David Ramenofsky, MD Bryan Kestenbaum, MD

Transcription

1 Association of Serum Phosphate Concentration with Vascular Calcification in Patients Free of Chronic Kidney Disease: The Multi Ethnic Study of Atherosclerosis David Ramenofsky, MD Bryan Kestenbaum, MD

2 Are Elevated Serum Phosphate Levels Bad? The Framingham Offspring Study Associations between serum phosphate levels and cardiovascular events and mortality in patients with normal kidney function: Each 1 mg/dl increase in serum phosphate concentration within the normal range was associated with a 31% greater risk of the composite outcome Fatal or non fatal MI, angina, CVA s, peripheral vascular disease, or CHF

3 Could Arterial Calcification be the Link between Phosphate Cardiovascular Morbidity? Calcification of the major arteries affects most individuals > 60 years of age Associated with cardiovascular morbidity and mortality. Easily Measured and Clinically Significant Associated with hyperlipidemia, atherosclerosis, end stage renal disease (ESRD) and type 2 diabetes

4 How Do Arteries Calcify? Intimal Calcification: Atherosclerosis Medial Calcification: type 2 diabetes end stage renal disease Imaging to detect and quantify vascular calcification cannot discriminate between medial and intimal calcification.

5 What s the Mechanism of Arterial Calcification? Mechanisms are active and related to those involved in bone mineralization bone morphogenic proteins and osteopontin TNF alpha can promote osteoblastic differentiation and calcification Medial calcification induced by Phosphate smooth muscle cells cultured in vitro calcify, express bone specific markers and loose contractility when exposed to phosphate concentrations above 1.4 mmol/l

6 Phosphate Levels and Arterial Calcification Could vascular calcification be promoted in vivo with elevated phosphate levels? Multi Ethnic Study of Atherosclerosis (MESA) prospective cohort study moderate CKD (GFR ml/min/1.73m 2 ) no clinical cardiovascular disease Higher serum phosphate levels, even within the normal range, are associated with coronary artery calcification (CAC) and descending thoracic aorta calcification (DTAC)

7 Is CKD Necessary For Phosphate to Promote Arterial Calcification? Hypothesis: Increased phosphate levels, even within the normal range, would be associated with increased vascular calcification in patients free of CKD

8 Study Design Study Design: 1000 subjects from MESA 6814 participants aged years who identified their race/ethnicity as White/Caucasian, Black/African American, Chinese, or Spanish/Hispanic/Latino were recruited from six U.S. communities between July 2000 and August 2002 No clinical cardiovascular or renal disease Estimated GFR 60 ml/min/1.73m 2 Examined the associations of serum phosphate concentrations with the presence of calcification of the coronary arteries and descending thoracic aorta.

9 Measurements Phosphate levels were measured x1 Coronary artery calcium (CAC) and descending thoracic aorta calcium (DTAC) via electron beam baseline 3 years The mean value of two scan results was used for all analyses of CAC, and the value from the first scan was used for analyses of DTAC

10 Baseline Characteristics average age: 62 51% of the participants were female. White (40%), Black (27%), Chinese (13%), Hispanic (20%) Female participants had higher serum phosphate levels than men (no explanation for this). 21% of participants with serum phosphate levels <3 mg/dl were women 73% of patients with serum phosphate levels 3.6 were women.

11 Participant characteristics by phosphate categories Phosphate (mg/dl) Characteristic < >4.0 N Phosphate, mg/dl 2.73 (0.18) 3.26 (0.16) 3.77 (0.14) 4.30 (0.11) Age, yrs 62 (10) 62 (10) 63 (10) 60 (9) Female 40 (21%) 195 (44%) 200 (71%) 72 (83%) Race White 86 (46%) 164 (37%) 115 (41%) 30 (35%) Chinese 20 (11%) 60 (14%) 38 (14%) 10 (12%) Black 47 (25%) 126 (29%) 77 (27%) 20 (23%) Hispanic 34 (18%) 90 (21%) 52 (18%) 27 (31%)

12 Prevalence of Arterial Calcification CAC Prevalence: 49% DTAC Prevalence: 26% Every 0.5 mg/dl increase in phosphate was associated with: A 4% increase in CAC A 17% increase in DTAC This trend was significant for DTAC.

13 . Table 2. Association of phosphate with presence/absence of vascular calcification. *adjusted for age, gender and race **adjusted for age, gender, race, DM, LDL, cystatin C, BMI, CRP and SBP DTAC (gender interaction p=0.231) Phosphate N DTAC > 0 Demo adjusted* RR (95% CI) Fully adjusted** RR (95% CI) Continuous (per SD=0.50) (1.07, 1.32) 1.17 (1.05, 1.29) Groups < (ref) 1.00 (ref) (0.78, 1.29) 1.04 (0.80, 1.35) (1.12, 1.83) 1.41 (1.09, 1.82) > (0.82, 1.97) 1.25 (0.81, 1.93) CAC (gender interaction p=0.213) Phosphate N CAC > 0 Demo adjusted* RR (95% CI) Fully adjusted** RR (95% CI) Continuous (per SD=0.50) (1.00, 1.12) 1.04 (0.98, 1.10) Groups < (ref) 1.00 (ref) (0.94, 1.23) 1.07 (0.93, 1.24) (0.91, 1.24) 1.04 (0.88, 1.23) > (1.03, 1.64) 1.23 (0.98, 1.56)

14 Incidence of Arterial Calcification At 3 years CAC: 21% DTAC: 15% Every 0.5 mg/dl increase in phosphate was associated with a 23% increase in DTAC Not significant

15 Table 3. Association of phosphate with incident vascular calcification at follow-up. Phosphate Continuous (per SD=0.50) Calcification N Incidence Demo adjusted* RR (95% CI) Fully adjusted** RR (95% CI) DTAC (1.00, 151) 1.17 (0.94, 1.46) CAC (Agatston) (0.78, 1.15) 0.91 (0.70, 1.18) (at fu at least one scan >0) CAC (Agatston) (0.76, 1.15) 0.89 (0.66, 1.21) (at fu both scans>0)

16 Summary of Findings Higher serum phosphate concentrations within the normal laboratory range were associated with: A statistically significant increase in the prevalence of descending thoracic aorta calcification The incidence of DTAC over three years was also increased slightly higher prevalence of coronary artery calcification No associated increase in interval CAC at three years

17 Differences in Renal Insufficiency? Medial vascular calcification in the coronary arteries is more common in patients with renal disease; normal renal function might protect against the medial calcification of coronary arteries promoted by elevated serum phosphate levels Higher serum phosphate levels in humans might be a surrogate marker for other factors that promote vascular calcification in patients with CKD