THE IMPACT OF SERUM PHOSPHATE LEVELS IN CKD-MBD PROGRESSION

Transcription

1 THE IMPACT OF SERUM PHOSPHATE LEVELS IN CKD-MBD PROGRESSION Mario Cozzolino, MD, PhD, Fellow of the European Renal Association Department of Health Sciences University of Milan Renal Division & Laboratory of Experimental Nephrology September 30th, 2016 Item code: INTSP/C-ANPROM/FOS/16/0025a Date: Nov 2016

2 Declaration of Transparency Research Grants and Honoraria: Shire and Abbvie Advisory boards: Shire, Abbvie, Amgen and Vifor- Fresenius The content of the presentation does not necessarily reflect the opinion of Shire

3 Causes of Death in Patients with Reduced Kidney Function Unadjusted relative percentages of death by cause and egfr Percent by egfr category Relative percentage Other Neoplasm Infection CVD CVD Cardiovascular disease; egfr Estimated glomerular filtration rate Adapted from Thompson S, et al. J Am Soc Nephrol. 2015;26:

4 Causes of Death in Patients with Reduced Kidney Function Unadjusted relative percentages of death by cause and egfr for the sub-classification of CVD deaths Percent by egfr category Relative percentage Other Arrhythmia Valvular heart diseases Heart failure Cerebrovascular disease Ischemic heart disease Non Ischemicß à CV Disease Ischemicß à CV Disease CV: Cardiovascular Adapted from Thompson S, et al. J Am Soc Nephrol. 2015;26:

5 Is chronic kidney disease-mineral bone disorder (CKD-MBD) really a syndrome? Chronic Kidney Disease Mineral and Bone Disorder Cardiovascular! disease CKD-MBD Adapted from Cozzolino M. et al. Nephrol Dial Transplant, 2014; 29: Images courtesy of Prof. Cozzolino Cozzolino M, et al. Nephrol Dial Transplant. 2014;29:

6 Phosphate and CKD-MBD Ca PTH P Vit. D P: Phosphorous; Ca: Calcium, PTH: Parathyroid hormone; Vit. D: Vitamin D Adapted from Cozzolino M, et al. Curr Vasc Pharmacol. 2010;8:404 11

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8 Hyperphosphataemia and outcomes in ESRD Elevated serum phosphorus levels are linked to increased all-cause and cardiovascular mortality Progressive deterioration of kidney function Elevated P in serum and tissue Reference Block G, et al Slinin Y, et al Covic A, et al Tentori F, et al Gutiérrez O, et al Floege J, et al Patients n=40,538 HD n=14,829 HD Systematic review n=25,588 ESRD on HD n=10,044 beginning HD n=7,970 HD Increased mortality (All-cause and CV) HD: Hemodialysis, CV: Cardiovascular, ESRD: End-Stage Renal Disease, P: Phosphorus Block G, et al. J Am Soc Nephrol. 2004; 15: ; Slinin Y, et al. J Am Soc Nephrol. 2005;16: ; Covic A, et al. Nephrol Dial Transplant. 2009; 24: ; Tentori F, et al. Am J Kidney Dis. 2008; 52:519-30; Gutiérrez O, et al. N Engl J Med. 2008; 359:584-92; Floege J, et al. Nephrol Dial Transplant. 2011; 26:

9 Hyperphosphataemia and outcomes in ESRD Patients with elevated serum phosphorus levels have a higher risk for all-cause or cardiovascular mortality All-cause mortality in patients recieving HD (1) CV mortality in patients receiving HD (2) CV mortality in patients receiving PD (2) CV mortality in patients with CKD 3-4 (3) mg/dl <3.5 mg/dl >5.5 mg/dl mg/dl <3.5 mg/dl >5.5 mg/dl mg/dl <3.5 mg/dl >5.5 mg/dl Per increase of 1 mg/dl HR (95% CI) P < HR Hazard ratio, P phosphorous, CV cardiovascular, HD Haemodialysis, PD Peritoneal dialysis 1. Floege J, et al. Nephrol Dial Transplant. 2011;26: ; 2. Noordzij M, et al. Nephrol Dial Transplant. 2006;21: ; 3. Menon V, et al. Am J Kidney Dis. 2005;46:445-63

10 Seeking to control hyperphosphataemia and improve! outcomes Treatment of hyper-p necessitates a multimodal approach Dialysis Dietary restriction of phosphorus intake Challenges: Using food with low phosphorus content Balancing sufficient protein intake and restricting P intake Hidden phosphate due to insufficient labelling of processed food Insufficient control Phosphate binders Galassi A, et al. J Nephrol. 2015; 28:415-29

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12 Lack of treatment adherence:! A PROBLEM OF CHRONIC ILLNESSES Chronic diseases characteristic of low adherence rates: Ø HIV v 30-40% of patients are non adherent to antiretroviral therapy 1 Ø Chronic heart failure v 74.7% of patients had poor adherence to medication 2 Ø Type 2 diabetes mellitus 3 v Adherence to oral antidiabetic drugs (OAD) alone: 50.0% v Adherence to insulin + OAD: 44.0% v Adherence to insulin alone: 41.7% 1. Huang et al. AIDS Res Treat. 2013;2013:580974; 2. Yayehd et al. Ann Cardiol Angeiol. 2013;62:22-7; 3. Adisa R, & Fakeye T. Pharm Pract. 2013;11:156-65

13 Lack of treatment adherence:! a problem of chronic illnesses or specific to ESRD? Ø In general, adherence levels are lowest in patients with chronic disease who: 1 v do not perceive an immediate risk if they do not take their medication, v are required to change their lifestyle to adhere to their prescribed treatment program. Ø Patients on dialysis fall into this category. Ø In a US, cross sectional study of 233 patients on maintenance dialysis, 62% were non-adherent* to their prescribed phosphate binders 2 Ø Why do dialysis patients show particularly poor adherence to phosphate binder therapy? *Non-adherence defined as intake of <80% or >120% of the expected pill count. ESRD: End stage kidney disease 1. Arenas MD, et al. J Nephrol. 2010;23:525-34; 2. Chiu YW, et al. Clin J Am Soc. 2009;

14 Non-adherence in HD patients: THE PERFECT STORM Treatment adherence is multifactorial Demographic factors Clinical Factors Ø Age Ø Socioeconomic status Ø Education Ø Lifestyle Non-adherence Ø Ø Ø Ø Length of time on dialysis Comorbidity Treatment complexity Treatment side effects Psychosocial factors Ø Cognitive impairment Ø Social support Ø Patient-physician relationship Ø Mental disorders HD: Hemodialysis Adapted from Schmid H, et al. Eur J Med Res. 2009;14:185-90

15 Non-adherence in HD patients: THE PERFECT STORM Treatment adherence is multifactorial Demographic factors Clinical Factors Ø Age Ø Socioeconomic status Ø Education Ø Lifestyle Non-adherence Ø Ø Ø Ø Length of time on dialysis Comorbidity Treatment complexity Treatment side effects Psychosocial factors Ø Cognitive impairment Ø Social support Ø Patient-physician relationship Ø Mental disorders HD: Hemodialysis Adapted from Schmid H, et al. Eur J Med Res. 2009;14:185-90

16 Phosphate binders: WERE THEY CREATED EQUAL? Different phosphate binders are associated with varying pill burden Phosphate binders Typical pill burden Number of pills/day Aluminium salts No safe dose identified Calcium acetate 1000 mg each, equivalent to 250 mg of calcium per day 4-6 pills/day Calcium carbonate E.g mg each, equivalent to 500 mg calcium As prescribed Calcium acetate/ Magnesium carbonate 435 mg Ca-acetate/235 mg Mg-carbonate each 3-10 pills/day Sevelamer-HCl 3 pills (800 mg each) three times daily Up to 9 pills/day Sevelamer carbonate 3 pills (800 mg each) three times daily Up to 9 pills/day Lanthanum carbonate 1 pill (500 mg, 750 mg or 1000 mg) three times daily 3 pills/day HCL - hydrochloride Adapted from Covic A and Rastogi A. BMC Nephrol. 2013;14:153

17 Phosphate binders: WERE THEY CREATED EQUAL? Different phosphate binders are associated with varying pill burden Phosphate binders Typical pill burden Number of pills/day Aluminium salts No safe dose identified Calcium acetate 1000 mg each, equivalent to 250 mg of calcium per day 4-6 pills/day Calcium carbonate E.g mg each, equivalent to 500 mg calcium As prescribed Calcium Existing acetate/ phosphate Magnesium 435 binders mg Ca-acetate/235 are associated mg Mg-carbonate with eachdifferent side effect 3-10 pills/day profiles, carbonate which may affect phosphate binder choice or patient satisfaction Sevelamer-HCl 3 pills (800 mg each) three times daily Up to 9 pills/day Sevelamer carbonate 3 pills (800 mg each) three times daily Up to 9 pills/day Lanthanum carbonate 1 pill (500 mg, 750 mg or 1000 mg) three times daily 3 pills/day HCL - hydrochloride Adapted from Covic A and Rastogi A. BMC Nephrol. 2013;14:153

18 The BERMUDA TRIANGLE:! Phosphate binder pill burden - adherence - serum P levels A higher phosphate binder pill burden is associated with lower adherence and higher serum phosphorus levels Adherence to phosphate binders Mean serum phosphorus levels Adherence * (%) p=0.008, Error bars: 95% CI Pill burden from phosphate binders Phosphorus (mg/dl) p=0.03, Error bars: 95% CI Pill burden from phosphate binders Study design: Patients: Cross-sectional assessment of daily pill burden from phosphate binders 233 chronic dialysis patients from three units in the US *Adherence defined as an intake of % of the expected number of pills Adapted from Chiu YW, et al. Clin J Am Soc Nephrol. 2009;4:

19 Treatment non-adherence and phosphate binders:! A POTENTIAL VICIOUS CYCLE Patients who admitted to poor adherence were prescribed more phosphate binders, and took fewer of them, than their adherent counterparts Poor adherence Increase in pill burden Poor phosphate control Increase in prescribed PB dose Patients who admit to being non-adherent and exhibit higher phosphorus concentrations are being prescribed the highest doses of binders PB Phosphate binder Tomasello S, et al. Dial Transplant. 2004;33:236 42; Arenas MD, et al. J Nephrol. 2010;23:525-34

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21 Narrative review Blood Pressure, Proteinuria, and Phosphate as Risk Factors for Progressive Kidney Disease: A Hypothesis Mario Cozzolino, MD, PhD 1, Giorgio Gentile, MD, PhD 2, 3, Sandro Mazzaferro, MD 4, Diego Brancaccio, MD 5, Piero Ruggenenti, MD 2, 3, Giuseppe Remuzzi, MD, FRCP 2, 3 BLOOD PRESSURE: THE FIRST P FOR CKD PROGRESSION PROTEINURIA: THE SECOND P FOR CKD PROGRESSION PHOSPHATE: THE THIRD P FOR CKD PROGRESSION Cozzolino M, et al. Am J Kidney Dis. 2013;62:984-92

22 Hypertension CROSS-TALK AMONG THE 3 PS IN THE PATHOGENESIS OF CKD PROGRESSION Sodium retention, hypertrophy/hyperfiltration of the remnant glomerulus Impaired glomerular filtration barrier Urinary proteins (lipidated albumin, IgG, transferin, other) Intrarenal complement activation Vascular calcifications, atherosclerotic plaques Vasoconstriction of intrarenal/systemic vessels MAP-Kinases (P38, ERK1/ ERK2, other) NF-κB Inflammatory cytokines chemokines, adhesion molecules ê Klotho Oxidative stress (ROS, RNS) Tubulointerstitial infiltration ACE/Ang II/ AT1R signaling (internal or systemic) é PTH é FGF23/FGF23 resistance Increased renin ê 1α-hydroxylase Impaired Nrf2/ Keap 1 pathway Fibrosis TGFα/EGFR pathway é TACE ê Active vitamin D (calcitriol) Increased TFE3 High dietary phosphorus intake Nephron loss Impaired excretion of phosphates é Phosphorus Adapted from Cozzolino M, et al. Am J Kidney Dis. 2013;62:984-92

23 Hypertension CROSS-TALK AMONG THE 3 PS IN THE PATHOGENESIS OF CKD PROGRESSION Sodium retention, hypertrophy/hyperfiltration of the remnant glomerulus Impaired glomerular filtration barrier Urinary proteins (lipidated albumin, IgG, transferin, other) Intrarenal complement activation Vascular calcifications, atherosclerotic plaques Vasoconstriction of intrarenal/systemic vessels MAP-Kinases (P38, ERK1/ ERK2, other) NF-κB Inflammatory cytokines chemokines, adhesion molecules ê Klotho Oxidative stress (ROS, RNS) Tubulointerstitial infiltration ACE/Ang II/ AT1R signaling (internal or systemic) é PTH é FGF23/FGF23 resistance Increased renin ê 1α-hydroxylase Impaired Nrf2/ Keap 1 pathway Fibrosis TGFα/EGFR pathway é TACE ê Active vitamin D (calcitriol) Increased TFE3 High dietary phosphorus intake Nephron loss Impaired excretion of phosphates é Phosphorus Adapted from Cozzolino M, et al. Am J Kidney Dis. 2013;62:984-92

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25 Therapeutic goals Reduce Dietary P intake Reduce Serum P Reduce PTH Reduce FGF23 P - Phosphorous, PTH - Parathyroid hormone, FGF23 - Fibroblast growth factor Yamamoto KT, et al. Kidney Int. 2013;83:707-14; Selamet U, et al. Kidney Int. 2016;89:176-84; Haring R, et al. J Am Heart Assoc. 2016;5; Bover J, et al. Nephrol Dial Transplant. 2015;30:345-51; Cannata-Andia JB, Martin KJ. Nephrol Dial Transplant. 2016;31:541-7; Kendrick J, et al. Adv Chronic Kidney Dis. 2011; 18:113-9.

26 Potential outcome Reduce LV mass Slow CKD progression Reduce CV events Reduce mortality LV Left ventricular, CKD Chronic kidney disease, CV Cardiovascular Yamamoto KT, et al. Kidney Int. 2013;83:707-14; Selamet U, et al. Kidney Int. 2016;89:176-84; Haring R, et al. J Am Heart Assoc. 2016;5; Bover J, et al. Nephrol Dial Transplant. 2015;30:345-51; Cannata-Andia JB, Martin KJ. Nephrol Dial Transplant. 2016;31:541-7; Kendrick J, et al. Adv Chronic Kidney Dis. 2011; 18:113-9.

27 The treatment of hyperphosphataemia in CKD: calcium-based or calcium-free phosphate binders? Mario Cozzolino 1, Sandro Mazzaferro 2 and Vincent Brandenburg 3 1 Renal Division, S. Paolo Hospital, University of Milan, Milan, Italy, 2 Department of Clinical Science, La Sapienza University of Rome, Italy and 3 Division of Cardiology, University Hospital Aachen, RWTH Aachen, Germany Considerations for the choice of binder may include: Older age (>65 yrs) Male gender Post-menopause Diabetes Low bone turnover Vascular/valvular calcification Inflammation Cozzolino M, et al. Nephrol Dial Transplant. 2011;26:402 7