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Role of serum phosphate level in cardiovascular events in non-CKD patients

Phosphorus is essential for life and exists in the body as phosphate. Phosphates are components of RNA, DNA, adenosine triphosphate (ATP), cell membrane, and bone. Despite its importance, the accumulation of phosphate can produce deleterious effects. However, the accumulation of phosphate occurs long before the rise in serum phosphate above the upper normal limit since several observational studies in both general population andearly-stage CKD patient shave identified the relationship between high-normal serum phosphate and adverse cardiovascular outcomes. FGF 23 is produced by osteoblasts and osteocytes in the bone under physiological condition. In the kidney, FGF-23 binds to FGF receptor in the proximal tubule in the presence of co receptor klotho resulting an inhibition of proximal tubular phosphateere absorption and a suppression of 1,25dihydroxy vitamin D synthesis. Current knowledge remains incomplete, but clearly prevention of vascular calcification is a dynamic, multifaceted process. Endogenous inhibitors of crystal formation and of osteogenic differentiation of vascular smooth muscle cells have been identified, including matrix Gla protein and fetuin-A, experimental studies have shown that exposure of experimental animals to high ambient ABSTRACT


INTRODUCTION
Phosphorus is essential for life and exists in the body as phosphate. Phosphates are components of RNA, DNA, adenosine triphosphate (ATP), cell membrane, and bone. Despite its importance, the accumulation of phosphate can produce deleterious effects. However, the accumulation of phosphate occurs long before the rise in serum phosphate above the upper normal limit since several observational studies in both general population andearly-stage CKD patient shave identified the relationship between high-normal serum phosphate and adverse cardiovascular outcomes. 1,2 FGF 23 is produced by osteoblasts and osteocytes in the bone under physiological condition. In the kidney, FGF-23 binds to FGF receptor in the proximal tubule in the presence of co receptor klotho resulting an inhibition of proximal tubular phosphateere absorption and a suppression of 1,25dihydroxy vitamin D synthesis. 3 Current knowledge remains incomplete, but clearly prevention of vascular calcification is a dynamic, multifaceted process. Endogenous inhibitors of crystal formation and of osteogenic differentiation of vascular smooth muscle cells have been identified, including matrix Gla protein and fetuin-A, experimental studies have shown that exposure of experimental animals to high ambient phosphorus is followed by expression of an osteogenic phenotype in vascular smooth muscle cells and by vascular calcification. [4][5][6][7][8] Other potential mechanisms linking rising phosphorus levels to vascular disease include inhibition of 1,25-dihydroxy vitamin synthesis and increased parathyroid hormone (PTH) production. [9][10][11] Phosphorus levels correlate with atherosclerosis in both animal models and humans with advanced chronic kidney disease, but whether this relationship exists among individuals with normal kidney function is unknown. Several observational studies of dialysis populations have shown that high serum phosphorus levels are antecedent associations of mortality and cardiovascular events, independent of calcium and PTH levels. [12][13][14][15] If high phosphorus levels truly cause vascular disease, then it seems natural to hypothesize that this relationship also applies within the normal range of phosphorus levels, even in the presence of normal kidney function.
Coronary artery calcium levels are believed to reflect accurately the overall burden of atherosclerosis and to exhibit dosage-response relationships with the incidence of future cardiovascular events. [16][17][18] Studying phosphorous levels and coronary artery calcification can potentially reveal the mechanisms by which serum phosphorous may lead to cardiovascular disease and, perhaps, suggest the existence of novel mechanisms for developing atherosclerosis.

This observational study was conducted in a Tertiary
Centre, department of medicine, GSVM Medical College, Kanpur from December 2016 to October 2018. 300 patients were included in the study.
All consenting patients more than 18 years of age having Clinical features or positive biochemical markers (Troponin-I for MI and serum BNP for CHF) suggestive of myocardial infarction and heart failure. Subjects less than 18 years of age, Pregnant females, CKD patients, Patients with hypoparathyroidism, patients with hypovitaminosis D and non-consenting were excluded from study. A brief medical history of subjects related to study was taken followed by blood investigations like complete blood count, Liver function test, Kidney function test, Serum Na+/K+/Ca++, Trop I / serum BNP, Serum Phosphate, vitamin D3 level, iPTH along with USG whole abdomen, Urine Routine/Microscopic examination and ECG.

Statistical analysis
The data was processed in Excel sheet and analysis was carried out using SPSS Software. Quantitative variables were analyzed using mean and Standard Deviation. Comparison between groups was done using Independent t test (for 2 groups) and ANOVA (for more than 2 groups). p-value of <0.05 was taken as statistically significant.

RESULTS
In this study, author included 300 patients. Further they divided it into Case and Control Group, each containing 150 patients. Case group is subdivided into myocardial infarction (n=98), heart failure (n=27) and patients which have both myocardial infarction and heart failure (n=25) subgroups. Baseline characteristics were comparable. Mean age of patients in case group was 58.43±13.54 years while in control group 53.41±12.54 years. Half of the patients in both groups were in 41-60 years age group. 60% patients were male in case group while in control group 56.7%. Risk factors like smoking, alcohol intake and diabetes were comparable in both groups. Mean HbA1c in case group was 5.8±0.9 while in control group was 5.1±0.5. Serum Cholesterol in case group was 165.07±33.80 which was comparable to control group 147.87±21.14. Serum triglyceride level in case group was 162.29±44.87 as compared to control group having 124.72±21.17. Serum LDL level in case group was 121.57±25.59 comparable to control group 112.73±21.56 (Table 1).     23 There are some studies exploring associations between serum Phosphate level and cardiovascular comorbidities in community adults without apparent kidney disease.
A report from participants in the Framingham Offspring Study, the average age of the study population was approximately 20 years older than in Cardia study. Several associations of higher serum Phosphate level mirrored the findings in our study. contributions of genetic and environmental factors to the associations remain speculative. Unlike many cardiovascular risk factors uncovered in observational studies, potential interventions that can address some of the hypotheses suggested by this study may already exist.
Present study findings suggest that extending these studies to high-risk individuals without CKD in the general population has the potential to improve public health. Quite apart from the underlying determinants, the associations seen in this study suggest that high phosphorus levels might be a modifiable risk factor among cardiovascular comorbidities that should be screened and managed accordingly.

Limitations of study
This was single center study having small study population. It was Non-experimental design, observational study. Majority of data comes from studies showing correlation between serum Phosphate level and cardiovascular disease comes from advanced CKD patients. So, large population studies should be carried out to determine role of serum Phosphate level in cardiovascular comorbidities in patients not having apparent kidney disease.

CONCLUSION
Serum Phosphate level is emerging as a risk factor for cardiovascular disease in advanced kidney disease. But role of serum Phosphate level in cardiovascular comorbidities among Non-CKD patients is still under debate. There are only few studies for the same. In our study we concluded that higher Serum Phosphate level in Non-CKD patients is also related to increased cardiovascular comorbidities like MI and CHF. Large epidemiological studies to be done to generalize the results of this study in general population.