoted KDIGO to reexamine the currency of its guidelines. 1 Therefore, Workgroup issued a selective update of the 2009 KDIGO CKD-MBD Guideline. 1 A total of 12 recomme datio s were identified for revision, based on new data. 1 Large gaps of knowledge still remained, despite the availability of results from several new key clinical trials. The structured approach was modeled after the GRADE system, which describes grades to the quality of the overall evidence and strength for each recommendation. Where appropriate, the Work Group issued not graded 1 Markus Ketteler, Executive summary of the 2017 KDIGO Chronic Kidney Disease Mineral and Bone Disorder (CKD-MBD) Guideline Update: what s changed and why it matters, Kidney International (4/2017).

95 KDIGO - Guidelines: Grading Grade A B Quality of evidence High Moderate Meaning We are co fide t that the true effect ies c ose to that of the estimate of the effect The true effect is ike y to be c ose to the estimate of the effect, but there is a possibi ity that it is substa tia y differe t C Lo The true effect may be substa tia y differe t from the estimate of the effect D Very o The estimate of effect is very u certai, a d ofte i be far from the truth Grade Strength Wording Leve 1 Leve 2 Stro g Weak We recommend should Most patie ts shou d receive the recomme ded course of actio We suggest might Differe t choices i be appropriate for differe t patie ts. KDIGO Clinical Practice Guideline for CKD-MBD Kidney International Supplements (2017) 7, 1 59.

96 Contents of KDIGO guidelines Diagnosis of CKD MBD: biochemical abnormalities Parameters (P, Ca, PTH, ALP, calcidiol (25 OHD), individual values of serum calcium and phosphate, evaluated together, rather than the mathematical construct of calcium-phosphate product (Ca x P). Diagnosis of CKD MBD: bone Recommended and not recommended routine measurements, causes for bone biopsies Treatment of CKD MBD targeted at lowering high serum phosphorus and maintaining serum calcium Treatment of abnormal PTH levels in CKD MBD Diagnosis of CKD MBD: vascular calcification Method, classification as highest cardiovascular risk Treatment of bone with bisphosphonates, other osteoporosis medications, and growth hormone Evaluation and treatment of kidney transplant bone disease

97 What is on the agenda? 1. The KDIGO guidelines Development process Overview Background Contents and Grading 2. Serum phosphate and calcium targets and treatment 3. Abnormal PTH levels in CKD-MBD and treatment 4. Conclusions

98 Serum phosphorus eve s greater tha 5.5 mg/d (1.8 mmo /L) Are i depe de t y associated ith a 20% to 40% i crease i morta ity risk i ESRD pts. I additio, hyperphosphatemia appeared to be i vo ved i the deve opme t of atherosc erotic heart disease, seco dary hyperparathyroidism,a d bo e disease amo g CKD pts. Sullivan, JAMA 2009

99 Lower, challenging serum phosphorus target Normal range: mg/dl ( mmol/l) KDIGO Clinical Practice Guideline for CKD-MBD Kidney International Supplements (2017) 7, 1 59.

100 High P serum eve s are stro g y a d i depe de t y associated ith a more rapid dec i e of re a fu ctio i patie ts ith adva ced CKD. Caravaka F, Revista Nefrologia, 2011.

101 Choice of phosphate binder: No specific recommendation, aluminium is not recommended KDIGO Clinical Practice Guideline for CKD-MBD Kidney International Supplements (2017) 7, 1 59.

102 Weekly Phosphate Balance in HD patients B e f o r e A f t e r Diet 1000 mg/day 7 x 1000 (per eek) = 7000 mg Absorptio 60% Diet 1000 mg/day 7000 x 60% = 4200 mg 7 x 1000 (per week) = 7000 mg Dia ysis 800 mg Absorption 60% 3 x 800 (per eek) = 2400 mg 7000 x 60% = 4200 mg Ba a ce Dialysis = 800 mg 1800 mg 3 x 800 (per week) = 2400 mg Balance = 1800 mg Red i e mg Co a Beverages mg Beer mg Red i e + Beer mg Red i e + Co a Beverages mg + - Faeces e imi atio ~ 15 % - 20 % Polyphosphates in foods 1000 mg /day

103 Effect of Food Additives on Hyperphosphatemia in ESRD Po yphosphates, etc. ortho-phosphoric acid, etc. Meats,cheeses,baked goods,beverages (to preserve moisture or co or, to emu sify i gredie ts, to e ha ce f avor, to stabi ize foods) Sullivan C. et Al., JAMA, 2009

104 Phosphate elimination by hemodialysis treatment possibilities Prolonged treatment time P removal (mean, per week) 3 x 4 3 x 5 h/wk + 13 % 1 Long-term sp reduction 3 x 4 6 x 3 h/wk - 22 % 2 3 x 4 6 x 8 h/wk % 3 Procedure High-flux HD Online-HDF (post-dilution) Treatment details: % 4-24 % 5 P clearance (ml/min) Dialysate flow ml/min % Blood flow ml/min % Dialyzer surface m² % 1 Vaithilingam AJKD 43:85, 2004; 2 Achinger, KI 67 Suppl 95:S28, 2005; 3 Mucsi KI 53:1399, Lornoy, J Ren Nutr 16: ; 5 Minutolo, JASN13:1046, 2002; 6 Mandolfo IJAO 26:113, 2002.

105 Management of *Dietary restrictio (of protei ) *Dia ysis *Phosphate bi ders : - aluminum salts - calcium salts - iron containing compounds - magnesium salts - sevelamer - lanthanum carbonate *Vitami D a a ogs parica cito *Ca cimimetics ci aca cet Hyperphosphatemia KDIGO Clinical Practice Guideline for CKD-MBD Kidney International Supplements (2017) 7, 1 59.

106 Hemodial Int Apr;18(2): doi: /hdi Epub 2014 Jan 20.

107 Maintaining serum calcium Normal range: mg/dl ( mmol/l) KDIGO Clinical Practice Guideline for CKD-MBD Kidney International Supplements (2017) 7, 1 59.

108 Explanation to recommendation Recommendation was made on the basis of: the RCT by Block et al. 1 in a much larger, similar cohort and 2 additional RCTs 2,3 in hyperphosphatemic CKD patients 3 RTCs represent hard endpoint data when prospectively comparing the calcium-free binders, mostly sevelamer, with calciumcontaining binders in predialysis or dialysis adult patients, respectively New meta-analisys additionally fortified the Work recommendation Group determined 4,5,6,7 that there is new evidence suggesting that: excess exposure to calcium through diet, medications, or dialysate may be harmful across all GFR categories of CKD, regardless of whether other candidate markers of risk such as hypercalcemia, arterial calcification, adynamic bone disease, or low PTH levels are also present 1. Block, 2012; 2,3. DiOrio 2012&2013; 4. Jamal 2013; 5. Palmer 2016; 6. Patel 2016; 7. Sekercioglu 2016.

109 Coronary artery calcification (CAC): Randomized clinical trials comparing Sevelamer HCl and CaPBs Study Desig Resu ts Treat-to-Goa - Study (TTG) Chertow GM et al., KI patients, 1 year follow up Patients on sevelamer or any CaPB (CaAc or CaCO 3 ) PB doses to achieve sp and sca target levels Primary endpoint: No difference in sp and Ca x P Significantly lower increase of CACS in Sevelamer pts Significant decrease in LDL and total cholesterol in sevelamer group Re age i Ne Dia ysis (RIND) Block GA et al., KI incident HD pts, sevelamer or any CaPB for 18 months Management of parameters of bone metabolism at investigators discretion Lo er i crease of CACS i seve amer group Significant decrease in LDL and total cholesterol in sevelamer group CARE II Qunibi et al, AJKD 2008 BRiC Barreto et al., Nephrol Clin Pract pts (52 weeks) on Ca Ac or Sevelamer, both + atorvastatin 71 pts, on Ca Ac or sevelamer for 12 months Dialysate calcium and vit D regimen changes during study No difference in calcification No difference in LDL levels No difference in calcification No difference in bone turnover No difference in LDL levels

110 What is on the agenda? 1. The KDIGO guidelines Development process Overview Background Contents and Grading 2. Serum phosphate and calcium targets and treatment 3. Abnormal PTH levels in CKD-MBD and treatment 4. Conclusions

111 1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD MBD Work Group. KDIGO c i ica practice guide i e for the diag osis, eva uatio, preve tio, a d treatme t of chro ic kid ey disease mi era a d bo e disorder (CKD MBD). Kidney Int Suppl. 2009; S1 S130. Abnormal PTH levels and treatment Unfortunately, there is still an absence of RCTs that define an optimal PTH level for patients with CKD G3a to G5. The choice of dialysate calcium concentrations will impact serum PTH levels. Parathyroidectomy remains a valid treatment option, especially when PTH-lowering therapies fail, as advocated in Recommendation from the 2009 KDIGO CKD-MBD Guideline. 1

112 Abnormal PTH levels and treatment KDIGO Clinical Practice Guideline for CKD-MBD Kidney International Supplements (2017) 7, 1 59.