High Coronary Calcification Scores Predict Mortality in Pre-Dialysis CKD Patients Reference: Haas MH. The risk of death in patients with a high coronary calcification score: Does it include predialysis patients? Kidney International. 2010;77;1057–1059.

Introduction High coronary artery calcification scores (CACS) is associated with mortality in patients with normal kidney function. The relation is not yet established between high CACS and end-stage renal disease. Studies correlating CACS and renal calcification have been generally focused on predialysis patients. Chiu et al. recently carried out a study on predialysis chronic kidney disease (CKD) patients with high CACS. The study has been comprehensively discussed by Haas in his review. The following article summarizes the author’s comments on various aspects of the study.

CACS and Cardiovascular Mortality Coronary artery calcification scores are generally estimated using computed tomography. The method is beneficial in assessing the possibility of coronary heart disease and mortality. In patients without CKD, CACS values are considerably higher compared to Framingham Risk scores. The CACS values increase the distinctive capabilities of models, which use conventional risk factors and therefore, used in estimating cardiovascular events. Coronary artery calcification values in CKD patients initially found its application in recognizing pathophysiological mechanisms of vascular calcification. Electron beam computed tomography was the first instrument that was used to measure the CACS values of CKD patients on dialysis. The instrument failed to show any correlation between calcium, phosphate, and calcium-phosphate product to the CACS values. In addition, the coronary angiograms were not possible to correlate with CACS.

CACS and Cardiovascular Mortality Successive studies on excessive calcification relate coronary calcification with diminishing life expectancy. Coronary calcification is associated with calcium and phosphate metabolism factors such as osteoprotegerin, fetuin, pulse wave velocity, troponin T, matrix Glaprotein, or ENPP1. Despite several studies carried on coronary calcification, no study evidences an association between coronary angiograms and level of calcification. Association of CACS with reduction or prevention of vascular calcification is also not established. Vascular calcification is generally observed in early stages in CKD patients. The investigations carried so far have generally focused on CACS in predialysis CKD patients.

CACS and Cardiovascular Mortality In a recent report, Chiu et al. attempted to correlate coronary calcification with all- cause mortality in predialysis stage 1-5 CKD patients. The study patients had a history of diabetes for at least 10 years with high protein excretion. A majority of patients had been diagnosed with diabetic nephropathy. In a small portion of patients, kidney biopsies had been performed. This subgroup of study patients is associated with high-risk of mortality and cardiovascular complications. Cardiovascular disease in patients with 1–5 stage CKD and diabetes, increases the all-cause mortality rate from 1.8–3.35. In the study carried out by Chiu et al., patients with highest coronary calcification scores had high all-cause mortality. High-risk of mortality associated with coronary calcification was established using multivariant analysis.

CACS and Cardiovascular Mortality However, the study also observed that factors such as serum albumin, kidney function, and ethnicity also indicated mortality. The study was first of its kind that relates high coronary calcification with higher rate of mortality. The outcome measure of the study was all-cause mortality. This parameter has been used as an alternate measure for cardiovascular calcification. Hence, the study could not establish whether cardiovascular disease was associated with mortality. However, the baseline values were well related with survival. Based on the fact that age and baseline CACS were strong indicators of progressive coronary calcification, patients with high baseline values were anticipated to have strangest progression of calcification.

Issues Related to the Study The outcome of the study gives rise to two questions: (a) Does prediction of mortality through CACS aid in preventing or reversing progression of calcification? (b) Does reversing of progression of calcification improve survival?

Classically, coronary calcification in CKD patients is differentiated from calcification that takes place in patients with normal kidney function by the presence of calcium deposit in medial wall of artery. calcification in patients with normal kidney function is featured with calcium deposition in intima. The former condition is also known as arteriosclerosis, while the later one is known as atherosclerosis. The medial arteriosclerosis stiffens artery and in rare conditions narrows arterial lumen. A recent autopsy study of patients with different stages of chronic renal failure showed intimal sclerosis in all stages of CKD. Coronary calcification was seen in only about 18% of CKD patients 4–5D. The medial calcification was observed with intimal sclerosis (see Fig. 1).

The finding was support of the hypothesis that medial calcification is an amplification of preexisting atherosclerosis and not a distinct disease. A majority of patients included in the study were thought to have intimal calcification as they had a mean estimated glomerular filtration rate of 52±26 mL/min. Due to the presence of diabetes, coronary calcification was more prominent. Prevention of atherosclerosis either by treating or preventing risk factors can delay dialysis.

Coronary calcification cannot be reversed once progressed. Progression of coronary calcification has been observed in several reports despite the use of phosphate binder such as sevelamer and calcium carbonate. Reduction in phosphate can be an alternate approach in reversing progression of calcification. High phosphate levels have been associated with CACS. Therefore, reducing phosphate levels may provide clinical benefits in CKD patients. Another approach in reducing calcification can be the use of sodium thiosulfate. The molecule binds to precipitated calcium and thereby reduces calcium load and heals calcemic arteriolopathy. Sodium thiosulfate has been clinically evidenced for its effect on coronary calcification in hemodialysis.

Although most of the study carried out to reduce coronary calcification is focused on reducing mortality associated with calcification, this concept is not clinically established. Progression of calcification barring calciphylaxis, is not linked to death. Coronary artery calcification scores does not predict the extent of atherosclerosis and is also not related to coronary events. Death due to cardiovascular events occurs only in a small proportion of patients with severe coronary calcification. Use of statin to reduce lipid levels is known to be beneficial in reducing mortality despite progression of CACS. It is therefore important to correlate the improvement of survival with reduction in coronary calcification. From the study carried out by Chiu et al., it can be concluded that CACS does predict mortality, but in reduced capacity. Although CACS is useful in predicting mortality risk in patients with different stages of CKD, it is not an established alternative for other risk factors.

Summary High CACS in patients with normal kidney functions are associated with mortality. The study carried out by Chiu et al. shows that CACS is also useful in predicting mortality risk in patients with different stages of CKD. However, CACS has a limited capacity in predicting mortality, as it is not an alternative for other risk factors. The study calls for establishment of link between reduction in survival and reduction in coronary calcification.

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